Precision oncology in surgery: patient selection for operable pancreatic cancer

Objective: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection. Background: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease. Method: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram. Results: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables. Conclusions: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease

Impact of maternal ART on mother-to-child transmission (MTCT) of HIV at six weeks postpartum in Rwanda

BACKGROUND: In 2010, Rwanda adopted ART for prevention of mother to child transmission of HIV from pregnant women living with HIV during pregnancy and breasfeeding period. This study examines rates of mother-to-childtransmission of HIV at 6–10 weeks postpartum and risk factors for mother-to-child transmission of HIV (MTCT) among HIV infected women on ART during pregnancy and breastfeeding. METHODS: A cross-sectional survey study was conducted between July 2011–June 2012 among HIV-exposed infants aged 6–10 weeks and their mothers/caregivers. Stratified multi-stage, probability proportional to size and systematic sampling to select a national representative sample of clients. Consenting mothers/caregivers were interviewed on demographic and program interventions. Dry blood spots from HIV-exposed infants were collected for HIV testing using DNA PCR technique. Results are weighted for sample realization. Univariable analysis of socio-demographic and programmatic determinants of early mother-to-child transmission of HIV was conducted. Variables were retained for final multivariable models if they were either at least of marginal significance (p-value < 0.10) or played a confounding role (the variable had a noticeable impact > 10% change on the effect estimate). RESULTS: The study sample was 1639 infants with HIV test results. Twenty-six infants were diagnosed HIV-positive translating to a weighted MTCT estimate of 1.58% (95% CI 1.05–2.37%). Coverage of most elimination of MTCT (EMTCT) program interventions, was above 80, and 90.4% of mother-infant pairs received antiretroviral treatment or prophylaxis. Maternal ART and infant antiretroviral prophylaxis (OR 0.01; 95%CI 0.001–0.17) and maternal age older than 25 years were significantly protective (OR 0.33; 95%CI 0.14–0.78). No disclosure of HIV status, not testing for syphilis during pregnancy and preterm birth were significant risk factors for MTCT. Factors suggesting higher sociodemographic status (flush toilet, mother self-employed) were borderline risk factors for MTCT. CONCLUSION: ART for all women during pregnancy and breastfeeding was associated with the estimated low MTCT rate of 1.58%. Mothers who did not receive a full package of anti-retroviral therapy according to the Rwanda EMTCT protocol, and young and single mothers were at higher risk of MTCT and should be targeted for support in preventing HIV infection

A new era for understanding amyloid structures and disease

The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-β structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention

Functional prediction of long non-coding RNAs in ovarian cancer-Associated fibroblasts indicate a potential role in metastasis

© 2017 The Author(s). Cancer-Associated fibroblasts (CAFs) contribute to the poor prognosis of ovarian cancer. Unlike in tumour cells, DNA mutations are rare in CAFs, raising the likelihood of other mechanisms that regulate gene expression such as long non-coding RNAs (lncRNAs). We aimed to identify lncRNAs that contribute to the tumour-promoting phenotype of CAFs. RNA expression from 67 ovarian CAF samples and 10 normal ovarian fibroblast (NOF) samples were analysed to identify differentially expressed lncRNAs and a functional network was constructed to predict those CAF-specific lncRNAs involved in metastasis. Of the 1,970 lncRNAs available for analysis on the gene expression array used, 39 unique lncRNAs were identified as differentially expressed in CAFs versus NOFs. The predictive power of differentially expressed lncRNAs in distinguishing CAFs from NOFs were assessed using multiple multivariate models. Interrogation of known transcription factor-lncRNA interactions, transcription factor-gene interactions and construction of a context-specific interaction network identified multiple lncRNAs predicted to play a role in metastasis. We have identified novel lncRNAs in ovarian cancer that are differentially expressed in CAFs compared to NOFs and are predicted to contribute to the metastasis-promoting phenotype of CAFs

Biodistribution and clearance of stable superparamagnetic maghemite iron oxide nanoparticles in mice following intraperitoneal administration

Nanomedicine is an emerging field with great potential in disease theranostics. We generated sterically stabilized superparamagnetic iron oxide nanoparticles (s-SPIONs) with average core diameters of 10 and 25 nm and determined the in vivo biodistribution and clearance profiles. Healthy nude mice underwent an intraperitoneal injection of these s-SPIONs at a dose of 90 mg Fe/kg body weight. Tissue iron biodistribution was monitored by atomic absorption spectroscopy and Prussian blue staining. Histopathological examination was performed to assess tissue toxicity. The 10 nm s-SPIONs resulted in higher tissue-iron levels, whereas the 25 nm s-SPIONs peaked earlier and cleared faster. Increased iron levels were detected in all organs and body fluids tested except for the brain, with notable increases in the liver, spleen, and the omentum. The tissue-iron returned to control or near control levels within 7 days post-injection, except in the omentum, which had the largest and most variable accumulation of s-SPIONs. No obvious tissue changes were noted although an influx of macrophages was observed in several tissues suggesting their involvement in s-SPION sequestration and clearance. These results demonstrate that the s-SPIONs do not degrade or aggregate in vivo and intraperitoneal administration is well tolerated, with a broad and transient biodistribution. In an ovarian tumor model, s-SPIONs were shown to accumulate in the tumors, highlighting their potential use as a chemotherapy delivery agent