High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines.

Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression.

Stressful life events produce a state of vulnerability to depression in some individuals. The mechanisms that contribute to vulnerability to depression remain poorly understood. A rat model of intense stress (social defeat (SD), first hit) produced vulnerability to depression in 40% of animals. Only vulnerable animals developed a depression-like phenotype after a second stressful hit (chronic mild stress). We found that this vulnerability to depression resulted from a persistent state of oxidative stress, which was reversed by treatment with antioxidants. This persistent state of oxidative stress was due to low brain-derived neurotrophic factor (BDNF) levels, which characterized the vulnerable animals. We found that BDNF constitutively controlled the nuclear translocation of the master redox-sensitive transcription factor Nrf2, which activates antioxidant defenses. Low BDNF levels in vulnerable animals prevented Nrf2 translocation and consequently prevented the activation of detoxifying/antioxidant enzymes, ultimately resulting in the generation of sustained oxidative stress. Activating Nrf2 translocation restored redox homeostasis and reversed vulnerability to depression. This mechanism was confirmed in Nrf2-null mice. The mice displayed high levels of oxidative stress and were inherently vulnerable to depression, but this phenotype was reversed by treatment with antioxidants. Our data reveal a novel role for BDNF in controlling redox homeostasis and provide a mechanistic explanation for post-stress vulnerability to depression while suggesting ways to reverse it. Because numerous enzymatic reactions produce reactive oxygen species that must then be cleared, the finding that BDNF controls endogenous redox homeostasis opens new avenues for investigation

Women’s responses to changes in U.S. preventive task force’s mammography screening guidelines: results of focus groups with ethnically diverse women

Background: The 2009 U.S. Preventive Services Task Force (USPSTF) changed mammography guidelines to recommend routine biennial screening starting at age 50. This study describes women’s awareness of, attitudes toward, and intention to comply with these new guidelines. Methods: Women ages 40–50 years old were recruited from the Boston area to participate in focus groups (k = 8; n = 77). Groups were segmented by race/ethnicity (Caucasian = 39%; African American = 35%; Latina = 26%), audio-taped, and transcribed. Thematic content analysis was used. Results: Participants were largely unaware of the revised guidelines and suspicious that it was a cost-savings measure by insurers and/or providers. Most did not intend to comply with the change, viewing screening as obligatory. Few felt prepared to participate in shared decision-making or advocate for their preferences with respect to screening. Conclusions: Communication about the rationale for mammography guideline changes has left many women unconvinced about potential disadvantages or limitations of screening. Since further guideline changes are likely to occur with advances in technology and science, it is important to help women become informed consumers of health information and active participants in shared decision-making with providers. Additional research is needed to determine the impact of the USPSTF change on women’s screening behaviors and on breast cancer outcomes

Does minimally invasive lumbar disc surgery result in less muscle injury than conventional surgery? A randomized controlled trial

The concept of minimally invasive lumbar disc surgery comprises reduced muscle injury. The aim of this study was to evaluate creatine phosphokinase (CPK) in serum and the cross-sectional area (CSA) of the multifidus muscle on magnetic resonance imaging as indicators of muscle injury. We present the results of a double-blind randomized trial on patients with lumbar disc herniation, in which tubular discectomy and conventional microdiscectomy were compared. In 216 patients, CPK was measured before surgery and at day 1 after surgery. In 140 patients, the CSA of the multifidus muscle was measured at the affected disc level before surgery and at 1 year after surgery. The ratios (i.e. post surgery/pre surgery) of CPK and CSA were used as outcome measures. The multifidus atrophy was classified into three grades ranging from 0 (normal) to 3 (severe atrophy), and the difference between post and pre surgery was used as an outcome. Patients’ low-back pain scores on the visual analogue scale (VAS) were documented before surgery and at various moments during follow-up. Tubular discectomy compared with conventional microdiscectomy resulted in a nonsignificant difference in CPK ratio, although the CSA ratio was significantly lower in tubular discectomy. At 1 year, there was no difference in atrophy grade between both groups nor in the percentage of patients showing an increased atrophy grade (14% tubular vs. 18% conventional). The postoperative low-back pain scores on the VAS improved in both groups, although the 1-year between-group mean difference of improvement was 3.5 mm (95% CI; 1.4–5.7 mm) in favour of conventional microdiscectomy. In conclusion, tubular discectomy compared with conventional microdiscectomy did not result in reduced muscle injury. Postoperative evaluation of CPK and the multifidus muscle showed similar results in both groups, although patients who underwent tubular discectomy reported more low-back pain during the first year after surgery

Mini-open anterior spine surgery for anterior lumbar diseases

Minimally invasive surgeries including endoscopic surgery and mini-open surgery are current trend of spine surgery, and its main advantages are shorter recovery time and cosmetic benefits, etc. However, mini-open surgery is easier and less technique demanding than endoscopic surgery. Besides, anterior spinal fusion is better than posterior spinal fusion while considering the physiological loading, back muscle function, etc. Therefore, we aimed to introduce the modified “mini-open anterior spine surgery” (MOASS) and to evaluate the feasibility, effectiveness and safety in the treatment of various anterior lumbar diseases with this technique. A total of 61 consecutive patients (46 female, 15 male; mean age 58.2 years) from 1997 to 2004 were included in this study, with an average follow-up of 24–52 (mean 43) months. The disease entities included vertebral fracture (20), failed back surgery (13), segmental instability or spondylolisthesis (10), infection (8), herniated disc (5), undetermined lesion for biopsy (4), and hemivertebra (1). Lesions involved 13 cases at T12–L1, 18 at L1–L2, 18 at L2–L3, 22 at L3–L4 and 11 at L4–L5 levels. All patients received a single stage anterior-only procedure for their anterior lumbar disease. We used the subjective clinical results, Oswestry disability index, fusion rate, and complications to evaluate our clinical outcome. Most patients (91.8%) were subjectively satisfied with the surgery and had good-to-excellent outcomes. Mean operation time was 85 (62–124) minutes, and mean blood loss was 136 (minimal-250) ml in the past 6 years. Hospital stay ranged from 4–26 (mean 10.6) days. Nearly all cases had improved back pain (87%), physical function (90%) and life quality (85%). Most cases (95%) achieved solid or probable solid bony fusion. There were no major complications. Therefore, MOASS is feasible, effective and safe for patients with various anterior lumbar diseases

Cost-effectiveness of microendoscopic discectomy versus conventional open discectomy in the treatment of lumbar disc herniation: a prospective randomised controlled trial [ISRCTN51857546]

BACKGROUND: Open discectomy is the standard surgical procedure in the treatment of patients with long-lasting sciatica caused by lumbar disc herniation. Minimally invasive approaches such as microendoscopic discectomy have gained attention in recent years. Reduced tissue trauma allows early ambulation, short hospital stay and quick resumption of daily activities. A comparative cost-effectiveness study has not been performed yet. We present the design of a randomised controlled trial on cost-effectiveness of microendoscopic discectomy versus conventional open discectomy in patients with lumbar disc herniation. METHODS/DESIGN: Patients (age 18–70 years) presenting with sciatica due to lumbar disc herniation lasting more than 6–8 weeks are included. Patients with disc herniation larger than 1/3 of the spinal canal diameter, or disc herniation less than 1/3 of the spinal canal diameter with concomitant lateral recess stenosis or sequestration, are eliglible for participation. Randomisation into microendoscopic discectomy or conventional unilateral transflaval discectomy will take place in the operating room after induction of anesthesia. The length of skin incision is equal in both groups. The primary outcome measure is the functional assessment of the patient, measured by the Roland Disability Questionnaire for Sciatica, at 8 weeks and 1 year after surgery. We will also evaluate several other outcome parameters, including perceived recovery, leg and back pain, incidence of re-operations, complications, serum creatine kinase, quality of life, medical consumption, absenteeism and costs. The study is a randomised prospective multi-institutional trial, in which two surgical techniques are compared in a parallel group design. Patients and research nurses are kept blinded of the allocated treatment during the follow-up period of 2 years. DISCUSSION: Currently, open discectomy is the golden standard in the surgical treatment of lumbar disc herniation. Whether microendoscopic discectomy is more cost-effective than unilateral transflaval discectomy has to be determined by this trial