Identification of genetic variants and phenotypic characterization of a large cohort of patients with congenital hypopituitarism and related disorders

PURPOSE: Congenital hypopituitarism (CH) disorders are phenotypically variable. Variants in multiple genes are associated with these disorders, with variable penetrance and inheritance. METHODS: We screened a large cohort (N = 1765) of patients with or at risk of CH using Sanger sequencing, selected according to phenotype, and conducted next-generation sequencing (NGS) in 51 families within our cohort. We report the clinical, hormonal, and neuroradiological phenotypes of patients with variants in known genes associated with CH. RESULTS: We identified variants in 178 patients: GH1/GHRHR (51 patients of 414 screened), PROP1 (17 of 253), POU1F1 (15 of 139), SOX2 (13 of 59), GLI2 (7 of 106), LHX3/LHX4 (8 of 110), HESX1 (8 of 724), SOX3 (9 of 354), OTX2 (5 of 59), SHH (2 of 64), and TCF7L1, KAL1, FGFR1, and FGF8 (2 of 585, respectively). NGS identified 26 novel variants in 35 patients (from 24 families). Magnetic resonance imaging showed prevalent hypothalamo-pituitary abnormalities, present in all patients with PROP1, GLI2, SOX3, HESX1, OTX2, LHX3, and LHX4 variants. Normal hypothalamo-pituitary anatomy was reported in 24 of 121, predominantly those with GH1, GHRHR, POU1F1, and SOX2 variants. CONCLUSION: We identified variants in 10% (178 of 1765) of our CH cohort. NGS has revolutionized variant identification, and careful phenotypic patient characterization has improved our understanding of CH. We have constructed a flow chart to guide genetic analysis in these patients, which will evolve upon novel gene discoveries

Analysis and Geographical Representation of Cilento’s Monastic Architecture

This paper is part of a wider research on the Cilento monastic architec-tures of Italo-Greek origin located in southern Campania (Italy). The investigationconcentrates on the study, updating and analysis of the existing constructions forthe enrichment of the geographical information databases of the Cilento. On thisopportunity, the analysis focuses specifically on two monuments of Basilian foun-dation: the Abbey of Santa Maria di Pattano, in Vallo della Lucania, and the churchof San Nicola di Myra in Sacco Vecchia. The first case study presents superfe-tations that make it difficult to read the architectural languages and to interpretits conformation. On the other hand, the church of San Nicola in Myra, despitebeing located in one of the most famous ghost towns of the Cilento countrysideand showing important deterioration, still preserves its original morphology, char-acterized by a splendid hieratic character that is completely Basilian. The study ofthese constructions was carried out with digital models and geographic informa-tion systems, in order to obtain the original conformation of the Badia of Pattano.The comparative analysis of the information gathered on the other monument wasused to obtain the necessary data to clarify and identify the main constructionpatterns of the Byzantine and Basilian architectures of the area. These data willserve to enrich the current information and, furthermore, to develop more specificmultidisciplinary analyses in the future

Two Case Reports of Biliary Tract Injuries during Laparoscopic Cholecystectomy

Background and Study Aims. Biliary tract injuries (BTI) represent the most serious and potentially life-threatening complication of cholecystectomy occurring also during laparoscopic approaches. Patients and Methods. We describe and discuss two different cases of BTI occurring during laparoscopic cholecystectomy (LC). Results. Two patients developed BTI during LC and one evidenced the complication during the LC itself and was treated during the same LC in real time. The other patient evidenced BTI only after the primary intervention and was successfully reoperated in laparotomy after 10 days from the LC. Conclusions. The factors that predispose to the occurrence of BTI during cholecystectomy and the cautions to be used to prevent BTI are discussed

Diagnostic accuracy of p53 immunohistochemistry as surrogate of TP53 sequencing in endometrial cancer

Aberrant p53 immunohistochemical expression is used to identify the copy-number-high/TP53-mutant subgroup of endometrial cancer (EC). We aimed to determine the diagnostic accuracy of p53 immunohistochemistry as surrogate for TP53 sequencing through a systematic review and meta-analysis. Electronic databases were searched from their inception to June 2019. All studies assessing p53 expression and TP53 mutations in EC were included. Diagnostic accuracy was assessed based on area under the curve (AUC). Immunohistochemical criteria used to define aberrant p53 expression were “overexpression” and “overexpression or complete absence”. Subgroup analysis was based on the sequencing technique adopted (Polymerase Chain Reaction + sequencing, or next generation sequencing, NGS). Thirteen observational studies with 727 endometrial cancers were included. Both “overexpression” and “overexpression or complete absence” showed high diagnostic accuracy (AUC = 0.9088 and 0.9030, respectively). The subgroup with “overexpression” and NGS showed the best results, with very high diagnostic accuracy (AUC = 0.9927). In conclusion, immunohistochemistry for p53 is a highly accurate surrogate of TP53 sequencing. Overexpression of p53 in ≥70−80% showed the best accuracy in predicting TP53 mutations. Further studies in this field should adopt optimized immunohistochemical procedures and take into account less common p53 patterns (e.g. cytoplasmic expression)

Oxidative Stress and Platelet Activation in Homozygous Homocystinuria

Background — Severe hyperhomocysteinemia due to cystathionine β-synthase deficiency (CβSD) is associated with early atherothrombotic vascular disease. Homocysteine may exert its effects by promoting oxidative damage. In the present study, we investigated whether in vivo formation of 8-iso-prostaglandin (PG) F 2α , a platelet-active product of arachidonic acid peroxidation, is enhanced in CβSD and whether it correlates with in vivo platelet activation, as reflected by thromboxane (TX) metabolite excretion. Methods and Results — Urine and blood samples were obtained from patients with homozygous CβSD (n=13) and age-matched healthy subjects. Urinary 8-iso-PGF 2α excretion was significantly higher in CβSD patients than in control subjects (640±384 versus 213±43 pg/mg creatinine; P =0.0015) and correlated with plasma homocysteine (ρ=0.398, P =0.0076). Similarly, urinary 11-dehydro-TXB 2 excretion was enhanced in CβSD (1166±415 versus 324±72 pg/mg creatinine; P =0.0015) and correlated with urinary 8-iso-PGF 2α (ρ=0.362, P =0.0153). Vitamin E supplementation (600 mg/d for 2 weeks) was associated with a statistically significant increase in its plasma levels (from 16.6±4.6 to 40.4±8.7 μmol/L, P =0.0002) and with reductions in 8-iso-PGF 2α (from 790±159 to 559±111 pg/mg creatinine, P =0.018) and 11-dehydro-TXB 2 (from 1273±383 to 913±336 pg/mg creatinine, P =0.028). A statistically significant inverse correlation was found between urinary 8-iso-PGF 2α and plasma vitamin E levels (ρ=−0.745, P =0.0135). Conclusions — The results of the present study suggest that enhanced peroxidation of arachidonic acid to form bioactive F 2 -isoprostanes may represent an important mechanism linking hyperhomocysteinemia and platelet activation in CβSD patients. Moreover, they provide a rationale for dose-finding studies of vitamin E supplementation in this setting

Targeting androgen-independent pathways: new chances for patients with prostate cancer?

Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer (PC). Most patients eventually progress to a condition known as castration-resistant prostate cancer (CRPC), characterized by lack of response to ADT. Although new androgen receptor signaling (ARS) inhibitors and chemotherapeutic agents have been introduced to overcome resistance to ADT, many patients progress because of primary or acquired resistance to these agents. This comprehensive review aims at exploring the mechanisms of resistance and progression of PC, with specific focus on alterations which lead to the activation of androgen receptor (AR)-independent pathways of survival. Our work integrates available clinical and preclinical data on agents which target these pathways, assessing their potential clinical implication in specific settings of patients. Given the rising interest of the scientific community in cancer immunotherapy strategies, further attention is dedicated to the role of immune evasion in PC