Plitidepsin has a cytostatic effect in human undifferentiated (anaplastic) thyroid carcinoma.

Undifferentiated (anaplastic) thyroid carcinoma is a highly aggressive human cancer with very poor prognosis. Although there have been a few studies of candidate treatments, the fact that it is an infrequent tumor makes it very difficult to design clinical trials. A strong association has been observed between undifferentiated thyroid carcinoma and TP53 mutations in numerous molecular genetic and expression studies. Plitidepsin (Aplidin, PharmaMar, Madrid, Spain) is a novel anticancer compound obtained from a sea tunicate. This compound has been reported to induce apoptosis independently of TP53 status. We investigated the actions of plitidepsin in human thyroid cancer cells. In initial experiments using primary cultured cells from a differentiated (papillary) carcinoma, we found that 100 nmol/L plitidepsin induced apoptosis, whereas lower doses were cytostatic. Because our aim was to study the effects of plitidepsin at clinically relevant concentrations, subsequent experiments were done with a dosage regimen reflecting plasma concentrations observed in previously reported clinical trials: 100 nmol/L for 4 hours, followed by 10 nmol/L for 20 hours (4(100)/20(10) plitidepsin). This plitidepsin dosage regimen blocked the proliferation of a primary undifferentiated/anaplastic thyroid carcinoma culture obtained in our laboratory and of a commercial cell line (8305C) obtained from an undifferentiated thyroid carcinoma; however, it did not induce apoptosis. The proportion of cells in the G(1) phase of the cell cycle was greatly increased and the proportion in the S/G(2)-M phases greatly reduced, suggesting that plitidepsin blocks G(1)-to-S transition. Levels of the cyclin D1/cyclin-dependent kinase 4/p21 complex proteins were decreased and, in line with this, the levels of unphosphorylated Rb1 increased. The decrease in cell cycle proteins correlated with hypoacetylation of histone H3. Finally, we did experiments to assess how rapidly tumor cells return to their initial pretreatment proliferative behavior after 4(100)/20(10) plitidepsin treatment. Cells from undifferentiated tumors needed more than 3 days to recover logarithmic growth, and after 7 days, cell number was still significantly lower than in control cultures. 4(100)/20(10) plitidepsin inhibited the growth in soft agar. Together, our data show that plitidepsin is able to block in vitro cell cycle progression at concentrations similar to serum concentrations observed in vivo, and that this effect is persistent for several days after plitidepsin removal. Whether plitidepsin will prove to be clinically useful in the treatment of undifferentiated thyroid cancers remains to be established. However, our results raise the possibility that plitidepsin might be effective alone or in combination with radiotherapy and/or other drug treatments.     

Renin-angiotensin system blockade prevents the increase in plasma transforming growth factor beta 1, and reduces proteinuria and kidney hypertrophy in the streptozotocin-diabetic rat.

INTRODUCTION: Combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) is used to improve renal outcome achieved by monotherapy in diabetic patients. In addition, interference with the renin-angiotensin system (RAS) reduced expression and excretion of transforming growth factor beta 1 (TGF-beta 1) in diabetic nephropathy. The aim of this study was to investigate the effects of interrupting the RAS by ACE inhibitor (ACE-I) or ARB monotherapy or by combination therapy on proteinuria, kidney hypertrophy and plasma TGF-beta 1 in diabetic rats. MATERIALS AND METHODS: Forty-one male Wistar rats were allocated to five groups: 1 = control rats, 2 = diabetic rats (streptozotocin [STZ] 55 mg/kg), 3 = diabetic rats as above receiving enalapril (20 mg/kg/day), 4 = diabetic rats receiving losartan (80 mg/kg/day), 5 = diabetic rats receiving both losartan and enalapril. The study lasted 60 days. RESULTS: Urinary protein excretion, kidney weight, serum ACE activity and plasma TGF-beta1 increased significantly in untreated diabetic rats compared with controls. Administration of losartan, enalapril, or both for 60 days prevented these changes. Furthermore, combined therapy for 30 days normalised urinary protein excretion, while monotherapy did not. Losartan inhibited serum ACE activity both in vivo and in vitro. Plasma TGF-beta 1 levels were positively correlated with blood glucose levels (r=0.4059) and with urinary protein excretion (r=0.3558). CONCLUSIONS: Combination therapy with losartan and enalapril was more effective than monotherapy with either drug in achieving an early antiproteinuric response. Long-term treatment with losartan was as effective as the combined treatment, possibly due to a dual inhibitory effect on the RAS. The antiproteinuric effect may be related, in part, to reduced TGF-beta 1.     

Executive function and general intellectual functioning in dyskinetic cerebral palsy: Comparison with spastic cerebral palsy and typically developing controls

AimTo comprehensively describe intellectual and executive functioning (EF) in people with dyskinetic cerebral palsy (DCP), by comparing their performance with that of: 1) age- and sex-matched typically developing controls (TDC); and 2) participants with spastic cerebral palsy (SCP) matched for age, sex, term/preterm and gross motor function classification system (GMFCS).MethodThis cross-sectional study was conducted by the University of Barcelona in collaboration with five institutions. Participants were people with DCP (n = 52; 24 females, median age 20.5 y: 5mo, interquartile range [IQR] = 13.75 y: 7mo; GMFCS I–V). As comparison groups, participants with SCP (n = 20; 10 females, median age = 20.5 y: 5.5mo, IQR = 13.75 y 9mo; GMFCS I–V) and TDC (n = 52; 24 females, median age = 20 y: 4mo, IQR = 12 y 7mo) were included. Intelligence and EF were assessed using common tests in all participants.ResultsBoth CP groups had lower intelligence than TDC and performed poorer in almost all EF tasks. Intelligence was higher in DCP than SCP (z = ?2.51, p = 0.01). Participants with DCP also performed significantly better in goal-setting tasks (z = 2.27, p = 0.03) and information processing (z = ?2.54, p = 0.01) than those with SCP.ConclusionPeople with DCP present lower general intellectual functioning and poorer EF across multiple domains than typically developing controls. People with DCP have higher general intellectual functioning and better EF than people with SCP when levels of motor severity are similar.     

Pyruvate remediation of cell stress and genotoxicity induced by haloacetic acid drinking water disinfection by‐products

Monohaloacetic acids (monoHAAs) are a major class of drinking water disinfection by‐products (DBPs) and are cytotoxic, genotoxic, mutagenic, and teratogenic. We propose a model of toxic action based on monoHAA‐mediated inhibition of glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) as a target cytosolic enzyme. This model predicts that GAPDH inhibition by the monoHAAs will lead to a severe reduction of cellular ATP levels and repress the generation of pyruvate. A loss of pyruvate will lead to mitochondrial stress and genomic DNA damage. We found a concentration‐dependent reduction of ATP in Chinese hamster ovary cells after monoHAA treatment. ATP reduction per pmol monoHAA followed the pattern of iodoacetic acid (IAA) > bromoacetic acid (BAA) >> chloroacetic acid (CAA), which is the pattern of potency observed with many toxicological endpoints. Exogenous supplementation with pyruvate enhanced ATP levels and attenuated monoHAA‐induced genomic DNA damage as measured with single cell gel electrophoresis. These data were highly correlated with the S_N2 alkylating potentials of the monoHAAs and with the induction of toxicity. The results from this study strongly support the hypothesis that GAPDH inhibition and the possible subsequent generation of reactive oxygen species is linked with the cytotoxicity, genotoxicity, teratogenicity, and neurotoxicity of these DBPs. Environ. Mol. Mutagen. 54:629–637, 2013. © 2013 Wiley Periodicals, Inc.     

Leptospirosis among zebu cattle in farms in Kaduna State,Nigeria

ObjectiveTo assess the occurrence of Leptospira spp serovar Hardjo among Zebu cattle in some livestock producing areas of Kaduna State, Nigeria.MethodsSera samples were obtained from 164 Zebu breed of cattle above one year osf age in seven cattle farms were screened for antibodies to Leptospira spp. serovar Hardjo using Enzyme linked immunosorbent assay (ELISA).ResultsAntibodies to Leptospira spp. serovar Hardjo were detected in eighteen (10.98%) out of the 164 animals sampled. There was no significant difference (P>0.05) in seropositivity between the different age groups or between different Zebu breeds.ConclusionThe presence of Leptospirosis among the Zebu breeds of cattle may poses a threat to livestock production and has public health implication due to its zoonotic potential.