An unusual presentation of primary male genital tuberculosis

Urogenital tuberculosis is a rare disease; however, it is the second most common location for tuberculosis after the lung. Currently, incidence of urogenital tuberculosis is increasing due to factors such as a higher prevalence of immunosuppression (especially that caused by human immunodeficiency virus infection) and drug abuse. Herein a new case of male genital primary tuberculosis is reported presenting as a scrotal tumor; the originality of this observation lies in its unusual pseudotumor form.     

Customized Treatment in Non-Small-Cell Lung Cancer Based on EGFR Mutations and BRCA1 mRNA Expression

Background

Median survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels.

Methodology/Principal Findings

We treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1–1.7]; P = 0.05).

Conclusions/Significance

Chemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00883480","term_id":"NCT00883480"}}NCT00883480     

Plasma membrane targeting of podocin through the classical exocytic pathway: effect of NPHS2 mutations

Podocytes are specialized epithelial cells of the glomerulus in the kidney, which interconnect at the top of the glomerular basement membrane through the slit diaphragm, an adherens-like junction that plays a crucial role in the glomerular filtration process. Podocin, a plasma membrane anchored stomatin-like protein, is expressed in lipid rafts at the insertion of the slit diaphragm in podocytes. Mutations in NPHS2 , the gene encoding podocin, are associated with inherited and sporadic cases of steroid-resistant nephrotic syndrome. Here, we show that brefeldin A induces accumulation of newly synthesized podocin in the endoplasmic reticulum, suggesting that podocin biosynthesis follows the classical secretory pathway, and we study the effect of 12 NPHS2 mutations associated with steroid-resistant nephrotic syndrome on the trafficking of the protein. We found that 9 podocin mutants were not targeted to the plasma membrane, 8 being retained in the endoplasmic reticulum and one being localized in late endosomes. Furthermore, by screening our database of patients with NPHS2 mutations, we found that podocin mutants retained in the endoplasmic reticulum are associated with earlier onset of the disease than those correctly targeted to the cell membrane. Our data suggest that most of NPHS2 mutations lead to retention of podocin in the endoplasmic reticulum and therefore provide a rationale for devising therapeutic approaches aimed at correcting the protein processing defect.     

Enhancing white lupin (Lupinus albus L.) adaptation to calcareous soils through selection of lime-tolerant plant germplasm and Bradyrhizobium strains

Aims

This study aimed to determine whether white lupin adaptation to moderately calcareous soils could be enhanced by lime-tolerant plants and Bradyrhizobium strains.

Methods

Fourteen landraces from Italy, Morocco and Egypt and some cultivars were grown in moderate-lime (ML) and low-lime (LL) soil with each of two inoculants, one commercial and one including three Bradyrhizobium strains well-nodulating under ML soil (isolated from other lupin species). Grain yield and above-ground biomass were assessed in large artificial environments that mimicked field conditions. Shoot, root and nodulation traits at onset of flowering were studied in a pot experiment.

Results

ML soil severely reduced plant yield, growth and nodulation but increased the harvest index relative to LL. Top-yielding genotypes for grain yield displayed significant rank inversion across soil types (P < 0.05). Lime-tolerant genotypes reduced their nodulation in ML soil less than limesusceptible ones. Some landraces outperformed the reference lime-tolerant cultivar Giza 1 in ML soil. One Italian landrace had a lime-tolerant response across agricultural locations. The Moroccan inoculant provided greater nodulation, more shoot residues but similar grain yield in ML soil, and less grain and shoot residues in LL soil, compared with the commercial inoculant.

Conclusions

Lupin adaptation to ML soil can be improved mainly through selection of lime-tolerant plants.     

hSMUG1 can functionally compensate for Ung1 in the yeast Saccharomyces cerevisiae

There are at least four distinct families of enzymes that recognize and remove uracil from DNA. Family-3 (SMUG1) enzymes have recently been identified and have a preference for uracil in single-stranded DNA when assayed in vitro. Here we investigate the in vivo function of SMUG1 using the yeast Saccharomyces cerevisiae as a model system. These organisms lack a SMUG1 homologue and use a single enzyme, Ung1 to carry out uracil-repair. When a wild-type strain is treated with antifolate agents to induce uracil misincorporation into DNA, S-phase arrest and cellular toxicity occurs. The arrest is characteristic of checkpoint activation due to single-strand breaks caused by continuous uracil removal and self-defeating DNA repair. When uracil-DNA glycosylase is deleted (deltaung1), cells continue through S-phase and arrest at G(2)/M, presumably due to the effects of stable uracil misincorporation in DNA. Pulsed field gel electrophoresis (PFGE) demonstrates that cells are able to complete DNA replication with uracil-substituted DNA and do not experience the extensive strand breakage attributed to uracil-DNA glycosylase-mediated repair. As a result, these cells experience early protection from antifolate-induced cytotoxicity. When either UNG1 or SMUG1 functions are reintroduced back into the null strain and then subjected to antifolate treatment, the cells revert back to the wild-type phenotype as shown by a restored sensitivity to drug and S-phase arrest. The arrest is accompanied by the accumulation of replication intermediates as determined by PFGE. Collectively, these data indicate that SMUG1 can act as a functional homolog of the family-1 uracil-DNA glycosylase enzymes.     

Conservation and multivariate analysis utility in characterization of ecogegraphical relationships of Trifolium and Lotus species

The maintenance of species in an environment and the durability of rangeland and fallow improvement depend on the choice of populations used. The study of abundance and the relationship between the natural distribution of spontaneous legumes species of forage and/or pastoral interest and environmental factors is an important step for an adequate utilization of local genetic resources. Collection of annual Trifolium species and the genus of Lotus were conducted at 45 sites in Morocco in May/June 2004. Ecogeographical information was recorded at each site. Twelve species of annual Trifolium and two species of Lotus were identified. Most prolific were T. tomentosum and L. corniculatus. A principal components analysis and canonical variate analysis were conducted to group the sites, using the ecogeographical variables collected at each site. The variables that were found to be most important in grouping the sites were mean coldest month temperature, mean hottest month temperature, mean annual rainfall, latitude, longitude and soil pH. None of the species identified were limited to only one ecogeographical group.