Death following extreme temperature exposure: Histological, biochemical and immunohistochemical markers.

Introduction: Defining extreme temperatures as the cause of death remains challenging. It is mostly based on circumstantial, macroscopic and microscopic features.

Methods: We retrospectively compared groups of cases of fatal hypothermia, fatal hyperthermia and non-extreme temperature-related deaths.

Vinorelbine in Non-Small Cell Lung Cancer: Real-World Data From a Single-Institution Experience.

The use of vinorelbine as a single agent or in combination regimens in non-small cell lung cancer (NSCLC) is associated with satisfactory clinical activity. However, the role of vinorelbine-based chemotherapy in chemonaive locally advanced unresectable or metastatic NSCLC patients, according to real-world treatment patterns, has still not been widely explored. Eighty-one patients treated at a single institution were retrospectively analyzed.

Free-living marine nematodes from San Antonio Bay (Río Negro, Argentina).

The dataset of free-living marine nematodes of San Antonio Bay is based on sediment samples collected in February 2009 during doctoral theses funded by CONICET grants. A total of 36 samples has been taken at three locations in the San Antonio Bay, Santa Cruz Province, Argentina on the coastal littoral at three tidal levels. This presents a unique and important collection for benthic biodiversity assessment of Patagonian nematodes as this area remains one of the least known regions.

Hepatocellular carcinoma: Where are we?

Hepatocellular carcinoma (HCC) is the second cause of death due to malignancy in the world, following lung cancer. The geographic distribution of this disease accompanies its principal risk factors: Chronic hepatitis B virus and hepatitis C virus infection, alcoholism, aflatoxin B1 intoxication, liver cirrhosis, and some genetic attributes. Recently, type II diabetes has been shown to be a risk factor for HCC together with obesity and metabolic syndrome.

Free-living marine nematodes from San Julián Bay (Santa Cruz, Argentina).

The free-living marine nematodes of San Julián Bay dataset is based on sediment samples collected in January 2009 during the project PICT AGENCIA-FONCYT 2/33345-2005. A total of 36 samples have been taken at three locations in the San Julián Bay, Santa Cruz Province, Argentina on the coastal littoral at three tidal levels. This presents a unique and important collection for the nematode benthic biodiversity assessment as this area remains one of the least known regions in Patagonia.

Mitochondria of a human multidrug-resistant hepatocellular carcinoma cell line constitutively express inducible nitric oxide synthase in the inner membrane.

Mitochondria play a crucial role in pathways of stress conditions. They can be transported from one cell to another, bringing their features to the cell where they are transported. It has been shown in cancer cells overexpressing multidrug resistance (MDR) that mitochondria express proteins involved in drug resistance such as P-glycoprotein (P-gp), breast cancer resistant protein and multiple resistance protein-1.

Hyperlipidemia and hypothyroidism among metastatic renal cell carcinoma patients taking sunitinib malate. Related or unrelated adverse events?

Background: In recent years, new-onset hypothyroidism was extensively reported in patients receiving sunitinib for malignancy. Effects of sunitinib on serum lipids are not described, however a hyperlipidemic state is commonly observed in hypothyroid patients. Here we report about the incidence and severity of hypercholesterolemia and hypertriglyceridemia in a cohort of patients receiving sunitinib for metastatic renal cell carcinoma.

Delivery of doxorubicin across the blood-brain barrier by ondansetron pretreatment: a study in vitro and in vivo.

Doxorubicin (Dox) has got a limited efficacy in the treatment of central nervous system tumors because of its poor penetration through blood-brain barrier mediated by MDR efflux transporters. We investigated the possibility that ondansetron (Ond) enhances Dox cytotoxicity in cell lines interfering with P-glycoprotein and increases Dox concentration in rat brain tissues. The MDR phenotype was studied using human hepatocellular carcinoma cell line PLC/PRF/5 (P5 and P1(0.

"Effect of the drug transporters ABCB1, ABCC2, and ABCG2 on the disposition and brain accumulation of the taxane analog BMS-275,183".

BMS-275,183 is a novel oral C-4 methyl carbonate analogue of paclitaxel. Recently, a drug-drug interaction between BMS-275,183 and benzimidazole proton pump inhibitors (PPIs) was suggested in clinical trials resulting in elevated drug exposure and toxicity. We explored whether the interaction takes place at the level of P-glycoprotein (Pgp, MDR1, ABCB1), Breast Cancer Resistance Protein (BCRP, ABCG2) and MRP2 (ABCC2) using in vitro and in vivo models.

A Tenebrionid beetle's dataset (Coleoptera, Tenebrionidae) from Peninsula Valdés (Chubut, Argentina).

The Natural Protected Area Peninsula Valdés, located in Northeastern Patagonia, is one of the largest conservation units of arid lands in Argentina. Although this area has been in the UNESCO World Heritage List since 1999, it has been continually exposed to sheep grazing and cattle farming for more than a century which have had a negative impact on the local environment. Our aim is to describe the first dataset of tenebrionid beetle species living in Peninsula Valdés and their relationship to sheep grazing.

Real-world cabazitaxel safety: the Italian early-access program in metastatic castration-resistant prostate cancer.

Aim: Cabazitaxel is a novel taxane that is approved for use in metastatic castration-resistant prostate cancer based on the Phase III TROPIC study, which showed improved overall survival with cabazitaxel/prednisone versus mitoxantrone/prednisone. A global early-access program was initiated in order to provide early access to cabazitaxel in docetaxel-pretreated patients and to obtain real-world data.

Patients & Methods: We report interim safety results from an Italian prospective, single-arm, multicenter, open-label trial of 218 patients receiving cabazitaxel 25 mg/m2 every 3 weeks plus prednisolone 10 mg/day, until disease progression, unacceptable toxicity, investigator's decision or death.

Abcc4 together with abcb1 and abcg2 form a robust cooperative drug efflux system that restricts the brain entry of camptothecin analogues.

Purpose: Multidrug resistance-associated protein 4 (ABCC4) shares many features with P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), including broad substrate affinity and expression at the blood-brain barrier (BBB). However, the pharmacologic relevance of ABCC4 at the BBB is difficult to evaluate, as most drugs are also substrates of ABCB1 and/or ABCG2.

Experimental Design: We have created a mouse strain in which all these alleles are inactivated to assess their impact on brain delivery of camptothecin analogues, an important class of antineoplastic agents and substrates of these transporters.

Effect of the drug transporters ABCG2, Abcg2, ABCB1 and ABCC2 on the disposition, brain accumulation and myelotoxicity of the aurora kinase B inhibitor barasertib and its more active form barasertib-hydroxy-QPA.

We explored whether barasertib (AZD1152), a selective Aurora B kinase inhibitor, is a substrate for P-glycoprotein (Pgp, MDR1), breast cancer resistance protein (BCRP), and multidrug resistance protein 2 (MRP2) in vitro. Cell survival, drug transport, and competition experiments with barasertib pro-drug and the more active form of the drug (barasertib-hQPA) were performed using MDCKII (wild type, MDR1, BCRP, and MRP2) and LLCPK (wild type and MDR1) cells and monolayers, and Sf9-BCRP membrane vesicles. Moreover we tested whether P-gp and BCRP affect the oral pharmacokinetics, tissue distribution, and myelotoxicity of barasertib in vivo using Bcrp1(-/-)/Mdr1a/1b (-/-) (triple knockout) and wild type mice.

Sunitinib-induced hyperparathyroidism: a possible mechanism to altered bone homeostasis.

Background: Sunitinib malate is an orally bioavailable tyrosine kinase inhibitor that is active against many tyrosine kinase receptors involving crucial pathways in both healthy tissues and malignant tissues. Because its use in clinical practice is quite recent, many of its possible side effects remain unknown. In this report, the authors describe the incidence of new-onset hyperparathyroidism in a cohort of patients with metastatic renal cell carcinoma who received treatment with sunitinib.

The impact of sunitinib-induced hypothyroidism on progression-free survival of metastatic renal cancer patients: a prospective single-center study.

Background: Several studies have reported unexpected rates of hypothyroidism in patients treated with sunitinib. The biochemical basis of this impairment is unknown. A relationship between hypothyroidism and improved outcome has been suggested in some cancer patients.

Mitochondrial expression and functional activity of breast cancer resistance protein in different multiple drug-resistant cell lines.

The multidrug resistance (MDR) phenotype is characterized by the overexpression of a few transport proteins at the plasma membrane level, one of which is the breast cancer resistance protein (BCRP). These proteins are expressed in excretory organs, in the placenta and blood-brain barrier, and are involved in the transport of drugs and endogenous compounds. Because some of these proteins are expressed in the mitochondria, this study was designed to determine whether BCRP is expressed at a mitochondrial level and to investigate its function in various MDR and parental drug-sensitive cell lines.

Down-regulation of the HGF/MET autocrine loop induced by celecoxib and mediated by P-gp in MDR-positive human hepatocellular carcinoma cell line.

Many tumors are resistant to drug-induced cell-cycle arrest and apoptosis. We have reported that apoptosis can be restored in human multidrug-resistant (MDR) hepatocellular carcinoma cell lines by celecoxib. Here we show that P-glycoprotein (P-gp) mediates cell-cycle arrest and autophagy induced by celecoxib in human MDR overexpressing hepatocellular carcinoma cell line by down-regulation of the HGF/MET autocrine loop and Bcl-2 expression.

P-170 peptides with low similarity to the human proteome: tracing an effective and safe biological way towards effective and safe cancer chemotherapy.

We propose low-similarity P-170 peptide-based antibodies to neutralize the multidrug resistance phenomenon and, consequently, improve the treatment regimens for cancer chemotherapy. As a first step in the experimental validation of this approach, we report on the similarity analysis of the P-170 primary amino acid structure versus the human proteome and describe peptide motifs uniquely owned by the human P-170 glycoprotein.

Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/- (triple-knockout) and wild-type mice.

Unlabelled: We tested whether erlotinib hydrochloride (Tarceva, OSI-774), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, is a substrate for the ATP-binding cassette drug transporters P-glycoprotein (P-gp; MDR1, ABCB1), breast cancer resistance protein (BCRP; ABCG2), and multidrug resistance protein 2 (MRP2; ABCC2) in vitro and whether P-gp and BCRP affect the oral pharmacokinetics of erlotinib hydrochloride in vivo. In vitro cell survival, drug transport, accumulation, and efflux of erlotinib were done using Madin-Darby canine kidney II [MDCKII; wild-type (WT), MDR1, Bcrp1, and MRP2] and LLCPK (WT and MDR1) cells and monolayers as well as the IGROV1 and the derived human BCRP-overexpressing T8 cell lines. In vivo, the pharmacokinetics of erlotinib after p.

In vitro transport of gimatecan (7-t-butoxyiminomethylcamptothecin) by breast cancer resistance protein, P-glycoprotein, and multidrug resistance protein 2.

Lipophilic camptothecin derivatives are considered to have negligible affinity for breast cancer resistance protein (BCRP; ABCG2). Gimatecan, a new orally available 7-t-butoxyiminomethyl-substituted lipophilic camptothecin derivative, has been previously reported to be not a substrate for BCRP. Using a panel of in vitro models, we tested whether gimatecan is a substrate for BCRP as well as for P-glycoprotein (MDR1) or multidrug resistance protein 2 (MRP2; ABCC2), ATP-binding cassette drug efflux transporters involved in anticancer drug resistance, and able to affect the pharmacokinetics of substrate drugs.

Hepatocellular carcinoma: epidemiology and clinical aspects.

Liver cancer is one of the most frequent solid cancers that kills more than 650,000 people around the world each year. Though great improvements have been done in last 10 years on the understanding the molecular mechanisms involved in liver oncogenesis, the prognosis of patients affected by liver cancer is still poor for most of them. Even in those where a relatively early diagnosis is done, the course of the disease is often fatal due to the underlying liver cirrhosis.

Liver angiogenesis as a risk factor for hepatocellular carcinoma development in hepatitis C virus cirrhotic patients.

Aim: To evaluate the predictive value of hepatocyte proliferation and hepatic angiogenesis for the occurrence of Hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) cirrhotic patients.

Methods: One hundred-five patients (69 males, 36 females; age range, 51-90 year; median 66 year) with biopsy proven HCV cirrhosis were prospectively monitored for HCC occurrence for a median time of 64 mo. Angiogenesis was assessed by using microvessel density (MVD), hepatocyte turnover by MIB1 and PCNA indexes at inclusion in liver biopsies.

Concise review: Clinical relevance of drug drug and herb drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein).

The importance of P-glycoprotein (P-gp) in drug-drug interactions is increasingly being identified. P-gp has been reported to affect the pharmacokinetics of numerous structurally and pharmacologically diverse substrate drugs. Furthermore, genetic variability in the multidrug resistance 1 gene influences absorption and tissue distribution of drugs transported.

P-glycoprotein mediates celecoxib-induced apoptosis in multiple drug-resistant cell lines.

In several neoplastic diseases, including hepatocellular carcinoma, the expression of P-glycoprotein and cyclooxygenase-2 (COX-2) are often increased and involved in drug resistance and poor prognosis. P-glycoprotein, in addition to drug resistance, blocks cytochrome c release, preventing apoptosis in tumor cells. Because COX-2 induces P-glycoprotein expression, we evaluated the effect of celecoxib, a specific inhibitor of COX-2 activity, on P-glycoprotein-mediated resistance to apoptosis in cell lines expressing multidrug resistant (MDR) phenotype.

The effect of hydroxyurea on P-glycoprotein/BCRP-mediated transport and CYP3A metabolism of imatinib mesylate.

Purpose: It has been reported that the combination therapy of imatinib mesylate, a tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, is associated with remarkable antitumor activity in patients with recurrent glioblastoma multiforme. However, the mechanism of the added activity of hydroxyurea to imatinib is not known. The purpose of this study was to investigate in vitro, whether hydroxyurea could enhance the central nervous system penetration of imatinib, by inhibition of the ATP-dependent transporter proteins P-glycoprotein (ABCB1; MDR1; Pgp) and Breast Cancer Resistance Protein (ABCG2; BCRP), or by inhibition of cytochrome P450 3A (CYP3A) metabolism of imatinib.