KCTD1 is a new modulator of the KCASH family of Hedgehog suppressors.

The Sonic Hedgehog (Hh) signal transduction pathway plays a critical role in many developmental processes and, when deregulated, may contribute to several cancers, including basal cell carcinoma, medulloblastoma, colorectal, prostate, and pancreatic cancer. In recent years, several Hh inhibitors have been developed, mainly acting on the Smo receptor. However, drug resistance due to Smo mutations or non-canonical Hh pathway activation highlights the need to identify further mechanisms of Hh pathway modulation. Among these, deacetylation of the Hh transcription factor Gli1 by the histone deacetylase HDAC1 increases Hh activity. On the other end, the KCASH family of oncosuppressors binds HDAC1, leading to its ubiquitination and subsequent proteasomal degradation, leaving Gli1 acetylated and not active. It was recently demonstrated that the potassium channel containing protein KCTD15 is able to interact with KCASH2 protein and stabilize it, enhancing its effect on HDAC1 and Hh pathway. KCTD15 and KCTD1 proteins share a high homology and are clustered in a specific KCTD subfamily. We characterize here KCTD1 role on the Hh pathway. Therefore, we demonstrated KCTD1 interaction with KCASH1 and KCASH2 proteins, and its role in their stabilization by reducing their ubiquitination and proteasome-mediated degradation. Consequently, KCTD1 expression reduces HDAC1 protein levels and Hh/Gli1 activity, inhibiting Hh dependent cell proliferation in Hh tumour cells. Furthermore, analysis of expression data on publicly available databases indicates that KCTD1 expression is reduced in Hh dependent MB samples, compared to normal cerebella, suggesting that KCTD1 may represent a new putative target for therapeutic approaches against Hh-dependent tumour.

[The effect of antithrombin iii concentrations during cardiopulmonary surgery]. / Impiego dei concentrati di antitrombina III nella chirurgia coronarica.

BACKGROUND: Evaluation of influence of pre-op continuous e.v. heparin infusion in patients undergoing urgent myocardial surgical revascularization, on the anticoagulation threshold needed for cardiopulmonary bypass. Analysis of the efficacy of ATIII substitutional therapy to allow best ACT values during extracorporeal circulation, and to reduce intra and post-op bleeding and need for homologus transfusion. SETTING: Operative room and ICU of a cardiac surgery unit in a regional hospital. METHODS: Two groups of coronary patients in preoperative treatment with heparin were randomized in a prospective double blind study for an intraoperative treatment with heparin and ATIII (Group A) and heparin plus placebo (Group B). An investigation was made on the influence of preoperative heparin treatment regarding extracorporeal circulation, the variation of the coagulation parameters in CEC with substitutive therapy of ATIII and the reduction of the therapeutic strength of heparin during perfusion, the problem of bleeding and the incidence of blood transfusions and lastly the economic questions of the two procedures. RESULTS: The study showed the necessity of repeated bolus of heparin during CEC and the rapid loss of its effect in the group not subjected ATIII therapy. A less incidence of bleeding in Group A was observed; for this reason the patients received significantly less packed red cells and FFP and a discrete number of patients of this group were not transfused. Surely the method of using the ATIII is much more expensive from the economic point of view, but the benefits of avoiding the problems of a blood transfusion (infections, immunodepression etc.), of the reduced stay in the Intensive Care Unit, of the riduced risk involved with problems of bleeding and the need of repeated operative procedures make this method fundamental in patients with reduced plasma levels of ATIII such as coronary patients who are under heparin treatment for several days. CONCLUSIONS: Intraoperative administration of ATIII can reduce most problems due to heparinization of the extracorporeal circuit, such as onset of fibrinolysis, CID and platelets depletion or inactivation causing intra and post-op massive bleeding.

[Transfusional needs and blood saving strategies during orthotopic heart transplantation]. / Necessità trasfusionali e strategie di risparmio di sangue durante trapianto cardiaco ortotopico.

It is difficult to evaluate transfusional needs during cardiac surgery. One hundred fifty patients undergoing orthotopic cardiac transplantation were divided into two groups (A and B) according to the blood saving strategies. (Group A: no important saving strategies; group B: all blood saving techniques utilized). A low blood, plasma and platelet consumption was observed, with good clinical results, in group B. During orthotopic cardiac transplantation, it would be suitable to use all the saving transfusional blood strategies and a correct use of hemocomponents as during all cardiac surgery.

Subtotal parathyroidectomy for secondary hyperparathyroidism in chronic renal failure.

Twenty-seven patients on chronic haemodialysis and with secondary hyperparathyroidism underwent subtotal parathyroidectomy during the period 1985-1989. The operation was indicated by severe clinical symptoms and evidence of radiological abnormalities not responsive to conservative treatment (low phosphorus diet, phosphate binding substances, oral calcium and vitamin D). If despite intensive medical management, inadequate control of parathyroid hyperplasia continues surgical intervention becomes necessary. Ultra-sonography was performed pre-operatively in all 27 cases and detected 42 of 99 glands (42.5 per cent). Also scintigraphy was carried out in every patient but it gave a relatively low detection rate (24.5 per cent). Surgery was followed by improvement in 20 patients and progression of hyperparathyroidism in seven cases. Three of the seven patients failed to improve after subtotal parathyroidectomy, necessitating a re-intervention; the remaining four responded sufficiently to medical therapy. From our experience we conclude that subtotal parathyroidectomy for renal hyperparathyroidism is recommended.