DNA repair: from genome maintenance to biomarker and therapeutic target

A critical link exists between an individual's ability to repair cellular DNA damage and cancer development, progression, and response to therapy. Knowledge gained about the proteins involved and types of damage repaired by the individual DNA repair pathways has led to the development of a variety of assays aimed at determining an individual's DNA repair capacity. These assays and their use in the analysis of clinical samples have yielded useful though somewhat conflicting data. In this review article, we discuss the major DNA repair pathways, the proteins and genes required for each, assays used to analyze activity, and the relevant clinical studies to date. With the recent results from clinical trials targeting specific DNA repair proteins for the treatment of cancer, accurate, reproducible, and relevant analysis of DNA repair takes on an even greater significance. We highlight the strengths and limitations of these DNA repair studies and assays, with respect to the clinical assessment of DNA repair capacity to determine cancer development and response to therapy.     

Pindborg's tumor: a propos of a case

The calcifying epithelial odontogenic tumor was first described as an entity by Danish pathologist Jens Pindborg in 1955. It is an uncommon and locally invasive benign odontogenic tumor. The most characteristic findings are the presence of amyloid-like substance and calcified concentric liesegang rings.     

Euchromatic 16p+ heteromorphism: first report in North America

A heteromorphism of the short arm of 16 (16p+) was discovered in 2 unrelated infants. By G banding, the euchromatic variant appears as a light and a medium dark band just distal to the centromere. This results in an increase of the short arm by about 1/3. The same variant was present in the normal father and the normal paternal grandmother in one family and mildly retarded mother in the 2nd family. The anomalies of the 2 infants are not similar and are apparently unrelated to the 16p+ variant. Though the discovery of such euchromatic variants is highly significant for clinical diagnosis, their genetic significance and mode of origin remain to be elucidated.     

A multiple-micronutrient-fortified beverage affects hemoglobin, iron, and vitamin A status and growth in adolescent girls in rural Bangladesh

Adolescent girls have high nutrient needs and are susceptible to micronutrient deficiencies. The objective of this study was to test the effect of a multiple-micronutrient-fortified beverage on hemoglobin (Hb) concentrations, micronutrient status, and growth among adolescent girls in rural Bangladesh. A total of 1125 girls (Hb > or = 70 g/L) enrolled in a randomized, double-blind, placebo-controlled trial and were allocated to either a fortified or nonfortified beverage of similar taste and appearance. The beverage was provided at schools 6 d/wk for 12 mo. Concentrations of Hb and serum ferritin (sFt), retinol, zinc, and C-reactive protein were measured in venous blood samples at baseline, 6 mo, and 12 mo. In addition, weight, height, and mid-upper arm circumference (MUAC) measurements were taken. The fortified beverage increased the Hb and sFt and retinol concentrations at 6 mo (P < 0.01). Adolescent girls in the nonfortified beverage group were more likely to suffer from anemia (Hb <120 g/L), iron deficiency (sFt <12 microg/L), and low serum retinol concentrations (serum retinol <0.70 micromol/L) (OR = 2.04, 5.38, and 5.47, respectively; P < 0.01). The fortified beverage group had greater increases in weight, MUAC, and BMI over 6 mo (P < 0.01). Consuming the beverage for an additional 6 mo did not further improve the Hb concentration, but the sFt level continued to increase (P = 0.01). The use of multiple-micronutrient-fortified beverage can contribute to the reduction of anemia and improvement of micronutrient status and growth in adolescent girls in rural Bangladesh.     

Absence of Mycobacterium tuberculosis DNA in synovial fluid from patients with rheumatoid arthritis.

OBJECTIVES--To determine whether Mycobacterium tuberculosis DNA can be detected in synovial fluid of patients with rheumatoid arthritis (RA). METHODS--The polymerase chain reaction was applied to cellular components of synovial fluid. RESULTS--No evidence of M tuberculosis DNA was found in synovial fluid from 31 patients with RA and 13 control patients. CONCLUSION--The findings do not support a role for persistent M tuberculosis infection in the pathogenesis of RA.     

Consistency of the beneficial effect of metoprolol succinate extended release across a wide range dose of angiotensin-converting enzyme inhibitors and digitalis

BACKGROUND: The effects of beta-blockade with different extent of angiotensin-converting enzyme inhibitors (ACEI) and digitalization are unknown. To assess the effect of metoprolol succinate controlled release/extended release (CR/XL) combined with high versus low doses of ACEI and digitalis, we analyzed data from The Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) in which patients with heart failure and left ventricular ejection fraction < or =40% were randomized to metoprolol CR/XL versus placebo. METHODS AND RESULTS: Outcome was analyzed separately for those on a low dose (< or =median) of the ACEI or digitalis versus high dose (> median). The mean dose of ACEI in the high-dose group (n = 1457) was 3 times higher than that in the low-dose group (n = 2094). Mortality was reduced to a similar extent in the high- and low-dose ACEI subgroups (RR = .69 versus .64, respectively). Corresponding figures for combined mortality/all hospitalization and for mortality/hospitalization for heart failure were .85 versus .83, and .70 versus .68, respectively. Likewise, reduction in total mortality with metoprolol CR/XL was similar in patients receiving no digitalis (n = 1447; RR = .56), low dose (n = 1122; RR = .71), or high dose (n = 1421; RR = .71). CONCLUSION: This analysis of MERIT-HF demonstrates consistent and similar improvement in outcome of patients receiving metoprolol CR/XL when combined with either a high or low dose of an ACEI or digitalis, or no digitalis at all. Thus regardless of ACEI and digitalis dose and whether patients are treated with digitalis or not, it is very important to add a beta-blocker to the existing heart failure therapy. beta-blockers should not be withheld until target doses of ACEI have been achieved.     

Adjuvant Epidermal Growth Factor Receptor Inhibitors in Non‐Small Cell Lung Cancer

Nonrandomized studies have suggested a potential benefit with use of an EGFR tyrosine kinase inhibitor in the adjuvant setting in patients with EGFR-mutated non-small cell lung cancer. These nonrandomized studies cannot substitute for well-conducted, adequately powered, prospectively randomized phase III trials. Such trials are under way, and their results are eagerly anticipated.The optimal initial treatment for patients with stage I–II non-small cell lung cancer (NSCLC) is surgical resection [1]. In the appropriate setting, patients with stage IIIA NSCLC may also be offered surgical resection following neoadjuvant chemotherapy with or without radiotherapy [2]. Adjuvant chemotherapy with a cisplatin-based regimen can be recommended for selected patients with stage IB disease with high-risk features as well as for patients with stages II–IIIA [3, 4]. Adjuvant chemotherapy improves the 5-year survival rate by approximately 4% [5]. Cisplatin may be combined with vinorelbine, vinblastine, etoposide, gemcitabine, pemetrexed, or docetaxel [6–8]. The LACE collaborative group’s analysis concluded that multiple different chemotherapy regimens with cisplatin are equally effective. Unfortunately, despite the advances in the management of stage I–III NSCLC, the 5-year survival of these patients still remains inferior compared with other early stage solid malignancies.In the past decade, targeted therapy has transformed treatment for a subset of patients with advanced NSCLC harboring mutations or translocations that mediate sensitivity to targeted treatments. The best described of these are EGFR mutations and ALK or ROS1 translocations. EGFR inhibitors such as erlotinib, gefitinib, and afatinib target the tyrosine kinase domain of the EGFR receptor. Sensitizing EGFR mutations that predict response to these tyrosine kinase inhibitors (TKIs) include in-frame deletions in exon 19 and L858R substitution in exon 21 [9–11]. EGFR inhibitors have been shown to improve progression-free survival and response rates in patients with advanced stage NSCLC with sensitizing EGFR mutations in the first-line setting compared with platinum-based chemotherapy (hazard ratio [HR] 0.48 at 12 months) [12].In general, we use our most active drugs in the adjuvant setting. Because EGFR and ALK inhibitors are more active than chemotherapy in patients with targetable mutations, it would be rational to test EGFR TKIs or ALK inhibitors in patients with resected tumors that harbor EGFR-activating mutations or ALK gene rearrangements, respectively. The possibility of targeted agents improving cure rates in the adjuvant setting is not without precedent. The use of trastuzumab in combination with chemotherapy in the adjuvant setting for early stage HER2 receptor-positive breast cancer with moderate to high risk of recurrence has improved both disease-free survival (DFS) and overall survival (OS; HR 0.63 for OS and 0.60 for DFS) [13]. Similarly, the use of imatinib in patients with completely resected gastrointestinal stromal tumors (GIST) significantly improved recurrence-free survival at 1 year compared with observation alone (HR 0.35) [14].