Molecular Targeted Therapies of Aggressive Thyroid Cancer

Differentiated thyroid carcinomas (DTCs) that arise from follicular cells account >90% of thyroid cancer (TC) [papillary thyroid cancer (PTC) 90%, follicular thyroid cancer (FTC) 10%], while medullary thyroid cancer (MTC) accounts <5%. Complete total thyroidectomy is the treatment of choice for PTC, FTC, and MTC. Radioiodine is routinely recommended in high-risk patients and considered in intermediate risk DTC patients. DTC cancer cells, during tumor progression, may lose the iodide uptake ability, becoming resistant to radioiodine, with a significant worsening of the prognosis. The lack of specific and effective drugs for aggressive and metastatic DTC and MTC leads to additional efforts toward the development of new drugs. Several genetic alterations in different molecular pathways in TC have been shown in the past few decades, associated with TC development and progression. Rearranged during transfection (RET)/PTC gene rearrangements, RET mutations, BRAF mutations, RAS mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways determinant in the development of TC. Tyrosine kinase inhibitors (TKIs) are small organic compounds inhibiting tyrosine kinases auto-phosphorylation and activation, most of them are multikinase inhibitors. TKIs act on the aforementioned molecular pathways involved in growth, angiogenesis, local, and distant spread of TC. TKIs are emerging as new therapies of aggressive TC, including DTC, MTC, and anaplastic thyroid cancer, being capable of inducing clinical responses and stabilization of disease. Vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib for DTC refractory to radioiodine. These drugs prolong median progression-free survival, but until now no significant increase has been observed on overall survival; side effects are common. New efforts are made to find new more effective and safe compounds and to personalize the therapy in each TC patient

High dose torasemide is equivalent to high-dose furosemide with Hypertnic saline in the treatment of refractory congestive heart failure

OBJECTIVE:A randomised, double-blind study was performed to evaluate the effects of the combination of high-dose torasemide and hypertonic saline solution (HSS) infusion versus high-dose furosemide (frusemide) and HSS in the treatment of refractory New York Heart Association class IV congestive heart failure (CHF). MATERIALS AND METHODS:Eighty-four patients (55 males, 29 females) with refractory CHF, aged 55-84 years, with an ejection fraction <35%, serum creatinine <2 mg/dL, blood urea nitrogen </=60 mg/dL, a reduced urinary volume and a low natriuresis, were randomised to two groups. Group 1 (27 males, 15 females) received an intravenous infusion of furosemide 500mg plus HSS (150mL of 1.4-4.6% sodium chloride) twice daily in 30 minutes. Group 2 (28 males, 14 females) received torasemide 200mg twice daily plus HSS during a period lasting 4-8 days. Physical examination, measurement of bodyweight, blood pressure, heart rate, evaluation of signs of CHF, and serum and urinary parameters were controlled daily during hospitalisation. Chest x-ray, ECG and echocardiogram were obtained at entry, during hospitalisation and at discharge. During the treatment and after discharge the daily dietary sodium intake was 120 mmol, with a fluid intake of 1.0-1.5L in both groups. Bodyweight and 24-hour urinary volume, serum and urinary laboratory parameters, until reaching a compensated state, were controlled daily, when intravenous furosemide and torasemide were replaced with oral furosemide administration only (250-500mg twice daily). After discharge the double-blind design was discontinued and the subsequent period was an open-label study with furosemide only; the patients were followed up as outpatients weekly for the first 3 months and subsequently once a month. RESULTS:Baseline clinical characteristics of patients were similar in both groups. A significant increase in daily diuresis and natriuresis was observed in both groups. No difference was observed in serum sodium or potassium. Bodyweight was reduced in both groups. Blood pressure values decreased, and heart rate was corrected to normal values in both groups. In the follow-up period (12 +/- 3.9 months), 17 patients were re-admitted to the hospital for heart failure. Thirteen patients died during follow-up. CONCLUSION:We conclude that high-dose torasemide is equivalent to high-dose furosemide in the treatment of refractory CH

Novel Genes of the sox Gene Cluster, Mutagenesis of the Flavoprotein SoxF, and Evidence for a General Sulfur-Oxidizing System in Paracoccus pantotrophus GB17

The novel genes soxFGH were identified, completing the sox gene cluster of Paracoccus pantotrophus coding for enzymes involved in lithotrophic sulfur oxidation. The periplasmic SoxF, SoxG, and SoxH proteins were induced by thiosulfate and purified to homogeneity from the soluble fraction. soxF coded for a protein of 420 amino acids with a signal peptide containing a twin-arginine motif. SoxF was 37% identical to the flavoprotein FccB of flavocytochrome c sulfide dehydrogenase of Allochromatium vinosum. The mature SoxF (42,832 Da) contained 0.74 mol of flavin adenine dinucleotide per mol. soxG coded for a novel protein of 303 amino acids with a signal peptide containing a twin-arginine motif. The mature SoxG (29,657 Da) contained two zinc binding motifs and 0.90 atom of zinc per subunit of the homodimer. soxH coded for a periplasmic protein of 317 amino acids with a double-arginine signal peptide. The mature SoxH (32,317 Da) contained two metal binding motifs and 0.29 atom of zinc and 0.20 atom of copper per subunit of the homodimer. SoxXA, SoxYZ, SoxB, and SoxCD (C. G. Friedrich, A. Quentmeier, F. Bardischewsky, D. Rother, R. Kraft, S. Kostka, and H. Prinz, J. Bacteriol. 182:4476–4487, 2000) reconstitute a system able to perform thiosulfate-, sulfite-, sulfur-, and hydrogen sulfide-dependent cytochrome c reduction, and this system is the first described for oxidizing different inorganic sulfur compounds. SoxF slightly inhibited the rate of hydrogen sulfide oxidation but not the rate of sulfite or thiosulfate oxidation. From use of a homogenote mutant with an in-frame deletion in soxF and complementation analysis, it was evident that the soxFGH gene products were not required for lithotrophic growth with thiosulfate