Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent Carcinogenesis.

Head and neck squamous cell carcinoma remains challenging to treat with no improvement in survival rates over the past 50 years. Thus, there is an urgent need to discover more reliable therapeutic targets and biomarkers for HNSCC. Matriptase, a type-II transmembrane serine protease, induces malignant transformation in epithelial stem cells through proteolytic activation of pro-HGF and PAR-2, triggering PI3K-AKT-mTOR and NFKB signaling. The serine protease inhibitor lympho-epithelial Kazal-type-related inhibitor (LEKTI) inhibits the matriptase-driven proteolytic pathway, directly blocking kallikreins in epithelial differentiation. Hence, we hypothesized LEKTI could inhibit matriptase-dependent squamous cell carcinogenesis, thus implicating kallikreins in this process. Double-transgenic mice with simultaneous expression of matriptase and LEKTI under the keratin-5 promoter showed a prominent rescue of K5-Matriptase+/0 premalignant phenotype. Notably, in DMBA-induced SCC, heterotopic co-expression of LEKTI and matriptase delayed matriptase-driven tumor incidence and progression. Co-expression of LEKTI reverted altered Kallikrein-5 expression observed in the skin of K5-Matriptase+/0 mice, indicating that matriptase-dependent proteolytic pathway inhibition by LEKTI occurs through kallikreins. Moreover, we showed that Kallikrein-5 is necessary for PAR-2-mediated IL-8 release, YAP1-TAZ/TEAD activation, and matriptase-mediated oral squamous cell carcinoma migration. Collectively, our data identify a third signaling pathway for matriptase-dependent carcinogenesis in vivo. These findings are critical for the identification of more reliable biomarkers and effective therapeutic targets in Head and Neck cancer.

Impact of Bevacizumab on Experimentally Induced Endometriotic Lesions: Angiogenesis, Invasion, Apoptosis, and Cell Proliferation.

Endometriosis is responsible for pain symptoms with great impact on the patient's quality of life. Several medication lines have been studied aiming at its definitive treatment. Among them, angiogenesis inhibitor factors may be effective given that angiogenesis has fundamental role in the establishment and growth of endometriotic lesions. In this study, we investigated the influence of bevacizumab, anti-factor drug of endothelial growth (anti-VEGF), used at two different dosages, in experimental endometriosis induced in rats. After the induction of endometriosis lesions in rats, they were divided in 3 groups: control group, no treatment, and two other groups were treated with different dosages of the same medication for 4 weeks. At the end of the treatment, endometriotic lesions were removed and evaluated regarding area of lesions, presence of endometrial tissue in microscopy, positivity for anti-VEGF antibody in immunohistochemistry, and gene expression of Pcna, Mmp9, Tp63, and Vegfa. Bevacizumab acted by reducing the area of lesions in the groups that received medication (p = 0.002) and reducing gene expression to Tp63 in lesions (p = 0.04). There was no significant result in other evaluations. We observed that there was significant reduction of the area of lesions among groups, suggesting that bevacizumab has a positive effect on disease control. The gene expression of Tp63 was significantly lower in the group that received high dose of the drug when compared with the other two groups; therefore, we concluded that bevacizumab acts by reducing cell proliferation and differentiation in lesions, constituting a real option for treating endometriosis.

Menopause leading to increased vaginal wall thickness in women with genital prolapse: impact on sexual response.

INTRODUCTION: Hypoestrogenism causes structural changes in the vaginal wall that can lead to sexual dysfunction. A reduction in vaginal wall thickness has been reported to occur after menopause, although without precise morphometry. AIM: To measure vaginal wall thickness in women with genital prolapse in normal and hypoestrogenic conditions and to correlate sexual dysfunction with vaginal wall thickness and estradiol levels. METHODS: Surgical vaginal specimens from 18 normoestrogenic and 13 postmenopausal women submitted to surgery for genital prolapse grades I and II were examined. Patients were evaluated for FSH, estradiol, prolactin, glycemia, and serum TSH levels. For histological analysis, samples were stained with Masson's trichrome and hematoxylin-eosin. Sexual function was assessed by the Golombok-Rust Inventory of Sexual Satisfaction (GRISS). MAIN OUTCOME MEASURES: GRISS questionnaire, histological analysis, morphometric methods, Masson's trichrome. RESULTS: The vaginal wall was thicker in the postmenopausal than premenopausal group (2.72 +/- 0.72 mm and 2.16 +/- 0.43, P = 0.01, and 2.63 +/- 0.71 mm and 2.07 +/- 0.49 mm, P = 0.01, for the anterior and posterior walls, respectively). These thicknesses seem to be due to the muscular layer, which was also thicker in the postmenopausal group (1.54 +/- 0.44 and 1.09 +/- 0.3 mm, P = 0.02, and 1.45 +/- 0.47 and 1.07 +/- 0.44 mm, P = 0.03, for the anterior and posterior wall, respectively). The vaginal epithelium was thinner in the middle segment than in the proximal one in the posterior wall (0.17 +/- 0.07 mm, 0.15 +/- 0.05 mm, 0.24 +/- 0.09 mm, P = 0.02). There was no correlation between coital pain, vaginal wall thickness, and estradiol levels in either group. CONCLUSION: The vaginal wall is thicker after menopause in women with genital prolapse. In this study, vaginal thickness and estrogen levels were not related to sexual dysfunction.

Phakomatous choristoma of the orbit.

Phakomatous choristoma is a rare adnexal congenital tumor of lenticular anlage. The authors performed a standard orbital tomography of the orbits for the evaluation of a mass that was palpable in the left lower eyelid of a 3-month-old boy. Hematoxylin-eosin, special stainings and immunohistochemistry were performed on the excised mass. The histopathological and immunohistochemical findings confirmed the diagnosis of phakomatous choristoma. The CT scans showed that the mass was located in the orbit. Even though phakomatous choristoma is usually reported as a lower eyelid lesion, the orbital localization offers a better explanation for the chronological embryonic origin of this rare pediatric tumor.