A T cell gene expression panel for the diagnosis and monitoring of disease activity in patients with systemic lupus erythematosus.

Systemic Lupus Erythematosus (SLE) remains a challenging disease to diagnose and follow, as no reliable biomarkers are known to date. We designed a gene expression panel with 40 genes known to play a role in SLE pathogenesis. We found that the combined expression of these genes in SLE T cells can accurately differentiate SLE from healthy individuals and patients with other autoimmune diseases. The accuracy of the test increased further (83%) when only three out of the initial genes (OAS2, CD70 and IL10) were used. A T cell score, calculated from the combined expression levels of these genes, correlated positively with various SLE activity markers in a cross-sectional cohort and in a few patients that were followed prospectively. These data showcase the usefulness of measuring mRNA levels of key molecules in diagnosing and following patients with SLE.

Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer.

Resistance to platinum-based chemotherapy develops in the majority of patients with epithelial ovarian cancer (EOC). Platinum compounds form electrophilic intermediates that mediate DNA cross-linking and induce double-strand DNA breaks. Because the cellular response to electrophilic xenobiotics is partly mediated by Keap1-Nrf2 pathway, we evaluated the presence of Kelch-like ECH-associated protein 1 (Keap1) mutations and NF-E2-related factor 2 (Nrf2) pathway activation in EOC and correlated these with platinum resistance and clinical outcome. Nrf2 immunohistochemistry revealed nuclear localization (a surrogate of pathway activation) in over half of EOC patient specimens examined, with more common occurrence in the clear cell EOC subtype. Quantitative real-time PCR revealed that Nrf2 target genes were upregulated in tumors with nuclear positivity for Nrf2. Microarray analysis also showed upregulation of Nrf2 target genes in clear cell EOCs compared with other EOC subtypes. In addition, Keap1 sequence analysis revealed genetic mutations in 29% of clear cell samples and 8% of nonclear cell tumors. RNAi-mediated knockdown of Keap1 was associated with Nrf2 pathway activation and resistance to carboplatin in vitro. Importantly, patients with evidence of Nrf2 pathway activation had fewer complete clinical responses to platinum-based therapy, were enriched for platinum resistance, and had shorter median overall survival compared with those who did not show evidence of Nrf2 pathway activation. Our findings identify Keap1 mutations in EOC and they suggest a previously unrecognized role for the Keap1-Nrf2 pathway in mediating chemotherapeutic responses in this disease.

Therapeutic options for Burkholderia cepacia infections beyond co-trimoxazole: a systematic review of the clinical evidence.

Burkholderia cepacia complex (BCC) is an important group of pathogens affecting patients with cystic fibrosis and chronic granulomatous disease as well as immunocompromised and hospitalised patients. Therapeutic options are limited owing to high levels of resistance of the organism, either intrinsic or acquired, to many antimicrobial agents. Co-trimoxazole (trimethoprim/sulfamethoxazole) has been a drug of choice. However, in some cases it cannot be administered because of allergic or hypersensitivity reactions, intolerance or resistance. We systematically searched for relevant publications including clinical data in PubMed and Scopus. The search identified 48 relevant case reports (57 cases) and 8 cohort studies or trials. Nineteen (33.3%) of 57 patients included in the case reports received ceftazidime-based regimens, 14 (73.7%) of whom were cured. Meropenem was administered in seven patients (12.3%), one (14.3%) of whom improved and five (71.4%) were cured. Seven (12.3%) of 57 cases were treated with penicillins, four of which were piperacillin (all had a favourable outcome). Based on the data reported in the eight relevant cohort studies or trials identified, favourable outcomes were observed in 68.4% (26/38) to 100% (16/16) of cases treated with ceftazidime and 66.7% (6/9) of cases treated with meropenem. Also, 9/12 (75%) of patients receiving penicillins improved. Thus, Ceftazidime, meropenem and penicillins, mainly piperacillin, either alone or in combination with other antimicrobial agents, may be considered as alternative options for BCC infections, according to the in vitro antimicrobial susceptibility patterns and clinical results. However, the available clinical data are not sufficient and further clinical experience is required to clarify the appropriateness of these antibiotics for BCC infections.