Block-wise Exploration of Molecular Descriptors with Multi-block Orthogonal Component Analysis (MOCA).

Data tables for machine learning and structure-activity relationship modelling (QSAR) are often naturally organized in blocks of data, where multiple molecular representations or sets of descriptors form the blocks. Multi-block Orthogonal Component Analysis (MOCA), a new analytical tool, can be used to explore such data structures in a single model, identifying principal components that are unique to a single block or joint over multiple blocks. We applied MOCA to two sets of 550 and 300 molecules and up to 9213 molecular descriptors organized in 11 blocks.

Autopsies and quality of cause of death diagnoses.

Objective: The consequences of a low autopsy rate are not considered in determining the cause of death.

Method: We have analyzed the Cause of Death Register of the Swedish National Board of Health and Welfare since it started 1969 to and including 2016 to visualize the decline in the frequency of clinical autopsies over time and evaluated the effect on the quality of the cause of death diagnoses.

Results: Over the five decades studied, the frequency of clinical autopsies declined from almost 40% to less than 5%.

Mental Health, Culture and Resilience-Approaching the COVID-19 Pandemic From a South African Perspective.

It is understandable that the challenges of living through a severe contagious outbreak, like the coronavirus disease 2019 (COVID-19), cannot be tolerated for long and that some individuals may require emotional, psychological, and spiritual support in order to strengthen their resilience to navigate this difficult period. As clinicians and researchers in the field of mental health, we need to appreciate the roles that culture, spirituality, and religion play in comforting people who survive such an outbreak and provide possible solutions for public health authorities on how to promote wellness. This appreciation should direct us to seek a deeper understanding of how culture, spirituality, and religion can be used to endure an outbreak of this magnitude and how the interruption of common practices can impact the coping skills of those who are affected.

OPLS in batch monitoring - Opens up new opportunities.

In batch statistical process control (BSPC), data from a number of "good" batches are used to model the evolution (trajectory) of the process and they also define model control limits, against which new batches may be compared. The benchmark methods used in BSPC include partial least squares (PLS) and principal component analysis (PCA). In this paper, we have used orthogonal projections to latent structures (OPLS) in BSPC and compared the results with PLS and PCA.

Sorafenib prolongs liver regeneration after hepatic resection in rats.

Background: The multikinase inhibitor sorafenib inhibits angiogenesis and tumor cell proliferation. Sorafenib targets signaling pathways involved in liver regeneration. Previous works on regenerating mouse liver show differing results.

The anti-carcinogenic effect of statins in a rat model correlates with levels and synthesis of ubiquinone.

Ubiquinone (Q) is a product in the cholesterol synthesis pathway and is an essential component of the respiratory chain in the mitochondrial membrane. In addition, extra-mitochondrial Q has anti-oxidative properties and this fraction is increased during carcinogenesis. The aim of the present study was to investigate if extra-mitochondrial level of Q is affected by statin treatment in a rat model for liver cancer, and if this change correlates with inhibited carcinogenesis.

Review: Exploring anticarcinogenic agents in a rat hepatocarcinogenesis model--focus on selenium and statins.

In this review, we describe a rat model for chemically induced hepatocarcinogenesis that can be used for studying the anticarcinogenic effects of different agents. In this model the process of carcinogenesis can be followed through the different stages of initiation, promotion and progression. Mechanistic studies of anticarcinogenic agents can be carried out and two examples are given by studies on selenium and statins as anticarcinogenic agents.

Orthogonal PLS (OPLS) Modeling for Improved Analysis and Interpretation in Drug Design.

Partial least squares (PLS) regression is a flexible data analytical approach, which can be made even more versatile and useful by various modifications. In this article we describe the extension into orthogonal PLS modeling, in terms of two new methods, called OPLS and O2PLS, with similar prediction capacity but improved model interpretation.

Iron-regulatory gene expression during liver regeneration.

Background: In rat, the first 18-24 h after partial hepatectomy (PH) are characterized by an acute-phase reaction, after which liver regeneration predominates. Interleukin-6 (IL-6) induces the iron hormone hepcidin, which blocks iron uptake and may compromise iron uptake in the growing liver. The expressions of hepcidin and the iron-regulatory pathway of hepcidin gene expression during the late phase of liver regeneration are unknown.

Statins inhibit expression of thioredoxin reductase 1 in rat and human liver and reduce tumour development.

Background: Statins have been reported to have anti-carcinogenic properties in addition to their cholesterol-lowering effects, but the mechanism is unknown. Thioredoxin reductases (TrxR) are selenium-containing enzymes of great importance for carcinogenesis and their levels are increased in neoplastic cells. The aim of the present study was to investigate if statin treatment is associated with alterations in the hepatic expression of TrxR.

The effect of sodium selenite on liver growth and thioredoxin reductase expression in regenerative and neoplastic liver cell proliferation.

Selenium in supra-nutritional doses is tumour-preventative in animal models and in humans. In this work, we have compared the effect of sodium selenite on tumour growth in a rat hepatocarcinogenesis model with the effect of sodium selenite on the regeneration of liver mass after partial hepatectomy. In the tumour model, 5 μg/mL sodium selenite in the drinking water reduced the rate of tumour growth for up to 12 months after initiation; the volume fraction of liver cancers was 14±4% with a mean bromodeoxyuridine-index of 19±11% in the treated rats compared to a volume fraction of 26±7% with a mean bromodeoxyuridine-index of 42±27% in the control rats.

Antagonistic effects of selenium and lipid peroxides on growth control in early hepatocellular carcinoma.

Unlabelled: Activation of the activator protein 1 (AP-1) transcription factor as well as increased serum levels of vascular endothelial growth factor (VEGF) and interleukin (IL)-8 predict poor prognosis of patients with hepatocellular carcinomas (HCCs). Moreover, HCC patients display reduced selenium levels, which may cause lipid peroxidation and oxidative stress because selenium is an essential component of antioxidative glutathione peroxidases (GPx). We hypothesized that selenium-lipid peroxide antagonism controls the above prognostic markers and tumor growth.

Selenium homeostasis and induction of thioredoxin reductase during long term selenite supplementation in the rat.

Selenium is a candidate treatment for liver tumour prevention in chronic liver disease. In this study, we have studied selenium uptake, distribution and accumulation in rats provided with water containing tumour-preventive doses of sodium selenite for 10 weeks. Male Fischer 344 rats were given drinking water containing 1 μg/mL or 5 μg/mL sodium selenite.

Lovastatin prevents carcinogenesis in a rat model for liver cancer. Effects of ubiquinone supplementation.

Aim: This study tests the hypothesis that statins (HMGCoA reductase inhibitors) inhibit carcinogenesis and that this effect may be mediated by the statin-induced inhibition of ubiquinone synthesis.

Materials And Methods: The effects of lovastatin, with and without addition of ubiquinone, were studied in a rat model for chemically induced hepatocarcinogenesis. Intermediates in the mevalonate pathway were measured.

Extensions to amino acid description.

A new set of amino acid descriptor scales was recently introduced. The new scales relate to amino acid side chain (i) rigidity and (ii) flexibility. These two properties were found to be orthogonal to each other.

Selenite is a potent cytotoxic agent for human primary AML cells.

Selenite is a potent inhibitor of malignant cell growth. Although the cytotoxic effects have been extensively investigated in vitro, there are only a limited number of studies using primary tumor cells with concomitant comparison to conventional drugs. An ex vivo model with primary cells from 39 consecutive patients with acute myeloid leukemia (AML) were exposed to a panel of conventional cytotoxic drugs, and the effects on viability were compared to those of clinically achievable concentrations of selenite.

Relatives' perspective on the quality of geriatric care and rehabilitation--development and testing of a questionnaire.

We perceived a need for relatives' evaluation of geriatric care and rehabilitation during the care period as well as the first few weeks after discharge. The aim of this study was therefore to develop and test a questionnaire for use in telephone interviews with relatives of patients discharged from geriatric wards to measure their perceptions of the quality of care. The instrument development process comprised a literature review, focus group interviews, construction of items, test of content validity, a pilot study and finally the main data collection to test the construct validity and reliability.

Expression of iron regulatory genes in a rat model of hepatocellular carcinoma.

Background/aims: The altered iron metabolism in hepatocellular carcinomas (HCCs), characterized by the iron-deficient phenotype, is suggested to be of importance for tumour growth. However, the underlying molecular mechanisms remain poorly understood. We asked whether these iron perturbations would involve altered expression of genes controlling iron homeostasis.

Megavariate analysis of environmental QSAR data. Part II--investigating very complex problem formulations using hierarchical, non-linear and batch-wise extensions of PCA and PLS.

Three extensions of the basic PCA and PLS methodologies are described. These extensions are hierarchical, non-linear and batch-based in nature. The objectives of these methods are to assist in problem understanding and problem solving in very complex (QSAR) problem formulations.

Megavariate analysis of environmental QSAR data. Part I--a basic framework founded on principal component analysis (PCA), partial least squares (PLS), and statistical molecular design (SMD).

This paper introduces principal component analysis (PCA), partial least squares projections to latent structures (PLS), and statistical molecular design (SMD) as useful tools in deriving multi- and megavariate quantitative structure-activity relationship (QSAR) models. Two QSAR data sets from the fields of environmental toxicology and environmental chemistry are worked out in detail, showing the benefits of PCA, PLS and SMD. PCA is useful when overviewing a data set and exploring relationships among compounds and relationships among variables.

Patient perspective on quality of geriatric care and rehabilitation--development and psychometric testing of a questionnaire.

The aim was to develop and test a questionnaire for use in telephone interviews concerning patient evaluation of geriatric care and rehabilitation. Instrument development was performed comprising qualitative interviews, construction of items, content validation, pilot study and data collection for evaluation of care and rehabilitation, clinical utility, reliability and construct validity. Qualitative interviews were performed with 12 elderly participants.

Adriamycin cytotoxicity may stimulate growth of hepatocellular tumours in an experimental model for adjuvant systemic chemotherapy in liver transplantation.

Adjuvant treatment with adriamycin has been suggested to improve results after liver transplantation for hepatocellular cancer. Here we have applied an animal model for evaluation of treatment with adriamycin and/or cyclosporine A on liver tumour growth. Three chemically induced rat liver tumours with various degree of differentiation were transferred to the spleens of syngenic rats.

The role of thioredoxin reductase activity in selenium-induced cytotoxicity.

The selenoprotein thioredoxin reductase is a key enzyme in selenium metabolism, reducing selenium compounds and thereby providing selenide to synthesis of all selenoproteins. We evaluated the importance of active TrxR1 in selenium-induced cytotoxicity using transfected TrxR1 over-expressing stable Human Embryo Kidney (HEK-293) cells and modulation of activity by pretreatment with low concentration of selenite. Treatment with sodium selenite induced cytotoxity in a dose-dependent manner in both TrxR1 over-expressing and control cells.

Human sterol 12a-hydroxylase (CYP8B1) is mainly expressed in hepatocytes in a homogenous pattern.

The liver is the only organ where the complete synthesis of bile acids takes place. The present study was undertaken to investigate whether regional differences exist within the individual human hepatic lobuli regarding the pattern of expression of sterol 12alpha-hydroxylase (CYP8B1), a key enzyme in bile acid synthesis. A specific anti-human CYP8B1 peptide antiserum was developed and used for Western blotting and hepatic immunostaining of livers from various patients.