Phase I Trial of Viral Vector-Based Personalized Vaccination Elicits Robust Neoantigen-Specific Antitumor T-Cell Responses.

Purpose: Personalized vaccines targeting multiple neoantigens (nAgs) are a promising strategy for eliciting a diversified antitumor T-cell response to overcome tumor heterogeneity. NOUS-PEV is a vector-based personalized vaccine, expressing 60 nAgs and consists of priming with a nonhuman Great Ape Adenoviral vector (GAd20) followed by boosts with Modified Vaccinia Ankara. Here, we report data of a phase Ib trial of NOUS-PEV in combination with pembrolizumab in treatment-naïve patients with metastatic melanoma (NCT04990479).

OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.

Background: In the OlympiAD study, olaparib was shown to improve progression-free survival compared with chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA1 and/or BRCA2 mutation (BRCAm) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC). We now report the planned final overall survival (OS) results, and describe the most common adverse events (AEs) to better understand olaparib tolerability in this population.

Patients And Methods: OlympiAD, a Phase III, randomized, controlled, open-label study (NCT02000622), enrolled patients with a germline BRCAm and HER2-negative mBC who had received ≤2 lines of chemotherapy for mBC.

Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation.

Background: Olaparib is an oral poly(adenosine diphosphate-ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation.

Methods: We conducted a randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease. Patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with single-agent chemotherapy of the physician's choice (capecitabine, eribulin, or vinorelbine in 21-day cycles).

Long-Term Responders on Olaparib Maintenance in High-Grade Serous Ovarian Cancer: Clinical and Molecular Characterization.

Maintenance therapy with olaparib has improved progression-free survival in women with high-grade serous ovarian cancer (HGSOC), particularly those harboring mutations. The objective of this study was to characterize long-term (LT) versus short-term (ST) responders to olaparib. A comparative molecular analysis of Study 19 (NCT00753545), a randomized phase II trial assessing olaparib maintenance after response to platinum-based chemotherapy in HGSOC, was conducted.

RNA-Seq Differentiates Tumour and Host mRNA Expression Changes Induced by Treatment of Human Tumour Xenografts with the VEGFR Tyrosine Kinase Inhibitor Cediranib.

Pre-clinical models of tumour biology often rely on propagating human tumour cells in a mouse. In order to gain insight into the alignment of these models to human disease segments or investigate the effects of different therapeutics, approaches such as PCR or array based expression profiling are often employed despite suffering from biased transcript coverage, and a requirement for specialist experimental protocols to separate tumour and host signals. Here, we describe a computational strategy to profile transcript expression in both the tumour and host compartments of pre-clinical xenograft models from the same RNA sample using RNA-Seq.

Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines.

Background: Colorectal cancer (CRC) is a heterogeneous and biologically poorly understood disease. To tailor CRC treatment, it is essential to first model this heterogeneity by defining subtypes of patients with homogeneous biological and clinical characteristics and second match these subtypes to cell lines for which extensive pharmacological data is available, thus linking targeted therapies to patients most likely to respond to treatment.

Methods: We applied a new unsupervised, iterative approach to stratify CRC tumor samples into subtypes based on genome-wide mRNA expression data.

Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055).

The mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MAPK extracellular signal-regulated kinase (MEK)1/2 inhibitor selumetinib (AZD6244) with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (non-small cell lung cancers) and colorectal carcinoma was well tolerated and produced increased antitumor efficacy relative to the respective monotherapies.

Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244).

Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity.

Phytoestrogen content of cereals and cereal-based foods consumed in the UK.

Dietary phytoestrogens may be involved in the occurrence of chronic diseases. Reliable information on the phytoestrogen content in foods is required to assess dietary exposure and disease risk in epidemiological studies. However, there is little information on isoflavone, lignan, and coumestrol content of cereals and cereal-based foods, leading to an underestimation of intake.

Phytoestrogen content of foods of animal origin: dairy products, eggs, meat, fish, and seafood.

Dietary phytoestrogens may be involved in the occurrence of chronic diseases. Reliable information on the phytoestrogen content in foods is required to assess dietary exposure and disease risk in epidemiological studies. However, existing analyses have focused on only one class of these compounds in plant-based foods, and there is only little information on foods of animal origin, leading to an underestimation of intake.

Urinary sucrose and fructose as biomarkers of sugar consumption: comparison of normal weight and obese volunteers.

Using urinary sugars as a biomarker of consumption, we have previously shown that obese people consume significantly more sugars than individuals of normal weight. However, there is concern that recovery of this biomarker may differ between normal weight and obese individuals. A total of 19 subjects, divided into two groups according to their body mass index (BMI) (normal weight BMI < or = 25 kg/m(2), n=10; obese BMI > or = 30 kg/m(2), n=9), participated in a randomized crossover dietary intervention study of three diets providing 13, 30 and 50% of energy from sugars for 4 days each while living in a volunteer suite.

Phytoestrogen content of beverages, nuts, seeds, and oils.

Phytoestrogens are secondary plant metabolites that have received increasing attention for their bioactivity, in particular due to their structural and functional similarity to 17beta-estradiol. Although urinary and plasma phytoestrogens can be used as biomarkers for dietary intake, this is often not possible in large epidemiological studies or in the assessment of general exposure in free-living individuals. Accurate information about dietary phytoestrogens is therefore important, but there are very limited data concerning food contents.

Use of recovery biomarkers to calibrate nutrient consumption self-reports in the Women's Health Initiative.

Underreporting of energy consumption by self-report is well-recognized, but previous studies using recovery biomarkers have not been sufficiently large to establish whether participant characteristics predict misreporting. In 2004-2005, 544 participants in the Women's Health Initiative Dietary Modification Trial completed a doubly labeled water protocol (energy biomarker), 24-hour urine collection (protein biomarker), and self-reports of diet (assessed by food frequency questionnaire (FFQ)), exercise, and lifestyle habits; 111 women repeated all procedures after 6 months. Using linear regression, the authors estimated associations of participant characteristics with misreporting, defined as the extent to which the log ratio (self-reported FFQ/nutritional biomarker) was less than zero.

Urinary sugars biomarker relates better to extrinsic than to intrinsic sugars intake in a metabolic study with volunteers consuming their normal diet.

Background/objectives: Sugars in diet are very difficult to measure because of the unreliability of self-reported dietary intake. Sucrose and fructose excreted in urine have been recently suggested as a biomarker for total sugars intake. To further characterize the use of this biomarker, we investigated whether urinary sugars correlated better to extrinsic compared to intrinsic sugars in the diet.

Detection and quantification of sucrose as dietary biomarker using gas chromatography and liquid chromatography with mass spectrometry.

Several epidemiological studies suggest a link between the intake of refined sugars and an increased risk for colorectal, breast, pancreatic and endometrial cancer. However, other studies failed to confirm these conclusions and the reason for this may be the ambiguity of dietary assessment methods - mainly self-reporting - employed. Sucrose is an established biomarker for sugars intake, allowing the objective assessment of dietary sucrose.

Pollen proteolytic enzymes degrade tight junctions.

Background And Objective: Asthma and allergic rhinitis are significant, increasing causes of morbidity worldwide. Pollen, a major cause of seasonal rhinitis/conjunctivitis, carries proteolytic enzymes on its surface. We showed previously that peptidase allergens from house dust mites compromise epithelial barrier function by degrading the extracellular domains of the tight junction proteins, occludin and claudin, thus facilitating allergen delivery across epithelial layers.

Twenty-four-hour urinary thiamine as a biomarker for the assessment of thiamine intake.

Objective: To investigate 24-h urinary thiamine as a potential biomarker for thiamine intake for use in validation studies to assess the validity of dietary intake data collected by self-reporting dietary methods.

Subjects: Seven male and six female healthy participants living for 30 days in a metabolic suite under strictly controlled conditions consuming their usual diet as assessed beforehand from four consecutive 7-day food diaries kept at home. During the 30-day study, all 24-h urine specimens were collected, validated for their completeness and analysed for thiamine.

Urinary potassium is as reliable as urinary nitrogen for use as a recovery biomarker in dietary studies of free living individuals.

Twenty-four-hour urinary nitrogen (UN) is commonly used to validate dietary assessment methods. Potassium is more widespread in food than nitrogen, but the role of 24-h urinary potassium (UK) as a biomarker has been less studied and characterized. To investigate the performance of UK as a recovery biomarker compared with UN in subjects consuming their normal diet, 7 males and 6 females consumed known amounts of food based on their habitual varying diet (assessed beforehand from 4 consecutive 7-d food diaries) for 30 d in a metabolic suite.

Urinary sucrose and fructose as biomarkers for sugar consumption.

The use of 24-hour urinary sucrose and fructose as potential biomarkers for sugars consumption was investigated in two studies of 21 healthy participants living in a volunteer suite where dietary intake was known and all specimens collected. The dose-response was assessed in 12 males using a randomized crossover design of three diets containing constant levels of 63, 143, and 264 g of sugars for 10 days each. Both sugars and sucrose intake were significantly correlated with the sum of sucrose and fructose concentration in urine (0.

Red-clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial [ISRCTN42940165].

Introduction: Isoflavones are hypothesized to protect against breast cancer, but it is not clear whether they act as oestrogens or anti-oestrogens in breast tissue. Our aim was to determine the effects of taking a red clover-derived isoflavone supplement daily for 1 year on mammographic breast density. Effects on oestradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), lymphocyte tyrosine kinase activity and menopausal symptoms were also assessed.

Group level validation of protein intakes estimated by 24-hour diet recall and dietary questionnaires against 24-hour urinary nitrogen in the European Prospective Investigation into Cancer and Nutrition (EPIC) calibration study.

A calibration approach was developed to correct for systematic between-cohort dietary measurement errors in the European Prospective Investigation into Cancer and Nutrition (EPIC), a large multicenter cohort study. To validate the 24-h diet recalls (24-HDRs) as reference measurements for between-cohort calibration, we estimated the agreement between center mean nitrogen (N) and total energy intakes and mean 24-h urinary N. Similar analyses using N and energy intake data from different dietary questionnaires (DQs) used at study baseline were conducted to estimate the effect of the calibration approach.

Comparison of estimated renal net acid excretion from dietary intake and body size with urine pH.

Objective: The aim of this study was to examine whether estimated net acid excretion (NAE) from two dietary assessment instruments can predict urine pH in healthy volunteers.

Design: The Observing Protein and Energy Nutrition (OPEN) study, which was designed to assess dietary measurement error, included men and women aged 40 to 69 years. Participants were asked to complete two food frequency questionnaires (FFQs) and two 24-hour recalls at approximately three-month intervals, and to return two 24-hour urine samples during the same period.

Using intake biomarkers to evaluate the extent of dietary misreporting in a large sample of adults: the OPEN study.

This paper describes the Observing Protein and Energy Nutrition (OPEN) Study, conducted from September 1999 to March 2000. The purpose of the study was to assess dietary measurement error using two self-reported dietary instruments-the food frequency questionnaire (FFQ) and the 24-hour dietary recall (24HR)-and unbiased biomarkers of energy and protein intakes: doubly labeled water and urinary nitrogen. Participants were 484 men and women aged 40-69 years from Montgomery County, Maryland.

Peptidase allergen Der p 1 initiates apoptosis of epithelial cells independently of tight junction proteolysis.

Loss of epithelial cell polarity, which can arise following disruption of tight junctions (TJs), is a precursor to the care-fully orchestrated removal of moribund cells from epithelia in apoptosis. Ordinarily, this cycle of events has minimally disruptive effects on the function of the epithelial barrier, but some agents have been identified that induce apoptosis and promote epithelial leakiness. The allergen Der p 1 is a cysteine peptidase that cleaves TJ adhesion proteins and induces apoptosis in epithelial cells.