Phosphatidylinositol 3-kinase (PI3K) promotes cancer cell survival, migration, growth and proliferation by generating phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the inner leaflet of the ...plasma membrane. PIP3 recruits pleckstrin homology domain-containing proteins to the membrane to activate oncogenic signaling cascades. Anticancer therapeutics targeting the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway are in clinical development. In a mass spectrometric screen to identify PIP3-regulated proteins in breast cancer cells, levels of the Rac activator PIP3-dependent Rac exchange factor-1 (P-REX1) increased in response to PI3K inhibition, and decreased upon loss of the PI3K antagonist phosphatase and tensin homolog (PTEN). P-REX1 mRNA and protein levels were positively correlated with ER expression, and inversely correlated with PI3K pathway activation in breast tumors as assessed by gene expression and phosphoproteomic analyses. P-REX1 increased activation of Rac1, PI3K/AKT and MEK/ERK signaling in a PTEN-independent manner, and promoted cell and tumor viability. Loss of P-REX1 or inhibition of Rac suppressed PI3K/AKT and MEK/ERK, and decreased viability. P-REX1 also promoted insulin-like growth factor-1 receptor activation, suggesting that P-REX1 provides positive feedback to activators upstream of PI3K. In support of a model where PIP3-driven P-REX1 promotes both PI3K/AKT and MEK/ERK signaling, high levels of P-REX1 mRNA (but not phospho-AKT or a transcriptomic signature of PI3K activation) were predictive of sensitivity to PI3K inhibitors among breast cancer cell lines. P-REX1 expression was highest in estrogen receptor-positive breast tumors compared with many other cancer subtypes, suggesting that neutralizing the P-REX1/Rac axis may provide a novel therapeutic approach to selectively abrogate oncogenic signaling in breast cancer cells.
The challenges of maintaining cohesion while making collective decisions in social or aggregating insects can result in the emergence of a leader or leaders. Larval aggregations of the steel-blue ...sawfly Perga affinis forage nocturnally, and some larvae lead the aggregation on foraging trips more often than expected by chance. We investigated the relationship between these leader and follower roles by comparing the weight and growth of individual larvae with different roles. Our observations reveal no significant difference between the growth of leaders and followers, suggesting that the role of leadership may not provide direct foraging benefits. However, by experimentally manipulating the social structure of larval aggregations, we found that individuals within aggregations that comprise a mixture of leaders and followers enjoy higher growth rates than those in aggregations comprising a single behavioural type. These data demonstrate, for the first time, individual benefits to maintaining a balance of leader and follower roles within larval aggregations, and highlight the importance of considering the perspectives of both leaders and followers when investigating the evolutionary significance of this behavioural variation within animal groups.
Summary
Background
Anthelmintic resistance combined with limited chemotherapeutic options has prompted a change in approaches to control of equine helminth infections. Targeted selective treatment ...strategies use diagnostics to reduce anthelmintic use by treating individuals with worm burdens or egg shedding levels above a set threshold. While faecal egg count analysis has limitations for informing tapeworm treatment, a commercially available saliva‐based diagnostic test accurately diagnoses horses with tapeworm infection.
Objectives
Evaluation of a saliva‐based diagnostic test to identify horses naturally infected with tapeworm and assess the impact of using the test to inform anthelmintic administration.
Study design
Retrospective longitudinal study.
Methods
Saliva was collected from horses (n = 237) at a UK welfare charity from autumn 2015 to autumn 2016. Horses diagnosed as positive for tapeworm infection using the EquiSal® Tapeworm test were anthelmintic treated according to weight. The number of horses that received anthelmintic treatment based on the test result was compared with an all‐group treatment approach and the reduction in anthelmintic usage calculated. Incoming horses were also tested (n = 143) and the information was used to inform quarantine treatments.
Results
In autumn 2015, 85% of 237 horses tested received no anthelmintic and the majority (71%) of these remained below the treatment threshold throughout the study. Of the 69 horses that received treatment, seven required treatment following three subsequent tests, while >50% of horses administered with anthelmintic fell below the treatment threshold at the following test. No increase in tapeworm prevalence within the 237 horses was observed during the study despite a substantial reduction in the application of antitapeworm treatments. A total of 41% of incoming horses required anticestode treatment.
Main limitations
Other management practices were not included in the analysis.
Conclusions
Compared with an all‐group treatment strategy, the diagnostic‐led approach used here considerably reduced application of anticestode anthelmintics. This could reduce selection pressure for anthelmintic resistance.
Piglet neonatal mortality rates are high (~20%), so nutritional strategies to reduce this are highly desirable. Maternal fat substitution (FS) may promote the preweaning survival of piglets by ...improving their energy status. Therefore, the aim of the present study was to investigate the effects of FS throughout pregnancy on offspring viability, together with the gene expression of stress-related markers in the liver. Sixteen pregnant sows were randomly allocated to one of two isocaloric diets, control (C) or FS in the form of palm oil, fed from 0 to 110 days gestation. Glucose tolerance was examined on Day 108. Median and low birthweight offspring were allocated to tissue sampling at either 7 days or 6 months postnatal age. In response to a glucose tolerance test, FS sows exhibited a raised glucose area under the curve with no change in basal glucose. Average piglet mortality (up to Day 28) was increased fourfold in the FS group, with surviving median-sized piglets exhibiting significantly lower fatty acid binding protein 1 (FABP1) expression at 7 days. There were no effects on the abundance of any other stress- or metabolic-related genes examined. Thus, this study demonstrates that maternal FS throughout gestation causes maternal glucose intolerance that may be linked to the observed increase in piglet mortality. However, the surviving offspring do not exhibit any detectable differences in postnatal growth or hepatic gene profile in later life.
Neoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with ...antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC.
We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m2 IV weekly ×12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor ER and grade).
Seventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER+ disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue.
Neoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR; however, 47% were responders using pCR and/or CPS + EG score ≤2. ER positive patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for patients with ER positive LABC.
Pathologic complete response (pCR) after neoadjuvant chemotherapy is associated with improved survival in locally advanced and inflammatory breast cancer. Neoadjuvant sunitinib + paclitaxel followed by doxorubicin + cyclophosphamide with G-CSF therapy resulted in a 27% pCR rate in this single-arm, phase II trial. ER+ patients had higher response rates (64%) using the CPS + EG score and pCR, suggesting promising incremental benefit.
Mutations that activate the N-ras oncogene are among the most frequently detected genetic alterations in human acute myeloid leukemias (AMLs), Philadelphia chromosome-negative myeloproliferative ...disorders (MPDs), and myelodysplastic syndromes (MDSs). However, because N-ras has not been shown to induce these disorders in an in vivo model, the role of N-ras in the evolution of myeloid leukemia is unclear. To investigate the potential of N-ras to induce myeloid leukemia, lethally irradiated mice were reconstituted with bone marrow (BM) cells infected with a retroviral vector carrying activated N-ras. Approximately 60% of these mice developed hematopoietic disorders, including severe MPDs resembling human chronic myelogenous leukemia (CML) or AML with differentiation (French-American-British FAB classification M2). Other reconstituted mice succumbed to hematopoietic defects that were pathologically similar to human MDSs. The latter disorders appeared to be due to a myeloid impairment that was demonstrated by enumeration of day-12 colony-forming units-spleen (CFU-S) and by in vitro colony assays. A high level of apoptosis associated with thymic atrophy and peripheral blood (PB) lymphopenia was also evident in N-rasreconstituted mice. Our results are consistent with a model in which antiproliferative effects are a primary consequence of N-rasmutations and secondary transforming events are necessary for the development of myeloid leukemia. This is the first report of an in vivo model for N-ras induced MPD and leukemia.
The challenges of maintaining cohesion while making collective decisions in social or aggregating insects can result in the emergence of a leader or leaders. Larval aggregations of the steel-blue ...sawfly Perga affinis forage nocturnally, and some larvae lead the aggregation on foraging trips more often than expected by chance. We investigated the relationship between these leader and follower roles by comparing the weight and growth of individual larvae with different roles. Our observations reveal no significant difference between the growth of leaders and followers, suggesting that the role of leadership may not provide direct foraging benefits. However, by experimentally manipulating the social structure of larval aggregations, we found that individuals within aggregations that comprise a mixture of leaders and followers enjoy higher growth rates than those in aggregations comprising a single behavioural type. These data demonstrate, for the first time, individual benefits to maintaining a balance of leader and follower roles within larval aggregations, and highlight the importance of considering the perspectives of both leaders and followers when investigating the evolutionary significance of this behavioural variation within animal groups.
Summary Background Interferon-free regimens are needed to treat hepatitis C virus (HCV) infections. We investigated the efficacy of combined simeprevir and sofosbuvir. Methods We enrolled patients ...with chronic HCV genotype 1 infections who had previously not responded to pegylated interferon (peginterferon) and ribavirin or were treatment naive. Patients were randomly assigned in a 2:1:2:1 ratio to receive 150 mg simeprevir and 400 mg sofosbuvir daily for 24 weeks with (group 1) or without (group 2) ribavirin or for 12 weeks with (group 3) or without (group 4) ribavirin, in two cohorts: previous non-responders with METAVIR scores F0–F2 (cohort 1) and previous non-responders and treatment-naive patients with METAVIR scores F3–F4 (cohort 2). The primary endpoint was sustained virological response 12 weeks after stopping treatment (SVR12). Analysis was done by intention to treat. Safety data from cohorts 1 and 2 were pooled for analysis. This study is registered with ClinicalTrials.gov , number NCT01466790. Findings 168 patients were enrolled and randomised, and 167 started treatment (n=80 in cohort 1 and n=87 in cohort 2). SVR12 was achieved in 154 (92%) patients (n=72 90%, 95% CI 81–96 in cohort 1 and n=82 94%, 87–98 in cohort 2). The most common adverse events in the pooled groups were fatigue (n=52 31%), headache (n=33 20%), and nausea (n=26 16%). Grade 4 adverse events were seen in one (2%) of 54 patients in each of groups 1 and 3 and in three (10%) of 31 patients in group 2, whereas grade 3–4 events were reported in less than 5% of all patients, except increased blood amylase concentration. Serious adverse events were seen in four (2%) patients, all in groups 1 and 2. Four (2%) patients discontinued all study treatment because of adverse events, three before week 12. Interpretation Combined simeprevir and sofosbuvir was efficacious and well tolerated. Funding Janssen.
In previously untreated patients with HCV genotype 1 infection without cirrhosis, the rate of sustained virologic response was 94% with 8 weeks of ledipasvir–sofosbuvir, 93% with 8 weeks of ...ledipasvir–sofosbuvir plus ribavirin, and 95% with 12 weeks of ledipasvir–sofosbuvir.
More than 3 million people in the United States are chronically infected with the hepatitis C virus (HCV).
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Although the number of new infections has been declining for decades, HCV-related morbidity and mortality are projected to continue rising for another 20 years.
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One half to three quarters of persons currently infected with HCV have not received a diagnosis and are untreated; many will have progression to decompensated cirrhosis, hepatocellular carcinoma, and other liver complications.
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Early diagnosis and treatment are essential to improve long-term health outcomes in this population. New guidelines from the Centers for Disease Control and Prevention . . .
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