RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer.

The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated whether RAGE contributes to the oncogenic actions of Insulin, which plays a key role in BC progression particularly in obese and diabetic patients. Analysis of the publicly available METABRIC study, which collects gene expression and clinical data from a large cohort (n = 1904) of BC patients, revealed that RAGE and the Insulin Receptor (IR) are co-expressed and associated with negative prognostic parameters. In MCF-7, ZR75 and 4T1 BC cells, as well as in patient-derived Cancer-Associated Fibroblasts, the pharmacological inhibition of RAGE as well as its genetic depletion interfered with Insulin-induced activation of the oncogenic pathway IR/IRS1/AKT/CD1. Mechanistically, IR and RAGE directly interacted upon Insulin stimulation, as shown by in situ proximity ligation assays and coimmunoprecipitation studies. Of note, RAGE inhibition halted the activation of both IR and insulin like growth factor 1 receptor (IGF-1R), as demonstrated in MCF-7 cells KO for the IR and the IGF-1R gene via CRISPR-cas9 technology. An unbiased label-free proteomic analysis uncovered proteins and predicted pathways affected by RAGE inhibition in Insulin-stimulated BC cells. Biologically, RAGE inhibition reduced cell proliferation, migration, and patient-derived mammosphere formation triggered by Insulin. In vivo, the pharmacological inhibition of RAGE halted Insulin-induced tumor growth, without affecting blood glucose homeostasis. Together, our findings suggest that targeting RAGE may represent an appealing opportunity to blunt Insulin-induced oncogenic signaling in BC.

Prenatal and postnatal findings of acrania.

INTRODUCTION: Acrania is a rare congenital anomaly in which the flat bones of the cranial vault are partial or complete absent with complete but abnormal development of the cerebral hemispheres. CASE REPORT: We report two cases, diagnosed prenatally by ultrasound and followed by medical pregnancy termination, one with isolated acrania and one with associated cleft lip and palate and spina bifida. DISCUSSION: The acrania pathogenesis is unknown and differential diagnosis should be made with other conditions like anencephaly and acalvaria. Genetic counselling is not easy because there is no evidence for a specific genetic origin, but the extreme rarity and sporadic nature suggests a low recurrence risk.

Prenatal diagnosis of congenital diaphragmatic hernia in a McFadden Kalousek type 2 triploid fetus.

Triploidy is characterized by an extra haploid set. We report a rare case of a prenatally diagnosed digynic type (McFadden/Kalousek type 2) triploid fetus with congenital diaphragmatic hernia (CDH). Prenatal ultrasonographic examination allows reliable detection of CDH and it is therefore of great importance for proper parental counselling, as well as performing fetal karyotype for associated chromosomal anomalies.

[Skin metastasis from renal carcinoma: epidemiologic and clinical features]. / Metastasi cutanee da carcinoma renale: aspetti epidemiologici e clinici.

The Authors present an additional case of a 70-years old male patient with skin metastasis from renal cell carcinoma, 15 months after nephrectomy. The patient died ten months later for advanced neoplastic disease. Skin metastasis affect 3-6% of patients with renal cell carcinoma. The surgical treatment is mandatory for single nodule. Chemotherapy is often ineffectual. The prognosis is poor, with a 0-8% 5-years survival for patients with multiple nodules.

[Appendiceal mucoceles. A case report]. / Il mucocele appendicolare. Analisi di un caso.

A case of benign mucocele presenting as a subocclusive syndrome is reported; the surgical treatment consisted in a right colectomy. Appendiceal mucoceles are rare lesions of the appendix, characterized by a gross enlargement of the appendix from accumulation of mucoid substance within the lumen. It is a rare condition, encountered in only 0.1-0.4% of all appendectomies with a female predominance and an average age at the time of diagnosis over 50 years. Following careful review of the literature, the difficulties in differential diagnosis are underlined, especially between benign and malignant forms and the possibility of a pre-operative diagnosis is examined. Abdominal ultrasound and CT scan of the abdomen or colonoscopy may suggest the diagnosis. However, often the diagnosis is an incidental event. The pathogenesis, histologic aspect of the lesion and the different surgical strategies are discussed. A frozen section examination should be performed in all patients, while the abdomen is open, because it may be impossible to predict the underlying pathology merely by inspecting the serosal surface of a dilated appendix. If a simple retentional cyst is uncovered, without atypia, appendectomy should be curative; if cystadenoma or cystadenocarcinoma of the appendix are found, more extended resection was necessary. However if the operation is done as an emergency, a frozen section examination is not always available: in those patients a more extended resection is suggested.

[Male breast cancer. Histochemical and flow cytometry analysis of 6 cases]. / Carcinoma mammario maschile. Analisi immunoistochimica e citofluorimetrica di 6 casi.

The authors studied immunohistochemical and flow cytometric parameters of 6 male breast carcinomas. All patients were ER positive and frequency of aneuplody was 66%. Diploid tumors showed low proliferative activity and S-phase fraction < 3%.

[A case of breast metastasis in bladder urothelioma]. / Su di un caso di metastasi mammaria da urotelioma vescicale.

A case of isolated mammary metastasis from surgically untreated urothelial vesical carcinoma is discussed. An integrated chemo-radiotherapeutical treatment had been planned, due to bad general condition; after this, an optimal subjective benefit and good objective response (reduction in lesion diameter < 50%, MR) were obtained. An isolated breast lesion appeared ten months after; its metastatic nature was only indirectly suspected by mammographic and echographic features. Only immunohistochemical study, realized on percutaneous needle biopsy specimen, definitively confirmed the urothelial metastatic origin. In present work, biological and prognostic significance of mammary metastases and the needing of distinguishing them from primary breast neoplasm are analysed, basing on the literature review.

[Malignant mesothelioma located in the pleura: its radical surgical treatment]. / Il mesotelioma maligno localizzato della pleura: trattamento chirurgico radicale.

The authors report a rare case of localized malignant pleural mesothelioma infiltrating the thoracic wall. The absence of widespread pleural involvement allowed for a radical operation with removal of a large portion of the thoracic wall. However, due to rarity of such tumor, an hypothesis on long term prognosis is difficult to formulate.

Blockade of central and peripheral luteinizing hormone-releasing hormone (LHRH) receptors in neonatal rats with a potent LHRH-antagonist inhibits the morphofunctional development of the thymus and maturation of the cell-mediated and humoral immune responses.

The development of the thymus and the hypothalamic-pituitary-gonadal axis are linked by bidirectional hormonally mediated relationships. In the present study, the direct involvement of the neuropeptide LHRH in the maturation of the thymus and development of the cell-mediated and humoral immune responses were assessed after treatment of neonatal (from post-natal day 1-day 5) female rats with a potent LHRH-antagonist (LHRH-anta, p-Glu-D-Phe 2.6,Pro3-LHRH, 50 micrograms/rat), and the effects compared to those resulting from neonatal castration. Whereas in control animals the maturation of mitogenic potential in thymocyte cultures showed a progressive and age-dependent increase, reaching a maximal activity at 30 days of age and then decreasing after puberty onset, in LHRH-anta-treated rats, the thymocyte's proliferative response was completely blocked at 7 days of age and remained very low at each time interval studied, until 3 months of age. A similar effect of the LHRH-anta treatment on splenocyte cultures was measured. Moreover, a reduced percentage of the T-helper lymphocyte subpopulation followed LHRH-anta administration. By contrast, in neonatally castrated rats, blastogenic activity was significantly higher, compared to control cultures, at each stage studied. Treatment with LHRH-anta produced a significant decrease in thymus wt, an alteration of the maturational pattern characterized by a cellular monomorphism, reduced thymocyte volume, reduction of the cortical area, and depauperation of the epithelial microenvironment. Moreover, a morphometric analysis revealed a selective decrease in the large lymphoid cell population of the subcapsular cortex at 7 and 15 days. On the other hand, neonatal castration produced an opposite effect, leading to a marked hypertrophy of the cortical area, and counteracted the post-puberal thymus atrophy. When LHRH-anta-treated adult (3-month-old) rats were challenged with an antigenic stimulus (multiple sc injections of complete Freund adjuvant and BSA) and antibody (anti-BSA antibodies of the immunoglobulin G class) production measured in the serum after 15 days, a marked and significant decrease in immunoglobulin G levels was observed, compared to the values measured in untreated control. The described immune deficiencies in LHRH-anta-treated rats were associated with a clear inhibition of sexual maturation. This study clearly indicates that the blockade of central and peripheral LHRH receptors during a critical period for maturation of both hypothalamus-hypophyseal-gonadal axis and brain-thymus-lymphoid axis dramatically impairs immune system development, suggesting a potential role of the neuropeptide LHRH in the bidirectional programming of both neuroendocrine and immune functions.