The tyrphostin AG1478 inhibits proliferation and induces death of liver tumor cells through EGF receptor-dependent and independent mechanisms

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death. Different signaling pathways are de-regulated in this pathogenesis, among them the epidermal growth factor receptor one (EGFR/Erb1). Here we show that blockage of this pathway by the tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) in different liver tumor cell lines promotes both inhibition of cell proliferation and induction of cell death, which are coincident with arrest in the G1 phase of the cell cycle, caspase-3 activation and DNA fragmentation. AG1478 up-regulates the expression of the pro-apoptotic member of the BCL-2 family BIM and down-regulates the expression of the anti-apoptotic BCL-XL and MCL1. Furthermore, it also decreases the levels of the caspase inhibitors HIAP2 and XIAP. The treatment of HCC cells with AG1478 enhanced the apoptosis induced by other pro-apoptotic stimuli, such as the physiological cytokine, TGF-β, highly expressed in liver tumors, or the chemotherapeutic drug doxorubicin. The effects observed by AG1478 were broader than the ones seen by silencing of the EGFR with siRNA, which indicates that this drug might act on other targets different from the EGFR. In this same line of evidence, AG1478 retained some cytotoxic effects in cells where EGFR has been targeted knock-down with shRNA. Interestingly, AG1478 preferentially acts on liver tumor cells, being untransformed cells much less responsive to its cytotoxic effects. In conclusion, AG1478 could be a potential therapeutic drug to be used in HCC.     

Microglial cell reaction in the gray and white matter in spinal cords from jimpy mice. An enzyme histochemical study at the light and electron microscope level

Jimpy is a genetic disorder which results in a severe hypomyelination in the central nervous system associated with a variety of astroglial and oligodendroglial abnormalities. In this study, we examined the morphology and distribution of microglial cells in spinal cord sections from jimpy and normal mice at 10–12 and 20–22 days postnatal using a specific microglial marker, the nucleoside diphosphatase staining. Compared to those of normal littermates, the spinal cords of jimpy mice showed an intense microglial cell reaction in white and gray matter, as revealed by quantitative analysis and light and electron microscope study. Microglial reactivity was apparent in all spinal cord areas, although it was more pronounced in white than in gray matter. The mean microglial densities in the jumpy white matter were about threefold (10–12 days) and fivefold (20–22 days) higher than in the normal, whereas in the gray matter, microglial density in jimpy was about 60% higher than in normal at both ages. Morphologically, microglial cells in the normal spinal cord showed a ramified appearance, similar in size and ramification pattern to those reported in other normal CNS areas. In contrast, microglial cells in the jimpy spinal cord showed a reactive morphology, characterized by a shortening and coarsening of their cell processes, swelling of their cell body and accumulation of lipid inclusions. Reactive microglial cells were found in close association with axons and oligodendroglial cells. The possible role of microglial cells in hypomyelination is discussed.     

12p13 rearrangements: 6 Mb deletion responsible for ID/MCA and reciprocal duplication without clinical responsibility

Congenital balanced reciprocal translocations are one of the most frequent structural chromosomal aberrations in the population. We report a familial translocation t(12;22)(p13.3;pter) responsible for intellectual disabilities and congenital anomalies characterized by FISH and array CGH. Two patients carried a der(12)t(12;22)(p13.3;pter), resulting in a 6 Mb 12pter deletion. Patients presented with intellectual disabilities, pre- and post-natal growth retardation, ponderal development delay, global hypotonia, feeding problems and dysmorphic features. Two relatives presented with the reciprocal 12pter duplication, which had no clinical manifestations associated. For this translocation, we propose a mechanism based on a non-allelic recombination model, in which recombination of direct oriented segmental duplications between non-homologous chromatids leads to the reciprocal translocation. The characterization of this translocation has been critical for the family. Translocation carriers have a risk of 40% of having offspring carrying unbalanced products. 12p13.3 deletion carriers present with a recognizable syndrome and on the contrary, 12p13.3 duplication carriers present without clinical manifestations. Other published cases of 12p13.3 duplication show that this syndrome has a variable phenotype. It is advisable to delineate the duplication size and to discard other genetic aberrations, in order to give an accurate genetic counseling in patients carrying 12pter duplications.     

Stable antigen-specific T-cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients

Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease of the central nervous system. Current therapies decrease the frequency of relapses and limit, to some extent, but do not prevent disease progression. Hence, new therapeutic approaches that modify the natural course of MSneed to be identified. Tolerance induction to self-antigens using monocyte-derived dendritic cells (MDDCs) is a promising therapeutic strategy in autoimmunity. In this work, we sought to generate and characterize tolerogenic MDDCs (tolDCs) from relapsing-remitting (RR) MSpatients, loaded with myelin peptides as specific antigen, with the aim of developing immunotherapeutics for MS. MDDCs were generated from both healthy-blood donors and RR-MSpatients, and MDDCmaturation was induced with a proinflammatory cytokine cocktail in the absence or presence of 1α,25-dihydroxyvitamin-D(3) , a tolerogenicity-inducing agent. tolDCs were generated from monocytes of RR-MSpatients as efficiently as from monocytes of healthy subjects. The RR-MStolDCs expressed a stable semimature phenotype and an antiinflammatory profile as compared with untreated MDDCs. Importantly, myelin peptide-loaded tolDCs induced stable antigen-specific hyporesponsiveness in myelin-reactive T cells from RR-MS patients. These results suggest that myelin peptide-loaded tolDCs may be a powerful tool for inducing myelin-specific tolerance in RR-MS patients.     

Lung Sarcoidosis Induced by TNF Antagonists in Rheumatoid Arthritis: A Case Presentation and a Literature Review

We report the case of a 72 year-old woman with established rheumatoid arthritis diagnosed with pulmonary granulomatosis compatible with sarcoidosis after 49 months of treatment with etanercept. The symptoms and radiology remitted after the suspension of treatment against tumor necrosis factor (TNF) and with a course of steroids. To date, 27 cases of histologically-proven pulmonary sarcoidosis have been reported in relation to anti-TNF therapy, with etanercept being more frequent in comparison with the anti-TNF monoclonal antibodies infliximab and adalimumab. Probable pathogenic mechanisms of the paradoxical effect of anti-TNF treatment are discussed. It is important for clinicians to be aware of this potential and uncommon complication of biological therapy with TNF antagonists.     

Differences in radiological patterns, tumour characteristics and diagnostic precision between digital mammography and screen-film mammography in four breast cancer screening programmes in Spain

Objectives

To compare tumour characteristics between cancers detected with screen-film mammography (SFM) and digital mammography (DM) and to evaluate changes in positive predictive values (PPVs) for further assessments, for invasive procedures and for distinct radiological patterns in recalled women.

Methods

242,838 screening mammograms (171,191 SFM and 71,647 DM) from 103,613 women aged 45–69 years, performed in four population-based breast cancer screening programmes in Spain, were included. The tumour characteristics and PPVs of each group were compared. Radiological patterns (masses, calcifications, distortions and asymmetries) among recalled women were described and PPVs were evaluated.

Results

The percentages of ductal carcinoma in situ (DCIS) were higher in DM than in SFM both in the first [18.5% vs. 15.8%(p?=?0.580)] and in successive screenings [23.2% vs. 15.7%(p?=?0.115)]. PPVs for masses, asymmetries and calcifications were higher in DM, being statistically significant in masses (5.3% vs. 3.9%; proportion ratio: 1.37 95%CI: 1.08–1.72). Among cancers detected by calcifications, the percentage of DCIS was higher in DM (60.3% vs. 46.4%, p?=?0.060).

Conclusions

PPVs were higher when DM was used, both for further assessments and for invasive procedures, with similar cancer detection rates and no statistically significant differences in tumour characteristics. The greatest improvements in PPVs were found for masses.     

The D category VI type 4 allele is prevalent in the Spanish population

BACKGROUND: The D category VI (DVI) is one of the clinically most important partial D. Three different molecular structures causing the DVI phenotype have been described. STUDY DESIGN AND METHODS: To determine the molecular basis of the DVI phenotype in the Spanish population, 20 DVI samples, previously detected in serologic screening, were examined by polymerase chain reaction with RHD exon-specific primers. Unexpected findings were further pursued by cDNA nucleotide sequencing. RESULTS: A novel pattern of RHD exon amplification was detected, which did not correspond to any of the previously described molecular structures. The cDNA sequence led to the identification of the new hybrid RHD-Ce(3-5)-D allele. The origin of exon 2 is undeterminable, because the 5' breakpoint was located within a region of RHD and RHCE identical sequence, which encompasses this exon. Sequencing of intron 5 allowed the 3' breakpoint to be mapped between the sixth and seventh polymorphic sites. Serologically, the hybrid protein has a D epitope expression pattern identical to the previously described DVI phenotypes and an antigen density slightly lower than DVI type 3. The new DVI variant is linked to the DCe haplotype and expresses the low-incidence BARC antigen. CONCLUSION: A novel structure causing the DVI phenotype, here named DVI type 4, has been characterized. This novel structure is the most frequent cause of DVI in Spain.     

The Influence of Medical Student Gender and Drug Use on the Detection of Addiction in Patients

Little is known about medical students’ interest in their training on drug addiction, their personal experience of consumption, and whether these aspects influence the detection of addiction in patients. Eighty-eight and one half percent considered that drug dependence issues are important to their professional future. The students report consuming alcohol (69%), cigarettes (19.5%), and illegal drugs (15.8%). Female students consumed fewer illegal drugs than the men (p =.022). Male students consumed more illegal drugs more frequently (p =.005), knew more consumers (p =.023), and those who drink alcohol consumed more illegal drugs than women who drink alcohol (p <.005). Drug and alcohol consumption among medical students may serve to normalize consumption and thus, may prevent the detection of addicts. It is important to educate and raise awareness about drugs and alcohol use, as this may influence detection. The focus should be particularly on the male group.