Molecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago-gastric adenocarcinoma.

BACKGROUND: Lapatinib, a dual EGFR and HER2 inhibitor has shown disappointing results in clinical trials of metastatic oesophago-gastric adenocarcinomas (OGAs), and in vitro studies suggest that MET, IGFR, and HER3 confer resistance. This trial applied Lapatinib in the curative neoadjuvant setting and investigated the feasibility and utility of additional endoscopy and biopsy for assessment of resistance mechanisms ex vivo and in vivo. METHODS: Patients with HER2 overexpressing OGA were treated for 10 days with Lapatinib monotherapy, and then in combination with three cycles of Oxaliplatin and Capecitabine before surgery. Endoscopic samples were taken for molecular analysis at: baseline including for ex vivo culture +/- Lapatinib to predict in vivo response, post-Lapatinib monotherapy and at surgery. Immunohistochemistry (IHC) and proteomic analysis was performed to assess cell kinetics and signalling activity. RESULTS: The trial closed early (n=10) due to an anastomotic leak in two patients for which a causative effect of Lapatinib could not be excluded. The reduction in Phosphorylated-HER2 (P-HER2) and P-EGFR in the ex vivo-treated biopsy demonstrated good correlation with the in vivo response at day 10. Proteomic analysis pre and post-Lapatinib demonstrated target inhibition (P-ERBB2, P-EGFR, P-PI3K, P-AKT, and P-ERK) that persisted until surgery. There was also significant correlation between the activation of MET with the level of P-Erk (P=0.0005) and P-PI3K : T-PI3K (total PI3K) ratio (P=0.0037). There was no significant correlation between the activation status of IGFR and HER3 with downstream signalling molecules. CONCLUSIONS: Additional endoscopy and biopsy sampling for multiple biomarker endpoints was feasible and confirmed in vitro data that MET is likely to be a significant mechanism of Lapatinib resistance in vivo.This research was funded by the Medical Research Council [Grant SK002].This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/bjc.2015.34

Renal artery stenosis-when to screen, what to stent?

Renal artery stensosis (RAS) continues to be a problem for clinicians, with no clear consensus on how to investigate and assess the clinical significance of stenotic lesions and manage the findings. RAS caused by fibromuscular dysplasia is probably commoner than previously appreciated, should be actively looked for in younger hypertensive patients and can be managed successfully with angioplasty. Atheromatous RAS is associated with increased incidence of cardiovascular events and increased cardiovascular mortality, and is likely to be seen with increasing frequency. Evidence from large clinical trials has led clinicians away from recommending interventional revascularisation towards aggressive medical management. There is now interest in looking more closely at patient selection for intervention, with focus on intervening only in patients with the highest-risk presentations such as flash pulmonary oedema, rapidly declining renal function and severe resistant hypertension. The potential benefits in terms of improving hard cardiovascular outcomes may outweigh the risks of intervention in this group, and further research is needed

Avaliação das técnicas de massagem e ordenha no tratamento do ingurgitamento mamário por termografia

OBJETIVO: evaluar los métodos de masaje y bombeo en el tratamiento de la congestión mamaria posparto a través de la termografía. MÉTODO: el estudio se realizó en el Banco de Leche Humana de un hospital en Curitiba, Brasil. Se seleccionaron al azar 16 mujeres en periodo de lactancia con congestión con clasificación lobar, ampular y glandular, moderada e intensa. Se compararon los patrones diferenciales de temperatura, antes y después del tratamiento por medio de masaje y bombeo. RESULTADOS: se encontró un degradado negativo de 0,3°C de temperatura entre el pre y post-tratamiento en el grupo experimental. Las mamas con intensa congestión eran 0,7°C más caliente en comparación a aquellos con congestión moderada. CONCLUSIÓN: el masaje y el bombeo electromecánico fueron superiores a los métodos manuales cuando se evaluaron por termografía. REBEC: U1111-1136-9027.OBJETIVO: avaliar técnicas de massagem e ordenha no tratamento do ingurgitamento mamário puerperal, por meio da termografia. MÉTODO: a pesquisa foi realizada no Banco de Leite Humano de um hospital de Curitiba, Brasil. Selecionaram-se, aleatoriamente, 16 lactantes com ingurgitamento com classificação lobar, ampolar e glandular moderado e intenso. Compararam-se os padrões diferenciais de temperatura, antes e após o tratamento realizado, por meio de massagem e ordenha. RESULTADOS: constatou-se um gradiente negativo de 0,3ºC de temperatura entre o pré e o pós-tratamento no grupo experimental. Mamas com ingurgitamento intenso foram 0,7ºC mais quentes quando comparadas com ingurgitamento moderado. CONCLUSÃO: a massagem e ordenha eletromecânicas são superiores às manuais, quando avaliadas por termografia. REBEC: U1111-1136-9027.OBJECTIVE: to evaluate techniques of massage and pumping in the treatment of postpartum breast engorgement through thermography. METHOD: the study was conducted in the Human Milk Bank of a hospital in Curitiba, Brazil. We randomly selected 16 lactating women with engorgement with the classification lobar, ampullary and glandular, moderate and intense. We compared the differential patterns of temperature, before and after the treatment by means of massage and pumping. RESULTS: we found a negative gradient of 0.3°C of temperature between the pre- and post-treatment in the experimental group. Breasts with intense engorgement were 0.7°C warmer when compared with moderate engorgement. CONCLUSION: massage and electromechanical pumping were superior to manual methods when evaluated by thermography. REBEC: U1111-1136-9027

PPL2 translesion polymerase is essential for the completion of chromosomal DNA replication in the african trypanosome

Faithful copying of the genome is essential for life. In eukaryotes, a single archaeo-eukaryotic primase (AEP), DNA primase, is required for the initiation and progression of DNA replication. Here we have identified additional eukaryotic AEP-like proteins with DNA-dependent primase and/or polymerase activity. Uniquely, the genomes of trypanosomatids, a group of kinetoplastid protozoa of significant medical importance, encode two PrimPol-like (PPL) proteins. In the African trypanosome, PPL2 is a nuclear enzyme present in G2 phase cells. Following PPL2 knockdown, a cell-cycle arrest occurs after the bulk of DNA synthesis, the DNA damage response is activated, and cells fail to recover. Consistent with this phenotype, PPL2 replicates damaged DNA templates in vitro, including templates containing the UV-induced pyrimidine-pyrimidone (6-4) photoproduct. Furthermore, PPL2 accumulates at sites of nuclear DNA damage. Taken together, our results indicate an essential role for PPL2 in postreplication tolerance of endogenous DNA damage, thus allowing completion of genome duplication

Comparative study on the use of specific and heterologous microsatellite primers in the stingless bees Melipona rufiventris and M. mondury (Hymenoptera, Apidae)

Due to their high degree of polymorphism, microsatellites are considered useful tools for studying population genetics. Nevertheless, studies of genetic diversity in stingless bees by means of these primers have revealed a low level of polymorphism, possibly the consequence of the heterologous primers used, since in most cases these were not specifically designed for the species under consideration. Herein we compared the number of polymorphic loci and alleles per locus, as well as observed heterozygosity in Melipona rufiventris and M. mondury populations, using specific and heterologous primers. The use of specific primers placed in evidence the greater frequency of polymorphic loci and alleles per locus, besides an expressive increase in observed heterozygosity in M. rufiventris and M. mondury, thereby reinforcing the idea that populational studies should be undertaken by preferably using species-specific microsatellite primers

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

X-Ray Repair Cross-Complementing Group 1 (XRCC1) Genetic Polymorphisms and Risk of Childhood Acute Lymphoblastic Leukemia: A Meta-Analysis

Background: Recently, there have been a number of studies on the association between XRCC1 polymorphisms and childhood acute lymphoblastic leukemia (ALL) risk. However, the results of previous reports are inconsistent. Thus, we performed a meta-analysis to clarify the effects of XRCC1 variants on childhood ALL risk. Methods: A meta-analysis was performed to examine the association between XRCC1 polymorphisms (Arg399Gln, Arg194Trp, and Arg280His) and childhood ALL risk. We critically reviewed 7 studies with a total of 880 cases and 1311 controls for Arg399Gln polymorphism, 3 studies with a total of 345 cases and 554 controls for Arg280His polymorphism, and 6 studies with a total of 783 cases and 1180 controls for Arg194Trp polymorphism, respectively. Odds ratio (OR) and its 95% confidence interval (CI) were used. Results: Significant association between XRCC1 Arg399Gln polymorphism and childhood ALL risk was observed in total population analyses (OR additive model = 1.501, 95 % CI 1.112–2.026, P OR = 0.008; OR dominant model = 1.316, 95 % CI = 1.104–1.569, POR = 0.002) and Asian subgroup analyses (ORadditive model = 2.338, 95%CI = 1.254–4.359, POR = 0.008; ORdominant model = 2.108, 95%CI = 1.498–2.967, POR = 0.000). No association was detected in Caucasians, Metizo and mixed populations. Ethnicity was considered as a significant source of heterogeneity in the meta-regression model. For the other two XRCC1 polymorphisms, no association with childhood ALL risk was found

Dissecting the Within-Africa Ancestry of Populations of African Descent in the Americas

The ancestry of African-descended Americans is known to be drawn from three distinct populations: African, European, and Native American. While many studies consider this continental admixture, few account for the genetically distinct sources of ancestry within Africa--the continent with the highest genetic variation. Here, we dissect the within-Africa genetic ancestry of various populations of the Americas self-identified as having primarily African ancestry using uniparentally inherited mitochondrial DNA.We first confirmed that our results obtained using uniparentally-derived group admixture estimates are correlated with the average autosomal-derived individual admixture estimates (hence are relevant to genomic ancestry) by assessing continental admixture using both types of markers (mtDNA and Y-chromosome vs. ancestry informative markers). We then focused on the within-Africa maternal ancestry, mining our comprehensive database of published mtDNA variation (∼5800 individuals from 143 African populations) that helped us thoroughly dissect the African mtDNA pool. Using this well-defined African mtDNA variation, we quantified the relative contributions of maternal genetic ancestry from multiple W/WC/SW/SE (West to South East) African populations to the different pools of today's African-descended Americans of North and South America and the Caribbean.Our analysis revealed that both continental admixture and within-Africa admixture may be critical to achieving an adequate understanding of the ancestry of African-descended Americans. While continental ancestry reflects gender-specific admixture processes influenced by different socio-historical practices in the Americas, the within-Africa maternal ancestry reflects the diverse colonial histories of the slave trade. We have confirmed that there is a genetic thread connecting Africa and the Americas, where each colonial system supplied their colonies in the Americas with slaves from African colonies they controlled or that were available for them at the time. This historical connection is reflected in different relative contributions from populations of W/WC/SW/SE Africa to geographically distinct Africa-derived populations of the Americas, adding to the complexity of genomic ancestry in groups ostensibly united by the same demographic label

The Effectiveness of Contract Farming for Raising Income of Smallholder Farmers in Low- and Middle-Income Countries: a Systematic Review

Contract farming is used by an increasing number of firms as a preferred modality to source products from smallholder farmers in low and middle-income countries. Quality requirements of consumers, economies of scale in production or land ownership rights are common incentives for firms to offer contractual arrangements to farmers. Prices and access to key technology, key inputs or support services are the main incentives for farmers to enter into these contracts. There is great heterogeneity in contract farming, with differences in contracts, farmers, products, buyers, and institutional environments. The last decade shows a rapid increase in studies that use quasi-experimental research designs to assess the effects of specific empirical instances of contract farming on smallholders. The objective of this systematic review was to distill generalised inferences from this rapidly growing body of evidence. The review synthesised the studies in order to answer two questions: 1: What is known about the effect size of contract farming on income and food security of smallholder farmers in low- and middle-income countries? 2: Under which enabling or limiting conditions are contract farming arrangements effective for improving income and food security of smallholders