Pancreatic solitary and synchronous metastasis from breast cancer: a case report and systematic review of controversies in diagnosis and treatment

Background

Metastases from breast cancer cause the frequent involvement of lung, bone, liver, and brain, while the occurrence of metastases to the gastrointestinal tract is rare, and more frequently discovered after a primary diagnosis of breast cancer. Solitary pancreatic metastases from breast cancer, without widespread disease, are actually unusual, and only 19 cases have been previously described; truly exceptional is a solitary pancreatic metastasis becoming evident together with the primary breast cancer.

Case presentation

A 68-year-old woman reported general fatigue, lethargy, and jaundice. Abdominal ultrasound (US) and magnetic resonance imaging (MRI) showed an ampulloma of Vater’s papilla; moreover, a neoplastic nodule in the left breast was diagnosed. She underwent surgery for both breast cancer and ampulloma of Vater’s papilla. Pathological examination of pancreatic specimen, however, did not confirm primary carcinoma of the duodenal papilla, but showed a metastatic involvement of pancreas from lobular breast cancer. Immunohistochemistry has been essential to confirm the origin of the malignancy: hormone receptors and mammaglobin were expressed in both the primary breast tumor and the pancreatic metastasis.

Conclusions

This is one of the few reported cases in literature of an isolated and synchronous pancreatic metastasis from breast cancer, where the definitive diagnosis was obtained only after surgery. We discuss the controversies in this diagnosis and the choice of correct treatment. The surgical resection of solitary metastases can be performed in the absence of disseminated disease.     

Lipid Peroxidation in Hyperlipidaemic Patients. A Study of Plasma using an HPLC-Based Thiobarbituric Acid Test

The question of “increased lipid peroxidation” in plasma from hyperlipidaemic patients was investigated using an improved HPLC-based assay for thiobarbituric acid-reactive material. Levels of TBARS in healthy human controls were at or close to zero, provided that butylated hydroxytoluene was added to the sample with the TBA reagents. Levels of plasma TBARS in hyperlipidaemic patients were elevated, although the absolute levels were much lower than those reported previously in the literature.     

Modulating Memory Performance in Healthy Subjects with Transcranial Direct Current Stimulation Over the Right Dorsolateral Prefrontal Cortex

Objective

The role of the Dorsolateral Prefrontal Cortex (DLPFC) in recognition memory has been well documented in lesion, neuroimaging and repetitive Transcranial Magnetic Stimulation (rTMS) studies. The aim of the present study was to investigate the effects of transcranial Direct Current Stimulation (tDCS) over the left and the right DLPFC during the delay interval of a non-verbal recognition memory task.

Method

36 right-handed young healthy subjects participated in the study. The experimental task was an Italian version of Recognition Memory Test for unknown faces. Study included two experiments: in a first experiment, each subject underwent one session of sham tDCS and one session of left or right cathodal tDCS; in a second experiment each subject underwent one session of sham tDCS and one session of left or right anodal tDCS.

Results

Cathodal tDCS over the right DLPFC significantly improved non verbal recognition memory performance, while cathodal tDCS over the left DLPFC had no effect. Anodal tDCS of both the left and right DLPFC did not modify non verbal recognition memory performance.

Conclusion

Complementing the majority of previous studies, reporting long term memory facilitations following left prefrontal anodal tDCS, the present findings show that cathodal tDCS of the right DLPFC can also improve recognition memory in healthy subjects.     

A map of the Monte Arci (Sardinia Island, Western Mediterranean) obsidian primary to secondary sources. Implications for Neolithic provenance studies

Four types of obsidians from the Monte Arci volcanic complex (Sardinia) were used by Neolithic men in the North Tyrrhenian area of the western Mediterranean. A map of their occurrences from primary sources (mother rocks) to distant secondary deposits in the surrounding plains is presented. Some 1457 specimens were macroscopically characterized and in addition ~15% of them fingerprinted from their elemental compositions as determined by electron microprobe, neutron activation analysis or ion beam analysis. The results show that secondary sources, up to now largely neglected in provenance studies of ‘archaeological’ obsidians will have from now to be taken into account. To cite this article: C. Lugliè et al., C. R. Palevol 5 (2006).     

AROS-29 is involved in adaptive response to oxidative stress

Transient adaptation to mild oxidative stress was induced in human osteosarcoma cells chronically grown in sub-toxic concentrations of diethylmaleate (DEM), a glutathione (GSH) depleting agent. The adapted cells, compared to untreated cells, contain increased concentrations of GSH (4-6 fold) which, upon DEM withdrawal from the culture medium, return to normal values and are more resistant to subsequent oxidizing stress induced either by toxic concentrations of the same agent or by (H₂O₂) treatment. To investigate the molecular mechanisms involved in the adaptive response to oxidative stress, we analyzed the gene expression profiles of DEM-adapted cells by differential display. The expression of adaptive response to oxidative stress (AROS)-29 gene, coding for a transmembrane protein of unknown function, as well as of some known genes involved in energy metabolism, protein folding and membrane traffic is up-regulated in adapted cells. The increased resistance to both DNA damage and apoptosis, in cells stably overexpressing AROS-29, demonstrated its functional role in the protection against oxidative stress.     

Paclitaxel and beta‐lapachone synergistically induce apoptosis in human retinoblastoma Y79 cells by downregulating the levels of phospho‐Akt

Paclitaxel (PTX) and beta‐lapachone (LPC) are naturally occurring compounds that have shown a large spectrum of anticancer activity. In this article we show for the first time that PTX/LPC combination induces potent synergistic apoptotic effects in human retinoblastoma Y79 cells. Combination of suboptimal doses of PTX (0.3 nM) and LPC (1.5 µM) caused biochemical and morphological signs of apoptosis at 48 h of treatment. These effects were accompanied by potent lowering in inhibitor of apoptosis proteins and by activation of Bid and caspases 3 and 6 with lamin B and PARP breakdown. PTX/LPC combination acted by favoring p53 stabilization through a lowering in p‐Akt levels and in ps166‐MDM2, the phosphorylated‐MDM2 form that enters the nucleus and induces p53 export and degradation. Treatment with wortmannin or transfection with a dominant negative form of Akt anticipated at 24 h the effects induced by PTX/LPC, suggesting a protective role against apoptosis played by Akt in Y79 cells. In line with these results, we demonstrated that Y79 cells contain constitutively active Akt, which forms a cytosolic complex with p53 and MDM2 driving p53 degradation. PTX/LPC treatment induced a weakness of Akt–MDM2–p53 complex and increased nuclear p53 levels. Our results suggest that phospho‐Akt lowering is at the root of the apoptotic action exerted by PTX/LPC combination and provide strong validation for a treatment approach that targets survival signals represented by phospho‐Akt and inhibitor of apoptosis proteins. J. Cell. Physiol. 222: 433–443, 2010. © 2009 Wiley‐Liss, Inc.     

Viral Mutation Rates

Accurate estimates of virus mutation rates are important to understand the evolution of the viruses and to combat them. However, methods of estimation are varied and often complex. Here, we critically review over 40 original studies and establish criteria to facilitate comparative analyses. The mutation rates of 23 viruses are presented as substitutions per nucleotide per cell infection (s/n/c) and corrected for selection bias where necessary, using a new statistical method. The resulting rates range from 10⁻⁸ to10⁻⁶ s/n/c for DNA viruses and from 10⁻⁶ to 10⁻⁴ s/n/c for RNA viruses. Similar to what has been shown previously for DNA viruses, there appears to be a negative correlation between mutation rate and genome size among RNA viruses, but this result requires further experimental testing. Contrary to some suggestions, the mutation rate of retroviruses is not lower than that of other RNA viruses. We also show that nucleotide substitutions are on average four times more common than insertions/deletions (indels). Finally, we provide estimates of the mutation rate per nucleotide per strand copying, which tends to be lower than that per cell infection because some viruses undergo several rounds of copying per cell, particularly double-stranded DNA viruses. A regularly updated virus mutation rate data set will be available at www.uv.es/rsanjuan/virmut.The mutation rate is a critical parameter for understanding viral evolution and has important practical implications. For instance, the estimate of the mutation rate of HIV-1 demonstrated that any single mutation conferring drug resistance should occur within a single day and that simultaneous treatment with multiple drugs was therefore necessary (72). Also, in theory, viruses with high mutation rates could be combated by the administration of mutagens (1, 5, 21, 44, 53, 83). This strategy, called lethal mutagenesis, has proved effective in cell cultures or animal models against several RNA viruses, including enteroviruses (11, 39, 44), aphtoviruses (83), vesiculoviruses (44), hantaviruses (10), arenaviruses (40), and lentiviruses (15, 53), and appears to at least partly contribute to the effectiveness of the combined ribavirin-interferon treatment against hepatitis C virus (HCV) (13). The viral mutation rate also plays a role in the assessment of possible vaccination strategies (16), and it has been shown to influence the stability of live attenuated polio vaccines (91). Finally, at both the epidemiological and evolutionary levels, the mutation rate is one of the factors that can determine the risk of emergent infectious disease, i.e., pathogens crossing the species barrier (46).Slight changes of the mutation rate can also determine whether or not some virus infections are cleared by the host immune system and can produce dramatic differences in viral fitness and virulence (75, 90), clearly stressing the need to have accurate estimates. However, our knowledge of viral mutation rates is somewhat incomplete, partly due to the inherent difficulty of measuring a rare and random event but also due to several sources of bias, inaccuracy, and terminological confusion. One goal of our work is to provide an update of published mutation rate estimates, since the last authoritative reviews on viral mutation rates were published more than a decade ago (29, 30). We therefore present a comprehensive review of mutation rate estimates from over 40 original studies and 23 different viruses representing all the main virus types. A second, and perhaps more ambitious, goal of our study is to consolidate the published literature by dealing with what we regard as the two main problems in the field: the use of different units of measurement and the bias caused by selection.The problem of units is linked to the different modes of replication in viruses. Under “stamping machine” or linear replication, multiple copies are made sequentially from the same template and the resulting progeny strands do not become templates until the progeny virions infect another cell. In contrast, under binary replication, progeny strands immediately become templates and hence the number of molecules doubles in each cycle of strand copying, increasing geometrically. This basic distinction leads to two different definitions of the mutation rate: per strand copying or per cell infection. If replication is stamping machine-like, there is only one cycle of strand copying per infected cell and hence the two units are equivalent. However, binary replication means that the virus completes several cycles of strand copying per cell. The actual replication mode of most viruses is probably intermediate between these two idealized cases, and although it is known to be closer to linear in some viruses (9, 19) and closer to binary in others (26, 55), it is often unknown. This leads to uncertainties in mutation rate estimates. For instance, in the case of poliovirus 1, the estimated rate per strand copying can vary by 10-fold depending on whether stamping machine or binary replication is assumed (27). Typically this difference in the unit of measurement has been overlooked in comparative studies. Here, we express published estimates in the same unit.The other issue that we address is selection. In general, deleterious mutations tend to be eliminated and hence are less likely to be sampled than neutral ones, introducing a bias in mutation rate estimates. To avoid this problem, selective neutrality is sometimes enforced by the experimenter, such that the number of mutations increases linearly with time (58, 88). The opposite strategy is to focus on lethal mutations, which have necessarily appeared during the last cell infection cycle, thus establishing a direct and time-independent relationship between the observed mutation frequency and the underlying mutation rate (13, 37). In between these two special cases, an explicit correction for selection is needed. Even if the effect of each individual mutation on viral fitness is unknown, the effect of selection can be statistically accounted for as long as the number of mutations sampled for estimating mutation rates is large. We do this here using empirical information about the distribution of mutational fitness effects previously obtained for several viruses (6, 23, 73, 80). Importantly, the basic properties of this distribution appear to be well conserved (78), and hence the proposed method should be applicable to a wide variety of viruses.Using the resulting mutation rate data, we retest some previously accepted general patterns, suggest new ones, infer the mode of replication of some viruses, and compare the rates of mutation to substitutions with those to insertions/deletions (indels).     

Structural stability of green fluorescent proteins entrapped in polyelectrolyte nanocapsules

Molecules of a green fluorescent protein mutant, GFPmut2, have been immobilized in nanocapsules, assemblies of charged polyelectrolyte multilayers, with the aim to study the effect of protein‐polyelectrolyte interactions on the protein stability against chemical denaturation. GFPmut2 proteins turn out to be stabilized and protected against the denaturating action of small chemical compounds. The nanocapsule protective effect on GFPmut2 is likely due to protein interactions with the negatively charged polymers, that induce an increase in the local rigidity of the protein nano‐environment. This suggestion is supported by Fluorescence Polarization measurements on GFPmut2 proteins bound to the NC layers. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Secretory and vascular effects of adrenomedullin in gastric ulcer: role of CGRP- and adrenomedullin-receptors

Adrenomedullin prevents damage of gastric mucosa in either reserpine-treated or pylorus-ligated rats. Pre-treatment with CGRP(8-37) resulted in a decrease of the gastro-protective effect of adrenomedullin in both models and reversed the inhibitory effect of adrenomedullin on gastric acid output in the pylorus-ligated rats. These adrenomedullin actions were less effectively modified by pre-treatment with adrenomedullin(22-52). These data suggest that the anti-ulcer effect of adrenomedullin is mainly related to its anti-secretory action, presumably mediated through CGRP-receptors.