Genetic diversity and population structure of Mycobacterium tuberculosis in HIV-1-infected compared with uninfected individuals in Burkina Faso

HIV-1 infection and HIV-1-induced immune deficiency may play a role in selecting particular Mycobacterium tuberculosis (MTB) strains (i.e. genotypes). We compared 43 MTB isolates obtained from HIV-1-infected patients with 77 MTB isolates obtained from HIV-1-uninfected patients in Burkina Faso, by means of DNA fingerprinting methods (MIRU-VNTR plus spoligotyping). This study suggests a lack of structure of the MTB population caused by HIV-1 infection and a similar genetic diversity of MTB in HIV-1-infected compared with uninfected individuals.     

Acute Respiratory Failure Involving an R Variant of Mycobacterium abscessus

We report the case of a cystic fibrosis patient colonized with a smooth-morphotype form of Mycobacterium abscessus who developed acute respiratory failure with the emergence of an isogenic rough (R) variant while he was recovering from peritonitis-induced shock. This report emphasizes the role of R forms in severe M. abscessus infections.     

Protein expression, survival and docetaxel benefit in node-positive breast cancer treated with adjuvant chemotherapy in the FNCLCC - PACS 01 randomized trial

Introduction

The PACS01 trial has demonstrated that a docetaxel addition to adjuvant anthracycline-based chemotherapy improves disease-free survival (DFS) and overall survival of node-positive early breast cancer (EBC). We searched for prognostic and predictive markers for docetaxel's benefit.

Methods

Tumor samples from 1,099 recruited women were analyzed for the expression of 34 selected proteins using immunohistochemistry. The prognostic and predictive values of each marker and four molecular subtypes (luminal A, luminal B, HER2-overexpressing, and triple-negative) were tested.

Results

Progesterone receptor-negativity (HR = 0.66; 95% CI 0.47 to 0.92, P = 0.013), and Ki67-positivity (HR = 1.53; 95% CI 1.12 to 2.08, P = 0.007) were independent adverse prognostic factors. Out of the 34 proteins, only Ki67-positivity was associated with DFS improvement with docetaxel addition (adjusted HR = 0.51, 95% CI 0.33 to 0.79 for Ki67-positive versus HR = 1.10, 95% CI 0.75 to 1.61 for Ki67-negative tumors, P for interaction = 0.012). Molecular subtyping predicted the docetaxel benefit, but without providing additional information to Ki67 status. The luminal A subtype did not benefit from docetaxel (HR = 1.16, 95% CI 0.73 to 1.84); the reduction in the relapse risk was 53% (HR = 0.47, 95% CI 0.22 to 1.01), 34% (HR = 0.66, 95% CI 0.37 to 1.19), and 12% (HR = 0.88, 95% CI 0.49 to 1.57) in the luminal B, HER2-overexpressing, and triple-negative subtypes, respectively.

Conclusions

In patients with node-positive EBC receiving adjuvant anthracycline-based chemotherapy, the most powerful predictor of docetaxel benefit is Ki67-positivity.     

DNA polymerase θ up-regulation is associated with poor survival in breast cancer,perturbs DNA replication,and promotes genetic instability

“Replicative stress” is one of the main factors underlying neoplasia from its early stages. Genes involved in DNA synthesis may therefore represent an underexplored source of potential prognostic markers for cancer. To this aim, we generated gene expression profiles from two independent cohorts (France, n = 206; United Kingdom, n = 117) of patients with previously untreated primary breast cancers. We report here that among the 13 human nuclear DNA polymerase genes, DNA Polymerase θ (POLQ) is the only one significantly up-regulated in breast cancer compared with normal breast tissues. Importantly, POLQ up-regulation significantly correlates with poor clinical outcome (4.3-fold increased risk of death in patients with high POLQ expression), and this correlation is independent of Cyclin E expression or the number of positive nodes, which are currently considered as markers for poor outcome. POLQ expression provides thus an additional indicator for the survival outcome of patients with high Cyclin E tumor expression or high number of positive lymph nodes. Furthermore, to decipher the molecular consequences of POLQ up-regulation in breast cancer, we generated human MRC5-SV cell lines that stably overexpress POLQ. Strong POLQ expression was directly associated with defective DNA replication fork progression and chromosomal damage. Therefore, POLQ overexpression may be a promising genetic instability and prognostic marker for breast cancer.     

Chronic active gastritis in X-linked lymphoproliferative disease

Gastric lesions in primary constitutive immune deficiencies include multifocal atrophic gastritis, erosive pangastritis, and a pattern of gastric lesions reminiscent of graft-versus-host disease. We describe the genetic anomalies in 2 monozygotic twins with an X-linked lymphoproliferative disease (XLP; MIM 308240), a rare familial setting of high susceptibility to Epstein-Barr virus (EBV). Since early childhood, both twin brothers exhibited a severe chronic active atrophic pangastritis. A germline screening of the SH2D1A (MIM 300490) and BIRC4 (MIM 300079) genes was performed, and also a high-resolution whole-genome SNP profiling (Infinium Sentrix Human-1 Genotyping BeadChip, Illumina). A 3 Megabase deletion in the Xq25 region, encompassing the SH2D1A gene, was defined by SNP array genotyping. Histologic analysis of yearly or twice yearly gastric biopsies in both children showed a Helicobacter pylori-negative, Epstein-Barr virus-negative chronic active atrophic pangastritis, with superficial ulcer formation, foveolar hyperplasia, glandular dilatation and ultimately pseudopyloric and intestinal metaplasia. No such chronic active inflammatory gastric lesions have been reported to date in XLP. The similarities between XLP and common variable immunodeficiency (MIM 240500) underscore the need for early recognition and close monitoring of these gastric lesions, with special regard to their neoplastic potential. No infectious cause was determined. We favor a dysimmune mechanism in the development of this chronic atrophic gastritis, presenting a striking similarity to the recently described atrophic autoimmune pangastritis.     

Chondroid cystic malformation of the lung with trisomy 8 mosaicism: a new cystic lung malformation

Neonatal cystic disorders of the lungs are a heterogeneous malformative group including giant lobar hyperinflation, congenital pulmonary airway malformations, intralobar pulmonary sequestration, and bronchogenic cyst. Here, we describe a giant cystic pulmonary malformation in a 5-year-old girl, morphologically characterized by a highly disorganized proliferation of numerous cartilage islands, abundant mesenchymal tissue with abundant adipose differentiation, and epithelium-lined cysts. Cytogenetic analysis revealed an isolated trisomy 8, as the sole karyotype anomaly, a finding further confirmed by a whole-genome single nucleotide polymorphism array genotyping. The trisomy 8 was observed by fluorescent in situ hybridization within the malformation, and also in adjacent pulmonary parenchyma. A search of the literature revealed only 2 cases having similarities with the present case, but bearing different names. We believe that this lesion differs from congenital pulmonary airway malformations and from adult-type pulmonary hamartomas. We propose for this malformative mass the name "chondroid cystic malformation of the lung."