Preablative stimulated thyroglobulin in predicting dynamic risk stratification after 1 year in patients with differentiated thyroid cancer

The aimThe aim of the study is to establish the utility of stimulated preablative stimulated thyroglobulin (ps-Tg) as a predictor of response to therapy and to determine a possible cut-off for ps-Tg as prognostic tool.Patients and methodsA total of 73 consecutive patients who underwent total thyroidectomy and remnant ablation with radioactive iodine therapy (RIT) were reviewed retrospectively. Patients were classified according to the dynamic risk stratification 1 year after initial treatment. The ps-Tg values were compared among the groups. ROC curve analysis was performed.ResultsThe mean age at diagnosis was 43.85 (range: 17–75) with a female-to-male ratio of 4.6. Ps-Tg value after total thyroidectomy and before RIT ranged from 0,1 to 256 ng/mL. When patients were restaged, 74% had excellent response to treatment, 12.3% indeterminate and 13.7% incomplete response 1 year after initial therapy. ROC curve analysis showed that the optimal cut-off for ps-Tg was 15 ng/mL with a sensivity of 61%; a specificity of 87%; PPV of 61% and NPV of 87%. Among the group of patients showing an excellent response to treatment after 1 year, 87% had ps-Tg < 15 ng/mL.ConclusionPs-Tg before RIT is associated with dynamic risk stratification at 1 year after therapy in patients with DTC. Higher ps-Tg levels were found in patients that had indeterminate, and particularly incomplete, response.     

The Neolithic Necropolis of La Feixa del Moro (Juberri,Andorra): New data on the first farming communities in the Pyrenees

The excavations carried out from 1983 to 1985 on an Andorran hillside by the former Andorra National Artistic Heritage Archaeological Research Service revealed one of the most important Neolithic sites in the Pyrenees. Directed by Xavier Llovera and Pere Canturri, the excavations uncovered a settlement with two interesting features: 1) it was located in a high mountain area, and 2) the same place possessed numerous domestic and funerary structures. Both factors have made La Feixa del Moro a key site in the prehistory of both the Pyrenees and the western Mediterranean in general. Three decades later, a pluridisciplinary team has begun a careful review of the documentation, studied the human remains and artefacts in the graves, carried out several forms of biochemical analysis and obtained new radiocarbon determinations for the individuals exhumed in two of the three burials in stone boxes (or cists). The objective is a better understanding of the first farming communities that settled in the Pyrenees.     

The taxonomy,chronostratigraphy and paleobiogeography of glyptosaurine lizards (Glyptosaurinae,Anguidae)

Glyptosaurine lizards (Glyptosaurinae, Anguidae) are an extinct group of heavily armored lizards known from North America, Europe and Asia. Glyptosaurine lizards, taxa that possess fully developed tuberculated dermal armor, appear to have been established in North America by late early Puercan time (To3). “Proxestops,” a taxon distinguished by a combination of vermiculate and tuberculated osteoderm sculpturing, is considered to be a non-glyptosaurine, a sister taxon of the Glyptosaurinae. Known from only fragmentary remains, its wide chronostratigraphic distribution suggests that “Proxestops” is a form genus that, in all probability, represents more than one taxon, that ranges from the middle Paleocene to the early Eocene of North America. Moreover, the taxa Odaxosaurus piger, Parodaxosaurus sanjuanensis and “Proxestops” are best considered “proto-glyptosaurines”. “Melanosaurins” and glyptosaurins were well-established by the early Eocene, especially in North America, and are here documented by their type species and chronostratigraphic levels. Both tribes are present in Europe (MP7), too, but the record is not as estensive as that of North America. The North American taxon Gaultia silvaticus (Wa0) is transitional between a “melanosaurin” and glyptosaurin. Because it lacks the well-defined hexagonal osteoderms that characterize the Glyptosaurini, it is removed from that group and considered to be a “melanosaurin”. The “melanosaurin” taxon “Xestops” savagei (Wa4–Wa6) cannot be referred to Xestops (Br2) based on non-corresponding elements and because superficial similarity does not justify assignment to this taxon. Arpadosaurus sepulchralis (Wa6?), whose holotype is a fragmentary right frontal, is considered a subjective junior synonym of A. gazinorum, based on minor differences in the epidermal scale pattern that probably represent individual variation. “Glyptosaurus” agmodon (Wa6?), based on a partial right maxilla, cannot be referred to Glyptosaurus (sensu stricto), and the material upon which this taxon is based bears strong resemblance to material identified as cf. “?Paraglyptosaurus” yatkolai (Wa5–Wa6). “Glyptosaurus” rhodinos (Wa5) is based on an incomplete parietal, and its reference to Glyptosaurus is considered problematic. Eoglyptosaurus donohoei (Wa7) is probably valid and is re-established here. Glyptosaurus (sensu stricto) is known solely from the middle Eocene (Br2) by G. sylvestris. Dimetoposaurus wyomingensis (Br3) is removed from Xestops vagans because its synonymy was based on superficial similarities. Helodermoides tuberculatus, the largest and last glyptosaurin (Ch3), is restricted to the Chadronian of North America. Only the “melanosaurin” Peltosaurus granulosus (Or2–Or3), which includes the species P. abbotti, seems to have crossed the Eocene-Oligocene boundary, and appears to be largely restricted to the Orellan, but extended into the Arikareean. European glyptosaurines are also represented by both glyptosaurins and “melanosaurins” early in the Eocene (MP7). Placosauriops-like “melanosaurins” are known from Dormaal (MP7), and the glyptosaurin taxon?Placosaurus ragei occurs at the same level. “Placosauriops abderhaldeni” has been identified from the Grube Messel (MP11), but this assignment remains dubious because the species has not been adequately diagnosed, and the holotype species is from the Geiseltal (MP13), which is some 4.5 million years younger. Placosauriops weigelti (MP13) is the only valid species of this genus. Paraxestops stehlini (MP14) is not referable to the North American taxon Xestops, and its relationship to Placosauriops has not been studied. The late Eocene glyptosaurins Placosaurus estesi (MP17) and P. rugosus (MP18) are the last glyptosaurines known from Europe and appear to have gone extinct at the Eocene-Oligocene boundary, casulties perhaps of the “Grande Coupure”. Asian glyptosaurines are known solely from one species, Stenoplacosaurus mongoliensis, from the middle Eocene (Sharamurunian) of China. Glyptosaurines most likely originated in North America, diversified by late Paleocene time, and rapidly spread across the North Atlantic into Europe by the early Eocene. Both “melanosaurins” and glyptosaurins took a foothold in Europe by the early Neustrian, but the glyptosaurins, aside from one occurrence (Dormaal, MP7), were conspicuously absent for most of Neustrian through early Robiacian time. In North America, glyptosaurins diversified during the early and middle Eocene, while in Europe small “melanosaurins” were a prominent part of the paleoherpetofauna, and glyptosaurins are unknown for most of the Neustrian through the Geiseltalian, in both the fossilferous Lagerstätten of Messel and Geiseltal. Stenoplacosaurus is the only known glyptosaurin glyptosaurine from Asia, and its abrupt appearance during the late Eocene suggests the possiblity of a Beringian dispersal from North America into Asia.     

Higher-level relationships of caenophidian snakes inferred from four nuclear and mitochondrial genes

Higher-level caenophidian snake relationships are inferred from sequence analyses of one nuclear gene (C-mos) and three mitochondrial genes (12S rRNA, 16S rRNA and ND4). Caenophidians, which are haenophidian closest relatives, have an Asiatic origin. An African clade comprising atractaspidids, psammophiines, 'lamprophiines' and 'pseudoxyrhophiines' is identified. We discern no evolutionary trend such as an improvement of the venom apparatus with a linear progression from the absence of a venom system to the presence of a front-fanged one. The venom apparatus is contemporary with the origin of colubroids and its absence in a few lineages results from secondary losses. The front-fanged venom system appeared three times independently. The active diurnal foraging mode (associated with a high metabolic rate) appears in a derived position among colubroids.     

Radionuclide therapy targeting PSMA for the treatment of metastatic prostate cancer: Current point of view and ways of improvement

Metastatic castration-resistant prostate cancer (mCRPC) still represents a challenge and an unmet clinical need. RadioLigand therapy targeting PSMA (PRLT) has been used for several years with success and low toxicity. The first radionuclide used were radiolabeled antibody with limited dose due to hematologic toxicity. Rapidly, small molecules targeting PSMA were developed and used with lower toxicity, mostly related to mild transient xerostomia and nausea due to physiological PSMA expression in the salivary glands and proximal bowel. Briefly, 2/3 of the patients may first respond to treatments followed by disease recurrence responding to further cycles for half of them. Therefore, there is a need to improve again the PRLT efficacy and the ways of improvement will be discussed in this review.     

Out-of-field doses from secondary radiation produced in proton therapy and the associated risk of radiation-induced cancer from a brain tumor treatment

PurposeTo determine out-of-field doses produced in proton pencil beam scanning (PBS) therapy using Monte Carlo simulations and to estimate the associated risk of radiation-induced second cancer from a brain tumor treatment.MethodsSimulations of out-of-field absorbed doses were performed with MCNP6 and benchmarked against measurements with tissue-equivalent proportional counters (TEPC) for three irradiation setups: two irradiations of a water phantom using proton energies of 78–147 MeV and 177–223 MeV, and one brain tumor irradiation of a whole-body phantom. Out-of-field absorbed and equivalent doses to organs in a whole-body phantom following a brain tumor treatment were subsequently simulated and used to estimate the risk of radiation-induced cancer. Additionally, the contribution of absorbed dose originating from radiation produced in the nozzle was calculated from simulations.ResultsOut-of-field absorbed doses to the TEPC ranged from 0.4 to 135 µGy/Gy. The average deviation between simulations and measurements of the water phantom irradiations was about 17%. The absorbed dose contribution from radiation produced in the nozzle ranged between 0 and 70% of the total dose; the contribution was however small in absolute terms. The absorbed and equivalent doses to the organs ranged between 0.2 and 60 µGy/Gy and 0.5–151 µSv/Gy. The estimated lifetime risk of radiation-induced second cancer was approximately 0.01%.ConclusionsThe agreement of out-of-field absorbed doses between measurements and simulations was good given the sources of uncertainties. Calculations of out-of-field organ doses following a brain tumor treatment indicated that proton PBS therapy of brain tumors is associated with a low risk of radiation-induced cancer.     

Regulation of the cancer cell membrane lipid composition by NaCHOleate : Effects on cell signaling and therapeutical relevance in glioma

This review summarizes the cellular bases of the effects of NaCHOleate (2-hydroxyoleic acid; 2OHOA; Minerval) against glioma and other types of tumors. NaCHOleate, activates sphingomyelin synthase (SGMS) increasing the levels of cell membrane sphingomyelin (SM) and diacylglycerol (DAG) together with reductions of phosphatidylethanolamine (PE) and phosphatidylcholine (PC). The increases in the membrane levels of NaCHOleate itself and of DAG induce a translocation and overexpression of protein kinase C (PKC) and subsequent reductions of Cyclin D, cyclin-dependent kinases 4 and 6 (CDKs 4 and 6), hypophosphorylation of the retinoblastoma protein, inhibition of E2F1 and knockdown of dihydrofolate reductase (DHFR) impairing DNA synthesis. In addition in some cancer cells, the increases in SM are associated with Fas receptor (FasR) capping and ligand-free induction of apoptosis. In glioma cell lines, the increases in SM are associated with the inhibition of the Ras/MAPK and PI3K/Akt pathways, in association with p27Kip1 overexpression. Finally, an analysis of the Repository of Molecular Brain Neoplasia Data (REMBRANDT) database for glioma patient survival shows that the weight of SM-related metabolism gene expression in glioma patients' survival is similar to glioma-related genes. Due to its low toxicity and anti-tumoral effect in cell and animal models its status as an orphan drug for glioma treatment by the European Medicines Agency (EMA) was recently acknowledged and a phase 1/2A open label, non-randomized study was started in patients with advanced solid tumors including malignant glioma. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.     

The ROS‐induced cytotoxicity of ascorbate is attenuated by hypoxia and HIF‐1alpha in the NCI60 cancer cell lines

Intravenous application of high‐dose ascorbate is used in complementary palliative medicine to treat cancer patients. Pharmacological doses of ascorbate in the mM range induce cytotoxicity in cancer cells mediated by reactive oxygen species (ROS), namely hydrogen peroxide and ascorbyl radicals. However, little is known about intrinsic or extrinsic factors modulating this ascorbate‐mediated cytotoxicity. Under normoxia and hypoxia, ascorbate IC₅₀ values were determined on the NCI60 cancer cells. The cell cycle, the influence of cobalt chloride‐induced hypoxia‐inducible factor‐1α (HIF‐1α) and the glucose transporter 1 (GLUT‐1) expression (a pro‐survival HIF‐1α‐downstream‐target) were analysed after ascorbate exposure under normoxic and hypoxic conditions. The amount of ascorbyl radicals increased with rising serum concentrations. Hypoxia (0.1% O₂) globally increased the IC₅₀ of ascorbate in the 60 cancer cell lines from 4.5 ± 3.6 mM to 10.1 ± 5.9 mM (2.2‐fold increase, P < 0.001, Mann–Whitney t‐test), thus inducing cellular resistance towards ascorbate. This ascorbate resistance depended on HIF‐1α‐signalling, but did not correlate with cell line‐specific expression of the ascorbate transporter GLUT‐1. However, under normoxic and hypoxic conditions, ascorbate treatment at the individual IC₅₀ reduced the expression of GLUT‐1 in the cancer cells. Our data show a ROS‐induced, HIF‐1α‐ and O₂‐dependent cytotoxicity of ascorbate on 60 different cancer cells. This suggests that for clinical application, cancer patients should additionally be oxygenized to increase the cytotoxic efficacy of ascorbate.     

Combined efficacy of tamoxifen and coenzyme Q10 on the status of lipid peroxidation and antioxidants in DMBA induced breast cancer

An increasing amount of experimental and epidemiological evidence implicates the involvement of oxygen derived radicals in the pathogenesis of cancer development. It is well known that chemical carcinogenesis is multistage process. Free radicals are found to be involved in both initiation and promotion of multistage carcinogenesis. Tamoxifen (TAM) is a potent antioxidant and a non-steroidal antiestrogen drug most used in the chemotherapy and chemoprevention of breast cancer. Besides its anticarcinogenic potential, it also produces some adverse toxic side effects, while taken for a long time. In order to minimise the side effects and to improve the antioxidant efficacy of tamoxifen, coenzyme Q₁₀ (CoQ₁₀) was added. Hence the present study was designed to investigate the combined efficacy of TAM along with CoQ₁₀ in 7, 12 dimethyl benz(a)anthracene (DMBA) induced peroxidative damage in rat mammary carcinoma. The experimental setup comprised of one control and five experimental groups and it was carried out in adult female Sprague-Dawley rats. Mammary carcinoma was induced by oral administration of DMBA (25 mg kg^–1 body wt) and the treatment was started by the oral administration of TAM (10 mg kg^–1 body wt day^–1) and CoQ₁₀ (40 mg kg^–1 body wt day^–1) dissolved in olive oil and continued for 28 days. Rats induced with DMBA showed a decline in the thiol capacity of the cell accompanied by high malondialdehyde content levels along with lowered activities of antioxidant status (superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione). In contrast, glutathione metabolising enzymes (glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione-S-transferase) were increased significantly in chemically induced carcinoma bearing rats. Administration of TAM along with CoQ₁₀ restored the activities to a significant level thereby preventing cancer cell proliferation. This study highlights the increased antioxidant enzyme activities in relation to the susceptibility of cells to carcinogenic agents and the response of tumour cells to the chemotherapeutic agents.