A target based approach identifies genomic predictors of breast cancer patient response to chemotherapy

BACKGROUND: The efficacy of chemotherapy regimens in breast cancer patients is variable and unpredictable. Whether individual patients either achieve long-term remission or suffer recurrence after therapy may be dictated by intrinsic properties of their breast tumors including genetic lesions and consequent aberrant transcriptional programs. Global gene expression profiling provides a powerful tool to identify such tumor-intrinsic transcriptional programs, whose analyses provide insight into the underlying biology of individual patient tumors. For example, multi-gene expression signatures have been identified that can predict the likelihood of disease reccurrence, and thus guide patient prognosis. Whereas such prognostic signatures are being introduced in the clinical setting, similar signatures that predict sensitivity or resistance to chemotherapy are not currently clinically available. METHODS: We used gene expression profiling to identify genes that were co-expressed with genes whose transcripts encode the protein targets of commonly used chemotherapeutic agents. RESULTS: Here, we present target based expression indices that predict breast tumor response to anthracycline and taxane based chemotherapy. Indeed, these signatures were independently predictive of chemotherapy response after adjusting for standard clinic-pathological variables such as age, grade, and estrogen receptor status in a cohort of 488 breast cancer patients treated with adriamycin and taxotere/taxol. CONCLUSIONS: Importantly, our findings suggest the practicality of developing target based indices that predict response to therapeutics, as well as highlight the possibility of using gene signatures to guide the use of chemotherapy during treatment of breast cancer patients

Early abdominal closure with mesh reduces multiple organ failure after ruptured abdominal aortic aneurysm repair: Guidelines from a 10-year case-control study

AbstractObjective: The objectives of this study were the comparison of patients who needed mesh closure of the abdomen with patients who underwent standard abdominal closure after ruptured abdominal aortic aneurysm repair and the determination of the impact of timing of mesh closure on multiple organ failure (MOF) and mortality. Methods: We performed a case-control study of patients who needed mesh-based abdominal closure (n = 45) as compared with patients who underwent primary closure (n = 90) after ruptured abdominal aortic aneurysm repair. Results: Before surgery, the patients who needed mesh abdominal closure had more blood loss (8 g versus 12 g of hemoglobin; P <.05), had prolonged hypotension (18 minutes versus 3 minutes; P <.01), and more frequently needed cardiopulmonary resuscitation (31% versus 2%; P <.01) than did the patients who underwent primary closure. During surgery, the patients who needed mesh closure also had more severe acidosis (base deficit, 14 versus 7; P <.01), had profound hypothermia (32°C versus 35°C; P <.01), and needed more fluid resuscitation (4.0 L/h versus 2.7 L/h; P <.01). With this adverse clinical profile, the patients who needed mesh closure had a higher mortality rate than did the patients who underwent primary closure (56% versus 9%; P <.01). However, the patients who underwent mesh closure at the initial operation (n = 35) had lower MOF scores (P <.05), a lower mortality rate (51% versus 70%), and were less likely to die from MOF (11% versus 70%; P <.05) than the patients who underwent mesh closure after a second operation in the postoperative period for abdominal compartment syndrome (n = 10). Conclusion: This study reports the largest experience of mesh-based abdominal closure after ruptured abdominal aortic aneurysm repair and defines clinical predictors for patients who need to undergo this technique. Recognition of these predictors and initial use of mesh closure minimize abdominal compartment syndrome and reduce the rate of mortality as the result of MOF. (J Vasc Surg 2002;35:246-53.

Inflammatory abdominal aortic aneurysms: A case-control study

AbstractPurpose: This study was designed to identify significant differences in the clinical and radiologic characteristics and outcome between patients with inflammatory and noninflammatory abdominal aortic aneurysms (AAAs).Methods: We reviewed 29 consecutive patients who underwent repair of an inflammatory AAA between 1985 and 1994. This group was matched in a case-control fashion by date of surgery and by the performing surgeon to a group of 58 patients who underwent repair of noninflammatory AAAs.Results: The two groups had comparable characteristics of age, gender, and cardiovascular risk factors. Patients with inflammatory AAAs were significantly more symptomatic than those with noninflammatory AAAs (93% vs 9%, p < 0.001), were more likely to have a family history of aneurysms (17% vs 1.5%, p = 0.007), and tended to be current smokers (45% vs 24%, p = 0.049). Thi most significant laboratory difference was an elevated sedimentation rate in patients with inflammatory AAAs (mean, 53 mm/hr vs 12 mm/hr, p < 0.00001). Inflammatory AAAs also were significantly larger than noninflammatory AAAs at presentation (6.8 cm vs 5.9 cm, p < 0.05). Although operative mortality was low in both groups, patients with an inflammatory AAA tended to have higher morbidity, including sepsis ( p < 0.01) and renal failure ( p = 0.04). Five-year survival rates, however, were similar for the two groups (79% for inflammatory and 83% for noninflammatory AAAs). On follow-up computed tomographic scans, the retroperitoneal inflammatory process resolved completely in 53% of the patients, but 47% of patients had persistent inflammation that involved the ureters in 32% and resulted in long-term solitary or bilateral renal atrophy in 47%.Conclusions: This case-control study provides preliminary evidence that inflammatory AAAs may have a relatively strong familial connection and that current smoking may play an important role in the inflammatory response. The study also documents that persistent retroperitoneal inflammation may be more prevalent than has been previously reported, and stresses the need for an improved understanding of the pathogenesis and long-term management of inflammatory AAAs. (J Vasc Surg 1996;23:860-9.

Contemporary management of acute mesenteric ischemia: Factors associated with survival

AbstractPurpose: Acute mesenteric ischemia (AMI) is a morbid condition with a difficult diagnosis and a high rate of complications, which is associated with a high mortality rate. For the evaluation of the results of current management and the examination of factors associated with survival, we reviewed our experience. Methods: The clinical data of all the patients who underwent operation for AMI between January 1, 1990, and December 31, 1999, were retrospectively reviewed, clinical outcome was recorded, and factors associated with survival rate were analyzed. Results: Fifty-eight patients (22 men and 36 women; mean age, 67 years; age range, 35 to 96 years) underwent study. The cause of AMI was embolism in 16 patients (28%), thrombosis in 37 patients (64%), and nonocclusive mesenteric ischemia (NMI) in five patients (8.6%). Abdominal pain was the most frequent presenting symptom (95%). Twenty-five patients (43%) had previous symptoms of chronic mesenteric ischemia. All the patients underwent abdominal exploration, preceded with arteriography in 47 (81%) and with endovascular treatment in eight. Open mesenteric revascularization was performed in 43 patients (bypass grafting, n = 22; thromboembolectomy, n = 19; patch angioplasty, n = 11; endarterectomy, n = 5; reimplantation, n = 2). Thirty-one patients (53%) needed bowel resection at the first operation. Twenty-three patients underwent second-look procedures, 11 patients underwent bowel resections (repeat resection, n = 9), and three patients underwent exploration only. The 30-day mortality rate was 32%. The rate was 31% in patients with embolism, 32% in patients with thrombosis, and 80% in patients with NMI. Multiorgan failure (n = 18 patients) was the most frequent cause of death. The cumulative survival rates at 90 days, at 1 year, and at 3 years were 59%, 43%, and 32%, respectively, which was lower than the rate of a Midwestern white control population (P <.001). Six of the 16 late deaths (38%) occurred because of complications of mesenteric ischemia. Age less than 60 years (P <.003) and bowel resection (P =.03) were associated with improved survival rates. Conclusion: The contemporary management of AMI with revascularization with open surgical techniques, resection of nonviable bowel, and liberal use of second-look procedures results in the early survival of two thirds of the patients with embolism and thrombosis. Older patients, those who did not undergo bowel resection, and those with NMI have the highest mortality rates. The long-term survival rate remains dismal. Timely revascularization in patients who are symptomatic with chronic mesenteric ischemia should be considered to decrease the high mortality rate of AMI. (J Vasc Surg 2002;35:445-52.

Effects of study design and allocation on participant behaviour-ESDA: study protocol for a randomized controlled trial

Background: What study participants think about the nature of a study has been hypothesised to affect subsequent behaviour and to potentially bias study findings. In this trial we examine the impact of awareness of study design and allocation on participant drinking behaviour. Methods/Design: A three-arm parallel group randomised controlled trial design will be used. All recruitment, screening, randomisation, and follow-up will be conducted on-line among university students. Participants who indicate a hazardous level of alcohol consumption will be randomly assigned to one of three groups. Group A will be informed their drinking will be assessed at baseline and again in one month (as in a cohort study design). Group B will be told the study is an intervention trial and they are in the control group. Group C will be told the study is an intervention trial and they are in the intervention group. All will receive exactly the same brief educational material to read. After one month, alcohol intake for the past 4 weeks will be assessed. Discussion: The experimental manipulations address subtle and previously unexplored ways in which participant behaviour may be unwittingly influenced by standard practice in trials. Given the necessity of relying on self-reported outcome, it will not be possible to distinguish true behaviour change from reporting artefact. This does not matter in the present study, as any effects of awareness of study design or allocation involve bias that is not well understood. There has been little research on awareness effects, and our outcomes will provide an indication of the possible value of further studies of this type and inform hypothesis generation

High Frequency Inductive Power Transfer Through Soil for Agricultural Applications

This work was supported by the UK Research and Innovation (UKRI), reference numbers: NE/ T011467/1 and NE/T011068/1, and the National Science Foundation (NSF), award no. 1935632: SitS NSF-UKRI: Wireless In-Situ Soil Sensing Network for Future Sustainable Agriculture’. (Corresponding author: Juan M. Arteaga.)Peer reviewedPublisher PD

Estimating HIV Incidence among Adults in Kenya and Uganda: A Systematic Comparison of Multiple Methods

CITATION: Kim, A. A. et al. 2011. Estimating HIV incidence among adults in Kenya and Uganda : a systematic comparison of multiple methods. PLos ONE, 6(3): e17535, doi:10.1371/journal.pone.0017535.The original publication is available at http://journals.plos.org/plosoneBackground: Several approaches have been used for measuring HIV incidence in large areas, yet each presents specific challenges in incidence estimation. Methodology/Principal Findings: We present a comparison of incidence estimates for Kenya and Uganda using multiple methods: 1) Epidemic Projections Package (EPP) and Spectrum models fitted to HIV prevalence from antenatal clinics (ANC) and national population-based surveys (NPS) in Kenya (2003, 2007) and Uganda (2004/2005); 2) a survey-derived model to infer age-specific incidence between two sequential NPS; 3) an assay-derived measurement in NPS using the BED IgG capture enzyme immunoassay, adjusted for misclassification using a locally derived false-recent rate (FRR) for the assay; (4) community cohorts in Uganda; (5) prevalence trends in young ANC attendees. EPP/Spectrum-derived and survey-derived modeled estimates were similar: 0.67 [uncertainty range: 0.60, 0.74] and 0.6 [confidence interval: (CI) 0.4, 0.9], respectively, for Uganda (2005) and 0.72 [uncertainty range: 0.70, 0.74] and 0.7 [CI 0.3, 1.1], respectively, for Kenya (2007). Using a local FRR, assay-derived incidence estimates were 0.3 [CI 0.0, 0.9] for Uganda (2004/2005) and 0.6 [CI 0, 1.3] for Kenya (2007). Incidence trends were similar for all methods for both Uganda and Kenya. Conclusions/Significance: Triangulation of methods is recommended to determine best-supported estimates of incidence to guide programs. Assay-derived incidence estimates are sensitive to the level of the assay's FRR, and uncertainty around high FRRs can significantly impact the validity of the estimate. Systematic evaluations of new and existing incidence assays are needed to the study the level, distribution, and determinants of the FRR to guide whether incidence assays can produce reliable estimates of national HIV incidence.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017535Publisher's versio

Diabetes is a Risk Factor for Pulmonary Tuberculosis: A Case-Control Study from Mwanza, Tanzania.

Diabetes and TB are associated, and diabetes is increasingly common in low-income countries where tuberculosis (TB) is highly endemic. However, the role of diabetes for TB has not been assessed in populations where HIV is prevalent. A case-control study was conducted in an urban population in Tanzania among culture-confirmed pulmonary TB patients and non-TB neighbourhood controls. Participants were tested for diabetes according to WHO guidelines and serum concentrations of acute phase reactants were measured. The association between diabetes and TB, and the role of HIV as an effect modifier, were examined using logistic regression. Since blood glucose levels increase during the acute phase response, we adjusted for elevated serum acute phase reactants. Among 803 cases and 350 controls the mean (SD) age was 34.8 (11.9) and 33.8 (12.0) years, and the prevalence of diabetes was 16.7% (95% CI: 14.2; 19.4) and 9.4% (6.6; 13.0), respectively. Diabetes was associated with TB (OR 2.2, 95% CI: 1.5; 3.4, p<0.001). However, the association depended on HIV status (interaction, p = 0.01) due to a stronger association among HIV uninfected (OR 4.2, 95% CI: 1.5; 11.6, p = 0.01) compared to HIV infected (OR 0.1, 95% CI: 0.01; 1.8, p = 0.13) after adjusting for age, sex, demographic factors and elevated serum acute phase reactants. Diabetes is a risk factor for TB in HIV uninfected, whereas the association in HIV infected patients needs further study. The increasing diabetes prevalence may be a threat to TB control

3D human liver tissue from pluripotent stem cells displays stable phenotype in vitro and supports compromised liver function in vivo.

Liver disease is an escalating global health issue. While liver transplantation is an effective mode of therapy, patient mortality has increased due to the shortage of donor organs. Developing renewable sources of human liver tissue is therefore attractive. Pluripotent stem cell-derived liver tissue represents a potential alternative to cadaver derived hepatocytes and whole organ transplant. At present, two-dimensional differentiation procedures deliver tissue lacking certain functions and long-term stability. Efforts to overcome these limiting factors have led to the building of three-dimensional (3D) cellular aggregates. Although enabling for the field, their widespread application is limited due to their reliance on variable biological components. Our studies focused on the development of 3D liver tissue under defined conditions. In vitro generated 3D tissues exhibited stable phenotype for over 1 year in culture, providing an attractive resource for long-term in vitro studies. Moreover, 3D derived tissue provided critical liver support in two animal models, including immunocompetent recipients. Therefore, we believe that our study provides stable human tissue to better model liver biology 'in the dish', and in the future may permit the support of compromised liver function in humans