Prognostic factors and survival in metastatic breast cancer: A single institution experience

Background

The current retrospective study aims to identify some determinants of survival in metastatic breast cancer.

Methods

The study concerned 332 patients with synchronous (SM) or metachronous (MM) metastatic breast cancer treated between January 2000 and December 2007. Statistical comparison between subgroups of patients concerning survival was carried out employing log-rank test for the invariable analysis and Cox model for the multivariable analysis. Factors included: age group (≤50 years vs. >50; ≤70 years vs. >70; ≤35 years vs. >35), menopausal status, presentation of metastatic disease (SM vs. MM), disease free interval (DFI) (≤24 months vs. >24 months; ≤60 months vs. >60 months), performance status at diagnosis of metastatic disease (PS) (0–1 vs. >1), hormone receptors (HR), number of metastatic sites (1 site vs. >1), nature of the metastatic site (visceral vs. non visceral), first line therapy, surgery of the primary tumor (SPT), locoregional radiotherapy (LRRT) and use or not of bisphosphonates.

Results

Overall survival at 5 years was 12%. Positive prognostic factors in univariate analysis were: age ≤ 70 years, hormono-dependence of the tumor, good PS (PS 0–1), less than two metastatic sites, no visceral metastases, DFI ≥ 24 months, SPT or LRRT. In multivariate analysis, favorable independent prognostic factors included: good PS (PS 0–1), absence of visceral metastases (liver, lung, brain) and age ≤ 70 years.

Conclusion

Many of the prognostic factors in metastatic breast cancer found in our study are known in the literature but some of them, like the application of locoregional treatment (radiotherapy or surgery) and the use of bisphosphonates, need to be further investigated in randomized clinical trials.     

Middle Palaeolithic and Neolithic Occupations around Mundafan Palaeolake,Saudi Arabia: Implications for Climate Change and Human Dispersals

The Arabian Peninsula is a key region for understanding climate change and human occupation history in a marginal environment. The Mundafan palaeolake is situated in southern Saudi Arabia, in the Rub’ al-Khali (the ‘Empty Quarter’), the world’s largest sand desert. Here we report the first discoveries of Middle Palaeolithic and Neolithic archaeological sites in association with the palaeolake. We associate the human occupations with new geochronological data, and suggest the archaeological sites date to the wet periods of Marine Isotope Stage 5 and the Early Holocene. The archaeological sites indicate that humans repeatedly penetrated the ameliorated environments of the Rub’ al-Khali. The sites probably represent short-term occupations, with the Neolithic sites focused on hunting, as indicated by points and weaponry. Middle Palaeolithic assemblages at Mundafan support a lacustrine adaptive focus in Arabia. Provenancing of obsidian artifacts indicates that Neolithic groups at Mundafan had a wide wandering range, with transport of artifacts from distant sources.     

Secreted recombinant P53 protein from Pichia pastoris is a useful antigen for detection of serum p53: autoantibody in patients with advanced colorectal adenocarcinoma

The detection of P53 alteration by serological method is easier to perform, does not require tumor tissues and is of interest for patients monitoring. In this study, we described the development of a home made ELISA test based on recombinant human P53 protein produced in Pichia pastoris and used as antigen for the detection of serum p53-Abs in colorectal carcinoma patients. The human P53 was secreted as a His-tagged protein by recombinant KM71 strain (Kα21) via the peptide signal α of the Saccharomyces cerevisiae mating type gene. The recombinant P53-His was able to detect p53-Abs in 23.4 % of patients. Serum p53-Abs correlated significantly with surgical treatment (P = 0.007), relapse during follow-up (P = 0.036), depth of invasion (P = 0.036) and the level of CA19-9 (P = 0.034). Survival analysis showed that patients negative for serum p53-Abs exhibited a prolonged disease free survival period (P log rank = 0.012). In conclusion, the secreted recombinant human P53-His produced in P. pastoris seems to be a useful antigen for detection of serum p53 Abs in patients with colorectal carcinoma.     

Dimethoate Induces Kidney Dysfunction, Disrupts Membrane-Bound ATPases and Confers Cytotoxicity Through DNA Damage. Protective Effects of Vitamin E and Selenium

Dimethoate (DM) is an organophosphate insecticide widely used in agriculture and industry and has toxic effects on non-target organisms especially mammalian. However, we still know little about DM-induced kidney injury and its alleviation by natural antioxidants. In the present study, selenium (Se), vitamin E, DM, Se+DM, vitamin E+DM, Se+vitamin E+DM were given to adult rats for 4 weeks. Plasma creatinine and uric acid, kidney MDA, PC, H₂O₂ and AOPP levels were higher, while Na⁺-K⁺-ATPase and LDH values were lower in the DM group than those of controls. A smear without ladder formation on agarose gel was shown in the DM group, indicating random DNA degradation and DM-induced genotoxicity. A decrease in kidney GSH, NPSH and plasma urea levels and an increase in GPx, SOD and catalase activities were observed in the DM group when compared to those of controls. Plasma cystatin C levels increased, indicating a decrease in glomerular filtration rate. When Se or vitamin E was added through diet, the biochemical parameters cited above were partially restored in Se+DM and vitamin E+DM than DM group. The joint effect of Se and vitamin E was more powerful against DM-induced oxidative stress and kidney dysfunction. The changes in biochemical parameters were substantiated by histological data. In conclusion, our results indicated a possible mechanism of DM-induced nephrotoxicity, where renal genotoxicity was noted, membrane-bound ATPases and plasma biomarkers were disturbed. Se and vitamin E ameliorated the toxic effects of this pesticide in renal tissue suggesting their role as potential antioxidants.     

A novel series of histamine H4 receptor antagonists based on the pyrido[3,2-d]pyrimidine scaffold: Comparison of hERG binding and target residence time with PF-3893787

In this work we describe the optimization of a lead compound based on the quinazoline template to give a new series of potent pyrido[3,2-d]pyrimidines as histamine H₄ receptor antagonists. The pyrido[3,2-d]pyrimidine ligands have significantly reduced hERG binding compared to clinical stage compound PF-3893787 while showing good affinities at the human and rodent histamine receptors. The receptor residence time of several of these new compounds was determined for the human H₄R and compared with JNJ7777120 and PF-3893787. The pyrido[3,2-d]pyrimidines showed residence times lower than JNJ7777120 but comparable to the residence time of PF-3893787. Overall, the pyrido[3,2-d]pyrimidines show an excellent in vitro profile that warrants their further investigation in relevant models of human disease.     

The Iranian vole Microtus irani occurs in Lebanon (Mammalia: Rodentia)

We studied 1140 bp cytochrome b sequences of social voles from three localities in Lebanon. The results were compared with published sequences representing seven species of social voles. New sequences from Lebanon clustered with reference samples of two species: M. guentheri and M. irani. While M. guentheri was already reported for Lebanon, M. irani is a new addition to the fauna of Lebanon, and the third known record for the species. Animals were collected in two localities above Tripolis at 855 m and 1430 m a.s.l., respectively.     

Piophila megastigmata McAlpine 1978 (Diptera: Piophilidae): the first record from northern Africa of this forensically relevant fly

Piophila megastigmata McAlpine (Diptera: Piophilidae) is recorded for the first time from Algeria, northern Africa. This is the first Palaearctic record of the species outside the Iberian Peninsula, and the only record from Africa apart from its type locality in eastern South Africa. The current report extends significantly the known distribution in the Palaearctic Region of a species of forensic interest and of potential economic importance as a food pest.     

Inability of Agrobacterium tumefaciens ribosomes to translate in vivo mRNAs containing non-Shine-Dalgarno translational initiators

Numerous data accumulated during the last decade have shown that the Shine-Dalgarno (SD) sequence is not a unique initiator of translation for Escherichia coli. Several other sequences, mostly of viral origin, have demonstrated their capability of either enhancing or initiating translation in vivo. A phage T7 gene 10 sequence, called "epsilon" (epsilon), has shown its high enhancing activity on translation in both Escherichia coli and Agrobacterium tumefaciens cells. In this study the epsilon, together with three other nucleotide sequences derived from the 5' non-translated regions of tobacco mosaic virus (TMV), papaya mosaic virus (PMV) and clover yellow mosaic virus (CYMV) RNAs are tested for translation initiation activity in A. tumefaciens cells. The obtained results indicate that none of them was capable of initiating translation in vivo of chloramphenicol acetyltransferase (CAT) mRNA. To determine whether their inactivity was related with structural differences in the ribosomal protein S1, the rpsA gene (coding for S1 protein in E. coli) was co-expressed in A. tumefaciens together with the cat gene placed under the translational control of the above sequences. Our results showed that the rpsA gene product did not make any of the four viral enhancers active in A. tumefaciens cells. The inability of A. tumefaciens ribosomes to translate mRNAs devoid of SD sequences indicates for a substantial difference in the ribosome structure of the two Gram negative bacteria E. coli and A. tumefaciens.     

Asymmetrical membranes and surface tension

The (31)P-nuclear magnetic resonance chemical shift of phosphatidic acid in a membrane is sensitive to the lipid head group packing and can report qualitatively on membrane lateral compression near the aqueous interface. We have used high-resolution (31)P-nuclear magnetic resonance to evaluate the lateral compression on each side of asymmetrical lipid vesicles. When monooleoylphosphatidylcholine was added to the external monolayer of sonicated vesicles containing dioleoylphosphatidylcholine and dioleoylphosphatidic acid, the variation of (31)P chemical shift of phosphatidic acid indicated a lateral compression in the external monolayer. Simultaneously, a slight dilation was observed in the inner monolayer. In large unilamellar vesicles on the other hand the lateral pressure increased in both monolayers after asymmetrical insertion of monooleoylphosphatidylcholine. This can be explained by assuming that when monooleoylphosphatidylcholine is added to large unilamellar vesicles, the membrane bends until the strain is the same in both monolayers. In the case of sonicated vesicles, a change of curvature is not possible, and therefore differential packing in the two layers remains. We infer that a variation of lipid asymmetry by generating a lateral strain in the membrane can be a physiological way of modulating the conformation of membrane proteins.     

A close encounter with DNA

Atomic force microscopy, associated with surface science, has the potential to resolve the secondary structure of DNA in liquid form with unusually high resolution and with unprecedented accuracy.