Synthesis of Curcumin Derivatives and Analysis of Their Antitumor Effects in Triple Negative Breast Cancer (TNBC) Cell Lines

We analyzed antitumor effects of a series of curcumin analogues. Some of them were obtained by reaction of substitution involving the two phenolic OH groups of curcumin while the analogues with a substituent at C-4 was prepared following an original procedure that regards the condensation of benzenesulfenic acid onto the nucleophilic central carbon of the curcumin skeleton. We analyzed cytotoxic effects of such derivatives on two TNBC (triple negative breast cancer) cell lines, SUM 149 and MDA-MB-231, but only three of them showed an IC50 in a lower micromolar range with respect to curcumin. We also focused on these three derivatives that in both cell lines exhibited a higher or at least equivalent pro-apoptotic effect than curcumin. The analysis of molecular mechanisms of action of the curcumin derivatives under study has highlighted that they decreased NF-κB transcriptional factor activity, and consequently the expression of some NF-κB targets. Our data confirmed once again that curcumin may represent a very good lead compound to design analogues with higher antitumor capacities and able to overcome drug resistance with respect to conventional ones, even in tumors difficult to treat as TNBC

Microcephaly and macrocephaly. A study on anthropometric and clinical data from 308 subjects

Head circumference is the auxological parameter that most correlates with developmental anomalies in childhood. Head circumference (HC) two standard deviations (SD) below or above the mean defines microcephaly and macrocephaly, respectively. The aim of this retrospective study was to explore anthropometric parameters and clinical characteristics among subjects with abnormalities in HC who had been referred for developmental assessment. One hundred and sixty four subjects with microcephaly and 144 subjects with macrocephaly were enrolled from birth to 18 months of age. Head circumference at birth and the association with variables related to maternal health status, gestational age, growth pattern, brain imaging and clinical characteristics were analyzed. In some cases, an etiological diagnosis was made. In the two considered conditions, we found different anthropometric and clinical associations, some of which were statistically significant, with implications for ongoing neurodevelopmental surveillance

Observations and radio tagging of Balaenoptera edeni near Puerto La Cruz, Venezuela

The 23 October to 13 November 1979 Venezuelan radio tagging and tracking experiments on whales (Balaenoptera edeni, Fig. 1) provided essential field tests of the new modifications to the WHOI radio whale tag (see list of tag reports), and the chance to try it on a new species. We found that we could approach and tag these whales from a slow (4 to 6 kt) vessel. Good radio tracking with automatic direction finding equipment was possible within 12 to 20 km, with longer ranges probable. In addition, the radio tags provided new information about the behavior of these whales.Prepared for the Office of Naval Research under Contract N00014-79-C-OO71; NR 083-004

Epigenetic changes and nuclear factor-\u3baB activation, but not microRNA-224, downregulate Raf-1 kinase inhibitor protein in triple\u2011negative breast cancer SUM 159 cells

Raf-1 kinase inhibitor protein (RKIP) is a tumor suppressor and metastasis inhibitor, which enhances drug\u2011induced apoptosis of cancer cells. Downregulation of RKIP may be significant in the biology of highly aggressive and drug\u2011resistant tumors, for example triple\u2011negative breast cancers (TNBCs). Potential causes for the low levels of RKIP expressed by SUM 159 TNBC cells were investigated in the present study. Bisulphite modification, methylation specific\u2011polymerase chain reaction (PCR) and a TransAM NF-\u3baB assay were performed and the results suggested that various mechanisms, including methylation of the gene promoter, histone deacetylation and nuclear factor\u2011\u3baB (NF\u2011\u3baB) activation, but not targeting by microRNA\u2011224 (miR/miRNA\u2011224), as determined by transfection of pre\u2011miR\u2011224 miRNA precursor or anti\u2011miR\u2011224 miRNA inhibitor, may downregulate RKIP in these cells. Furthermore, reverse transcription\u2011quantitative PCR, western blotting,3\u2011(4,5\u2011dimethylthiazol\u20112\u2011yl)\u20115\u2011(3\u2011carboxymethoxyphenyl)\u20112\u2011(4\u2011sulphophenyl)\u20112H\u2011tetrazolium cell growth assay and flow cytometry revealed that in SUM 159 cells, the demethylating agent 5\u2011aza\u20112'\u2011deoxycytidine (5\u2011AZA), the histone deacetylase inhibitor trichostatin A (TSA) and the NF\u2011\u3baB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) enhanced RKIP expression and resulted in significant cell growth inhibition and induction of apoptosis. 5\u2011AZA and TSA mainly produced additive antitumor effects, while the combination of DHMEQ and TSA exhibited significant synergy in cell growth inhibition and induction of apoptosis assays. Increasing evidence that aberrant activation of NF\u2011\u3baB signaling is a frequent characteristic of TNBC highlights the fact that this transcription factor may be a useful target for treatment of such tumors. In addition to DHMEQ, proteasome inhibitors may also represent valuable therapeutic resources in this context. Notably, proteasome inhibitors, in addition to the inhibition of NF\u2011\u3baB activation, may also restore RKIP levels by inhibiting proteasome degradation of the ubiquitinated protein. The current results contribute to the understanding of the molecular mechanisms of RKIP downregulation in TNBC and suggest possible novel therapeutic approaches for the treatment of these types of cancer

Plasma levels of lipoproteins and apolipoproteins in congenital hypothyroidism: effects of L-thyroxine substitution therapy

Thyroid status in humans is an important factor in the regulation of lipoprotein metabolism. There are several data on hypothyroidism in the adult population, but less information is available about congenital hypothyroidism. Since lipid metabolism at birth is substantially different from that of adults, it is not likely that the same abnormalities that occur in adult hypothyroidism are also present when this is diagnosed at early life. We studied 16 subjects with congenital hypothyroidism, seven at the time of diagnosis and also after normalization of thyroid hormone levels over a period of 2.0 +/- 1.0 months of substitution therapy with L-thyroxine (5.9 +/- 1.2 micrograms/kg/d) and nine already on L-thyroxine therapy for a period of 4.7 +/- 3.2 months. Thirty-nine apparently healthy subjects matched for age were selected as controls. In all subjects, total cholesterol (CHO), triglycerides (TG), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol (HDL-C), apolipoproteins (apo) A-I and B, lipoprotein(a) [Lp(a)] thyrotropin (TSH), (LDL-C), total and free thyroxine (T4), and triiodothyronine (T3) were determined. CHO, HDL-C, and apo A-I levels were significantly higher in patients at the time of diagnosis than in controls (respectively, P = .0079, .0007, and .0004), whereas TG, LDL-C, apo B, and Lp(a) levels were not significantly different. During L-thyroxine substitution therapy in these subjects, HDL-C and apo A-I levels significantly decreased (respectively, by a mean of -36.2% and -24.4%), with similar behavior in all subjects.(ABSTRACT TRUNCATED AT 250 WORDS

Comparison of anti-transglutaminase ELISAs and an anti-endomysial antibody assay in the diagnosis of celiac disease: A prospective study

Background: Most studies of anti-transglutaminase (anti-tTG) assays have considered preselected groups of patients. This study compared the sensitivity, specificity, and predictive value of an immunofluorescence method for anti-endomysial antibodies (EmAs) and two anti-tTG ELISAs, one using guinea pig tTG (gp-tTG) and the other human tTG (h-tTG) as antigen, in consecutive patients investigated for suspected celiac disease (CD). Methods: We studied 207 consecutive patients (99 men, 108 women; age range, 17-84 years) who underwent intestinal biopsy for suspected CD. Patients presented with one or more of the following: weight loss, anemia, chronic diarrhea, abdominal pain, dyspepsia, alternating bowel habits, constipation, pain in the joints, and dermatitis. At entry to the study, an intestinal biopsy was performed and a serum sample was taken for IgA EmAs, anti-gp-tTG, and anti-h-tTG. Results: Intestinal histology showed that 24 patients had partial or total villous atrophy; in these patients the diagnosis of CD was confirmed by follow-up. The remaining 183 patients had villous/crypt ratios that were within our laboratory's reference values and were considered controls. Serum EmAs, anti-gp-tTG, and anti-h-tTG were positive in all 24 CD patients; in the control group, none were positive for serum EmAs, but 15 of 183 (8.2%) were positive for anti-gp-tTG, and 6 of 183 (3.3%) were positive for anti-h-tTG. Sensitivity was 100% for all assays, whereas specificity was 100% for the EmA, 92% for the anti-gp-tTG, and 97% for the anti-h-tTG assay. The negative predictive value was 100% for all assays; the positive predictive value was 100% for the EmA, 80% [95% confidence interval (CI), 65-95%] for the anti-h-tTG (P = 0.03 vs EmA) and 60% (95% CI, 44-76%) for the anti-gp-tTG assay (P = 0.0002 vs EmA). Areas (95% CIs) under the ROC curves were 0.987 (0.97-1.0) for anti-h-tTG and 0.965 (0.94-0.99) for anti-gp-tTG. Most of the patients testing false positive for anti-tTG had Crohn disease or chronic liver disease. Conclusions: Although both anti-tTG ELISAs showed optimum sensitivity, their lack of specificity yielded positive predictive values significantly lower than those for the EmA assay. © 2002 American Association for Clinical Chemistry

Diagnostic accuracy of fecal calprotectin assay in distinguishing organic causes of chronic diarrhea from irritable bowel syndrome: a prospective study in adults and children

Fecal calprotectin (FC) has been proposed as a marker of inflammatory bowel disease (IBD), but few studies have evaluated its usefulness in patients with chronic diarrhea of various causes. We evaluated the diagnostic accuracy of a FC assay in identifying "organic" causes of chronic diarrhea in consecutive adults and children

Cetaceans of Venezuela: Their distribution and conservation status.

Sighting, stranding, and capture records of whales and dolphins for Venezuela were assembled and analyzed to document the Venezuelan cetacean fauna and its distribution in the eastern Caribbean. An attempt was made to confirm species identification for each of the records, yielding 443 that encompass 21 species of cetaceans now confirmed to occur in Venezuelan marine, estuarine, and freshwater habitats. For each species, we report its global and local distribution, conservation status and threats, and the common names used, along with our proposal for a Spanish common name. Bryde’s whale (Balaenoptera edeni) is the most commonly reported mysticete. The long-beaked common dolphin (Delphinus capensis) is the most frequent of the odontocetes in marine waters. The boto or tonina (Inia geoffrensis) was found to be ubiquitous in the Orinoco watershed. The distribution of marine records is consistent with the pattern of productivity of Venezuelan marine waters, i.e., a concentration at 63°07′W through 65°26′W with records declining to the east and to the west. An examination of the records for all cetaceans in the Caribbean leads us to conclude that seven additional species may be present in Venezuelan waters. (PDF file contains 61 pages.