The investigational food product "Cholesterol Reducing Strawberry Yogurt Drink (Tesco)" is a strawberry yogurt drink with added plant sterols. A 100g bottle (one serving) of cholesterol lowering strawberry yogurt drink contains 2g of free plant sterols. The magnitude of the effect given by this enriched food product, providing a daily intake of 1,5-2,4 g plant sterols/stanols, refers to the lowering/reducing blood cholesterol effects in the range "7 % to 10 %" within 2 to 3 weeks of treatment, as specified by Commission Regulation (EU) 384/2010 of 05/05/2010.
The dietary intervention will consist in 8 weeks consumption of PSS enriched Yogurt Drink, which provide a daily PSS intake of 3.4g/100g bottle plant sterols ester equivalent to 2g/100g bottle of free plant sterols.

The investigational food product "Low Fat Strawberry Yogurt Drinks (Morrisons)" is a strawberry flavoured yogurt drink with sweetener and sugar, vitamin C, B6 and D, British milk.
Placebo intervention consists in 8 weeks consumption of PSS non-enriched Yogurt Drinks. The placebo intervention is needed for the study design chosen (randomized double-blind placebo-controlled cross-over clinical trial). Placebo will be used in order to determine the efficacy of PSS intervention, comparing the effects of the two compounds (PSS and placebo) in the same experimental conditions and then avoiding bias.

Hypercholesterolemia

Breast Cancer

Obesity

Ingredients: Skimmed Milk, Strawberry Juice from Concentrate (5%), Plant Sterols Ester (3.4%)***, Sugar, Maize Starch, Flavourings, Colour (Anthocyanins), Starter Culture including Bifidobacterium (Milk), Thickener (Carob Gum), Sweetener (Sucralose), Milk Proteins.
*** Equivalent to 2% Free Plant Sterols

Cholesterol Reducing Strawberry Yogurt Drink (Tesco Ltd)

Ingredients: Yogurt (Milk), Water, Sugar, Strawberry Purée (1%), Modified Maize Starch, Carrot Concentrate, Flavouring, Acidity Regulator (Citric Acid), Vitamin C, Colour (Paprika Extract), Sweetener (Sucralose), Vitamin D, Vitamin B6.

Low Fat Strawberry Yogurt Drinks (Morrisons Ltd)

University of Leeds

Plant Sterol INtervention for Cancer Prevention (PINC)

Randomised Control Cross-over Trial to Test How Dietary Plant Sterols Modify Tumour Promoting Capabilities of Non-tumour Host Cells in Volunteers With Elevated LDL-C

The changes of oxysterols content in serum/plasma after 8 weeks of phytosterols intervention compared to placebo. After the dietary intervention, we expect to observe a change of -20% in circulating 27-hydroxycholesterol content (marker of oxysterols systemic levels).
Concentration of oxysterols using LC-MS/MS measurement of plasma in 50 subjects after placebo and after intervention.

Concentration of oxysterols using LC-MS/MS measurement of host cells in 50 subjects after placebo and after intervention.
Effect of phytosterols enriched foods consumption compared to placebo intervention on migratory and chemoresistance properties of breast cancer cell lines (MDA.MB.231, MDA.MB.468, MCF7 and T47D) when in co-culture with the host-cells collected in each step of the trial.

Effect of phytosterols enriched foods consumption compared to placebo intervention on migratory and chemoresistance properties of breast cancer cell lines (MDA.MB.231, MDA.MB.468, MCF7 and T47D) when in co-culture with the host-cells collected in each step of the trial.
Changes in proteins expression of oxysterols target genes.

Effect of phytosterols enriched foods consumption compared to placebo intervention on migratory and chemoresistance properties of breast cancer cell lines (MDA.MB.231, MDA.MB.468, MCF7 and T47D) when in co-culture with the host-cells collected in each step of the trial.
Changes in gene expression of oxysterols target genes.

Study of the effect of phytosterols on LDL-C concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Study of the effect of phytosterols on HDL-C concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Study of the effect of phytosterols on Total Cholesterol concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Study of the effect of phytosterols on Triglycerides concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Study of the effect of phytosterols on non-HDL-C concentration in 50 subjects after placebo and after intervention using Alere Afinion™.

Phytosterols panel serum/plasma levels after phytosterols enriched food or placebo intervention during all the steps of the trial.

RNA sequence will be measured with RNA-seq techniques before and after phytosterols intervention to identify the molecular effectors of the paracrine regulatory systems in the oxysterols, LDL-C and secondary BCa pattern.

Changes in interactions between proteins and DNA and using Chip/seq will be measured before and after phytosterols intervention to identify the molecular effectors of the paracrine regulatory systems in the oxysterols, LDL-C and secondary BCa pattern.

Data will be published in scientific journals, which will depend on the outcome of data analysis. Anonymized research data will be deposited with the University of Leeds data repository.

James Thorne

Chief Investigator

The Leeds Teaching Hospitals NHS Trust

University of Oslo

Enrolled participants will undergo 1:1 simple randomisation by the CI, to either Experimental arm or placebo arm.. Evaluations after intervention will be made at the end of the first 8 weeks of intervention (Day 56; 8th week) and at the end of the second 8 weeks intervention (Day 140; 20th week). Since a wash out period between the two food products consumption is provided, another evaluation after wash out period (Day 84; 12th week) will be performed. The wash out period consist in a 4 weeks food products free period, where will be ask to participants to maintain their usual dietary and life style habits excluding the consumption of any yoghurt drinks.

All trial investigators will be blinded to the intervention, except for the CI. The CI will keep a record of interventions administrated. All trial participants and outcome assessors will be blinded to the intervention. Each food product has the same flavour and taste, as well as the same packaging to ensure blinding in maintained throughout study.

Standard anthracyclines/taxanes based neoadjuvant chemotherapy chosen by the investigator and administered according to clinical practice, for 6 months, or 4.5 months in case of dose dense schedule (unless disease progression, unacceptable toxicity, patient's refusal or investigator's decision)

Standard anthracyclines/taxanes based neoadjuvant CT chosen by the investigator and administered according to clinical practice + Zoledronate 4 mg i.v. every 3-4 weeks and Atorvastatin 80 mg/die administered for 6 months, or 4.5 months in case of dose dense schedule (unless disease progression, unacceptable toxicity, patient's refusal or investigator's decision)

Triple Negative Breast Cancer

Zoledronate

Atorvastatin 80mg

Standard neoadjuvant cht chosen by the investigator and administered according to clinical practice

Standard neoadjuvant cht

Azienda Socio Sanitaria Territoriale ASST Lariana - Presidio Ospedaliero Ospedale S. Anna

Azienda Socio Sanitaria Territoriale - ASST Papa Giovanni XXIII

Azienda Ospedaliero Universitaria di Bologna Policlinico S.Orsola - Malpighi

Azienda Socio Sanitaria Territoriale - ASST di Cremona

Azienda Socio Sanitaria Territoriale - ASST di Lodi

Azienda Socio Sanitaria Territoriale Fatebenefratelli Sacco Sede Ospedale Fatebenefratelli

Azienda Socio Sanitaria Territoriale ASST Monza - Ospedale S. Gerardo

Azienda Ospedaliera Universitaria Federico II

Istituti Clinici Scientifici Maugeri

IFO - Istituto Nazionale dei Tumori Regina Elena

Neoadjuvant Zoledronate and Atorvastatin in Triple Negative Breast Cancer

Multicenter, Randomized, Phase II Study of Neoadjuvant Chemotherapy Associated or Not With Zoledronate and Atorvastatin in Triple Negative Breast Cancers - YAPPETIZER Study

Relative reductions of YAP and TAZ IHC-expression at surgery with respect to core-biopsy analysis.

The clinical primary activity endpoint of the second phase of study is the proportion of responder patients, defined as those obtaining a pCR, defined as ypT0ypN0 or as the absence of any residual tumor burden at surgery.

Relative reductions of YAP and TAZ IHC-expression at surgery with respect to core-biopsy analysis according to high/low p53 levels. A high level of p53 is defined by IHC expression ≥30%, while a low level by IHC expression <30%, as previously described

Proportion of responder patients according to high/low p53 levels

Disease free survival (DFS), defined as the time from the date of treatment start to the first of either recurrence or relapse, second cancer, or death, whichever comes first. Subjects alive not having relapse or recurrence or second cancer by the end of the study will be censored at the last disease assessment date.

Overall survival (OS), calculated for each patient as the time from the date of treatment start to the date of death from any cause. Patients not reported as having died at the end of the study will be censored at the date they were last known to be alive.

Proportions of patients with down regulation of YAP and TAZ gene expression by RNA-Seq in tumour tissue collected at definitive surgery with respect to tumour tissue collected at the time of core-biopsy for responder and non-responders patients.

Relative reduction of Ki67 IHC expression in tumour tissue samples collected at definitive surgery with respect to tumour tissue collected at the time of diagnostic core-biopsy for responder and non-responders patients.

In order to address the safety endpoint the study will evaluate:
- Incidence, nature, severity and seriousness of AEs, according of National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03

In order to address the safety endpoint the study will evaluate:
- Maximum toxicity grade experienced by each patient for each specific toxicity

In order to address the safety endpoint the study will evaluate:
Percentage of patients experiencing grade 3-4 toxicity for each specific toxicity
Percentage of patients with at least one SAE
Percentage of patients with at least one serious adverse drug reaction (SADR)
Percentage of patients with at least one suspect unexpected serious adverse reaction

Mario Negri Institute for Pharmacological Research

Associazione Italiana per la Ricerca sul Cancro

After providing informed consent for study participation, patients fulfilling the eligibility criteria will be randomized to receive standard anthracyclines/taxanes based neoadjuvant chemotherapy (ARM A) or the combination of zoledronate and atorvastatin associated with the above mentioned neoadjuvant chemotherapy (ARM B).
Randomization will use a biased-coin minimization procedure having as stratification factor the type of neoadjuvant chemotherapy chosen by the center and the p53 level in the FFPE diagnostic core biopsy determined by IHC (<30% vs >30% vs unknown).
Randomization and e-CFR will be handled by HeavyBase , an Open Source push based "peer to peer" electronic data management system.

The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period will be performed within three days before the scheduled proximal Roux-en-Y gastric bypass surgery. A gastroduodenoscopy with biopsy of the lower duodenum will be performed before the first pharmacokinetic study period.

The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period will be performed 5-7 days after the scheduled proximal Roux-en-Y gastric bypass surgery. A sampling of a tissue specimen from the jejunum will be collected during the operation.

The subjects will be administered 200 mg paracetamol, 250 mg amoxicillin and 50 mg talinolol dissolved in 40 ml water which must be drunken with additional 200 ml water on the first study day. This pharmacokinetic period and a gastrojejunoscopy with biopsy of the jejunum will be performed about one year after the scheduled proximal stomach bypass surgery.

Morbid Obesity

Administration of 5 ml Paracetamol Saft Hexal (= 200 mg paracetamol)

paracetamol

Administration of 5 ml Amoxypen® 250 mg Saft (= 250 mg amoxicillin)

amoxicillin

Administration of 1 tablet Cordanum® 50 (= 50 mg talinolol) dissolved with 40 ml tap water

talinolol

Gastroduodenoscopy with biopsy of the lower duodenum before the first pharmacokinetic study period

gastroduodenoscopy with biopsy

Gastrojejunoscopy with biopsy of the jejunum about one year after proximal Roux-en-Y gastric bypass

gastrojejunoscopy with biopsy

sampling of a tissue specimen from the jejunum during the operation

proximal Roux-en-Y gastric bypass

Department of Clinical Pharmacology, Ernst-Moritz-Arndt-University Greifswald

Surgical Clinic of the Clinical Centre Suedstadt Rostock

Bioavailability of Paracetamol, Amoxicillin and Talinolol Before, Immediately and One Year After Gastric Bypass Operation

Bioavailability of Paracetamol, Amoxicillin and Talinolol and Expression of Intestinal Drug Metabolizing Enzymes and Transport Proteins Before, Immediately and One Year After Proximal Roux-en-Y Gastric Bypass Operation in Patients With Morbid Adipositas

mRNA expression of duodenal and/or jejunal drug metabolizing enzymes (eg. CYP3A4, UGTs) and drug transport proteins (e.g. P-glycoprotein, MRP2, OATPB, PEPT)

protein content of duodenal and/or jejunal drug metabolizing enzymes (eg. CYP3A4, UGTs) and drug transport proteins (e.g. P-glycoprotein, MRP2, OATPB, PEPT)

University Medicine Greifswald

SOLID TUMOR

Istituto Clinico Humanitas

Regulation of Lymphocyte Anti-tumor Response in Metastatic Patients Treated With the mTOR Inhibitor Everolimus

Evaluate the sensitivity of mTORC1 and mTORC2 to Everolimus in T and NK cells.Everolimus inhibits kinase activity of mTOR when bound to Raptor (mTORC1). Whether mTORC2 is sensitive to Everolimus will be elucidated.

Determine the phenotype of T cells in patients with the use of mass cytometry and polychromatic flow cytometry. Everolimus alters the phenotype and dynamics of circulating T and NK cells.

Evaluate the ability of T-cells from patients to differentiate into effector cells (anti-tumor and anti- viral in vitro responses. Everolimus potentiates anti-tumor and anti-viral immune responses and that will affect the differentiation of naive T cell precursors into memory cells

sterol/breast neoplasms

Plant Sterol INtervention for Cancer Prevention (PINC)

Neoadjuvant Zoledronate and Atorvastatin in Triple Negative Breast Cancer

Bioavailability of Paracetamol, Amoxicillin and Talinolol Before, Immediately and One Year After Gastric Bypass Operation

Regulation of Lymphocyte Anti-tumor Response in Metastatic Patients Treated With the mTOR Inhibitor Everolimus

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