Perivascular adipose tissue (PVAT) releases numerous factors and adipokines with paracrine effects on both vascular structure and function. These effects are variable as they depend on regional ...differences in PVAT among blood vessels and vary with changes in adiposity. There is considerable evidence demonstrating an association between coronary PVAT and the development and progression of coronary artery disease, which is associated with inflammation, oxidative stress, angiogenesis, vascular remodelling and blood clotting. However, PVAT also has a protective role in vascular grafts, especially the no‐touch saphenous vein, in patients undergoing coronary artery bypass. This beneficial influence of PVAT involves factors such as adipocyte‐derived relaxing factor, nitric oxide (NO), leptin, adiponectin, prostanoids, hydrogen sulphide and neurotransmitters, as well as mechanical protection. This article aims to highlight and compare the dual role of PVAT in the development and progression of coronary atherosclerosis, as well as in increased graft patency. Different deleterious and protective mechanisms of PVAT are also discussed and the inside‐outside signalling paradigm of atherosclerosis development re‐evaluated. The bidirectional communication between the arterial and venous wall and their surrounding PVAT, where signals originating from the vascular wall or lumen can affect PVAT phenotype, has been shown to be very complex. Moreover, signals from PVAT also influence the structure and function of the vascular wall in a paracrine manner.
Linked Articles
This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue – Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc
This hypothesis-generating trial evaluated neoadjuvant ipatasertib–paclitaxel for early triple-negative breast cancer (TNBC).
In this randomized phase II trial, patients with early TNBC (T≥1.5cm, ...N0–2) were randomized 1:1 to receive weekly paclitaxel 80mg/m2 with ipatasertib 400mg or placebo (days 1–21 every 28days) for 12weeks before surgery. Co-primary end points were pathologic complete response (pCR) rate (ypT0/TisN0) in the intention-to-treat (ITT) and immunohistochemistry phosphatase and tensin homolog (PTEN)-low populations. Secondary end points included pCR rate in patients with PIK3CA/AKT1/PTEN-altered tumors and pre-surgery response rates by magnetic resonance imaging (MRI).
pCR rates with ipatasertib versus placebo were 17% versus 13%, respectively, in the ITT population (N=151), 16% versus 13% in the immunohistochemistry PTEN-low population (N=35), and 18% versus 12% in the PIK3CA/AKT1/PTEN-altered subgroup (N=62). Rates of overall and complete response (CR) by MRI favored ipatasertib in all three populations (CR rate 39% versus 9% in the PIK3CA/AKT1/PTEN-altered subgroup). Ipatasertib was associated with more grade ≥3 adverse events (32% versus 16% with placebo), especially diarrhea (17% versus 1%). Higher cycle 1 day 8 (C1D8) immune score was significantly associated with better response only in placebo-treated patients. All ipatasertib-treated patients with low immune scores and a CR had PIK3CA/AKT1/PTEN-altered tumors.
Adding ipatasertib to 12weeks of paclitaxel for early TNBC did not clinically or statistically significantly increase pCR rate, although overall response rate by MRI was numerically higher with ipatasertib. The antitumor effect of ipatasertib was most pronounced in biomarker-selected patients. Safety was consistent with prior experience of ipatasertib–paclitaxel. A T-cell-rich environment at C1D8 had a stronger association with improved outcomes in paclitaxel-treated patients than seen for baseline tumor-infiltrating lymphocytes. This dependency may be overcome with the addition of AKT inhibition, especially in patients with PIK3CA/AKT1/PTEN-altered tumors.
NCT02301988.
The study of human papillomavirus (HPV)-induced carcinogenesis uses multiple in vivo mouse models, one of which relies on the cytokeratin 14 gene promoter to drive the expression of all HPV early ...oncogenes. This study aimed to determine the HPV16 variant and sublineage present in the K14HPV16 mouse model. This information can be considered of great importance to further enhance this K14HPV16 model as an essential research tool and optimize its use for basic and translational studies. Our study evaluated HPV DNA from 17 samples isolated from 4 animals, both wild-type (n = 2) and HPV16-transgenic mice (n = 2). Total DNA was extracted from tissues and the detection of HPV16 was performed using a qPCR multiplex. HPV16-positive samples were subsequently whole-genome sequenced by next-generation sequencing techniques. The phylogenetic positioning clearly shows K14HPV16 samples clustering together in the sub-lineage A1 (NC001526.4). A comparative genome analysis of K14HPV16 samples revealed three mutations to the human papillomaviruses type 16 sublineage A1 representative strain. Knowledge of the HPV 16 variant is fundamental, and these findings will allow the rational use of this animal model to explore the role of the A1 sublineage in HPV-driven cancer.
► Bracken is an invasive, poisonous weed distributed worldwide. ► Bracken-eating human populations show increased cancer risk. ► Ptaquiloside (PTA) is a highly water-soluble bracken carcinogen. ► PTA ...residues are present in non-mains water and contaminated milk or meat.
Bracken (
Pteridium aquilinum) is a widely distributed carcinogenic fern, to whose toxins human populations are exposed through multiple routes. Animals are also affected by bracken toxins, leading to serious production losses yearly. Accordingly, several governmental reports regarding the safeguard of public health against bracken carcinogens have been recently issued. This review describes the main bioactive compounds identified in bracken and their biological effects at the molecular, cellular, pathological and populational levels, with particular emphasis on ptaquiloside, the main bracken carcinogen. Recent biopathological studies shedding further light on the genotoxicity immunotoxicity and carcinogenicity of ptaquiloside are discussed. Key steps on the long effort to understand bracken toxicology are also reviewed, along with the latest findings on new bracken toxins and human exposures routes. The presence of ptaquiloside and related terpene glycosides in milk, meat and water are of particular concern from the viewpoints of both human and animal health.
Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ ...dysfunction, age, genetics) and extrinsic (e.g., drug–drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision‐making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.
Clinical Pharmacology & Therapeutics (2011) 89 2, 259–267. doi:10.1038/clpt.2010.298
The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate ...linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician’s choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes.
Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline.
Of 468 assessable patients, 290 had Trop-2 expression data 64% (n = 151 SG) versus 60% (n = 139 TPC) and 292 had known BRCA1/2 mutation status 63% (n = 149 SG) versus 61% (n = 143 TPC). Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations.
SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.
•The majority of patients (80%) with mTNBC in the ASCENT study with available data had high/medium tumor Trop-2 expression.•Survival outcomes and ORRs were numerically higher in SG- versus TPC-treated patients with high/medium Trop-2 expression.•Benefit of SG in patients with high/medium Trop-2 expression was similar to that of overall primary efficacy population.•The small number of patients with low Trop-2 expression prevents definitive conclusions on benefit of SG in this subgroup.•Benefit of SG over TPC was also similar regardless of germline BRCA1/2 mutation status.
Cancers induced by human papillomavirus (HPV) infection remain a significant public health threat, fueling the study of new therapies. Laurel (
Laurus nobilis
) compounds and extracts recently showed
...in vitro
activity against HPV-transformed cell lines. This work aims to evaluate the
in vivo
efficacy and hepatic toxicity of a laurel extract in a transgenic mouse model of HPV16-induced cancer. The extract was administered in drinking water (20 mg per animal per day) for three consecutive weeks, using four experimental groups (
n
= 10) (group I: HPV16
−/−
without treatment, group II: treated HPV16
−/−
, group III: HPV16
+/−
without treatment and group IV: treated HPV16
+/−
). Following the treatment period, animals were sacrificed and skin samples were used to classify skin lesions histologically. Toxicological parameters included hematological and biochemical blood markers, splenic and hepatic histology and hepatic oxidative stress. The extract did not prevent the progression of HPV16-induced cutaneous lesions in this model. The treated wild-type animals showed mild hepatitis, while transgenic animals suffered weight loss. However, there were no changes concerning hematological, biochemical and hepatic oxidative stress markers.
Cancers induced by HPV remain a significant public health threat, fueling the study of new therapies.
Some diet profiles are associated with the risk of developing cancer; however, some nutrients show protective effects.
is widely consumed, having a balanced nutritional profile; however, its ...potential for cancer chemoprevention still needs comprehensive studies. In this study, we incorporated
into the diet of mice transgenic for the human papillomavirus type 16 (HPV16), which spontaneously develop pre-malignant and malignant lesions, and determined whether this seaweed was able to block lesion development. Forty-four 20-week-old HPV
and HPV
mice were fed either a base diet or a diet supplemented with 10% seaweed. At the end of the study, skin samples were examined to classify HPV16-induced lesions. The liver was also screened for potential toxic effects of the seaweed. Blood was used to study toxicological parameters and to perform comet and micronucleus genotoxicity tests.
significantly reduced the incidence of pre-malignant dysplastic lesions, completely abrogating them in the chest skin. These results suggest that
dietary supplementation has the potential to block the development of pre-malignant skin lesions and indicate its antigenotoxic activity against HPV-induced DNA damage. Further studies are needed to establish the seaweed as a functional food and clarify the mechanisms whereby this seaweed blocks multistep carcinogenesis induced by HPV.
Essential oils are natural compounds used by humans for scientific purposes due to their wide range of properties. Eugenol is mostly present in clove oil, while pulegone is the main constituent of ...pennyroyal oil. To guarantee the safe use of eugenol and pulegone for both humans and animals, this study addressed, for the first time, the effects of these compounds, at low doses (chronic toxicity) and high doses (acute toxicity), in laboratory animals. Thirty-five FVB/n female mice were randomly assigned to seven groups (n = 5): group I (control, non-additive diet); group II (2.6 mg of eugenol + 2.6 mg of pulegone); group III (5.2 mg of eugenol + 5.2 mg of pulegone); group IV (7.8 mg of eugenol + 7.8 mg of pulegone); group V (7.8 mg of eugenol); group VI (7.8 mg of pulegone); and group VII (1000 mg of eugenol + 1000 mg of pulegone). The compounds were administered in the food. Groups I to VI were integrated into the chronic toxicity study, lasting 28 days, and group VII was used in the acute toxicity study, lasting 7 days. Animals were monitored to assess their general welfare. Water and food intake, as well as body weight, were recorded. On the 29th day, all animals were euthanized by an overdose of ketamine and xylazine, and a complete necropsy was performed. Blood samples were collected directly from the heart for microhematocrit and serum analysis, as well as for comet assay. Organs were collected, weighed, and fixed in formaldehyde for further histological analysis and enzymatic assay. Eugenol and pulegone induced behavioral changes in the animals, namely in the posture, hair appearance and grooming, and in mental status. These compounds also caused a decrease in the animals’ body weight, as well as in the food and water consumption. A mortality rate of 20% was registered in the acute toxicity group. Both compounds modulated the serum levels of triglycerides and alanine aminotransferase. Eugenol and pulegone induced genetic damage in all animals. Eugenol increased the activity of the CAT enzyme. Both compounds increased the GR enzyme at the highest dose. Moreover, pulegone administered as a single compound increased the activity of the GST enzyme. Histopathological analysis revealed inflammatory infiltrates in the lungs of groups II, III, and IV. The results suggest that eugenol and pulegone may exert beneficial or harmful effects, depending on the dose, and if applied alone or in combination.
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