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. The MOCA models reveal relationships between the blocks and overarching trends across the whole dataset. Based on the MOCA joint components, we propose a quantitative metric for the redundancy of blocks, useful for a priori block-wise feature selection or evaluation of new molecular representations. The second data set includes 7 ecotoxicological study endpoints for crop protection chemicals, for which we (re-)discovered some general trends and linked them to molecular properties. Using a single MOCA model we estimated the predictive potential of each block and the model-ability of the target block.

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%. The rate of decline was not even. Political decisions and changes of healthcare organization in Sweden affected the slope of decline of autopsies superimposed on a linear decline over time reflecting changes in clinical routines. A request of clinical autopsies was highly dependent on the level of care at the time of death, with the lowest number of requests for persons who died in nursing homes. The age at the time of death was a major factor affecting the number of autopsies, resulting in an autopsy rate of less than 1% in the ages where most persons die. Although men were autopsied more often than women, a gender-specific difference was not seen after correction for the age of death. We also found a higher rate of unspecific and irrelevant diagnosis in the cases not autopsied and we know from earlier studies by us and other authors that the cause of death diagnoses were missed in between 30% and 50% of the cases not autopsied. CONCLUSION: The decline in the clinical autopsy rate reduced the value of the death certificate register. An increase in the number of autopsies performed will improve the understanding of disease and cause of death, as well as to better inform next of kin.

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. Our understanding of the roles that customs, beliefs, and values of South Africans play in building resilience will help inform and strengthen interventions that are aimed at controlling the spread of COVID-19.

Attitudes of Nurses and Physicians About Clinical Autopsy in Neonatal and Adult Hospital Care: A Survey in Sweden.

BACKGROUND: The rate of autopsies has dropped to low levels in Western countries. OBJECTIVE: The aim of this study was to describe the experiences and attitudes of registered nurses (RNs) and physicians (MD) toward clinical autopsies in neonatal and adult hospital care in Sweden. METHODS: RNs and MDs in neonatal and adult care specialized clinics at a university-affiliated hospital in Sweden were surveyed. Survey responses were tallied, and free-text comments were assessed with qualitative content analysis. RESULTS: Three hundred thirty-six surveys were distributed; the response rate was 35%. Most RNs and 14% of the MDs had limited or no experience participating in an autopsy. Notably, few RNs and approximately one third of the MDs were familiar with the autopsy processes and the treatment of the deceased person's body after an autopsy. More than one third of RNs had experience with talking to relatives regarding autopsy. Most agreed that an autopsy could be supportive for relatives during the grieving process and beneficial for the quality of healthcare. Most MDs (70%) thought that autopsies should be performed more frequently. Qualitative results emphasized that RNs and MDs thought that autopsy information supported the grieving process of relatives-especially parents who had lost a child. DISCUSSION: The survey data confirm belief in the value of clinical autopsies in neonatal and adult hospital care. RNs and MDs should receive training about the autopsy process and procedures for obtaining consent for an autopsy. RNs are in a position to support the decision making of relatives about providing consent for autopsy and have an opportunity to take a more active role in the autopsy process.

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. The experimental study used was a batch hydrogenation reaction of nitrobenzene to aniline characterized by both UV spectroscopy and process data. The key idea is that OPLS is able to separate the variation in data that is correlated to the process evolution (also known as 'batch maturity index') from the variation that is uncorrelated to process evolution. This separation of different types of variations can generate different batch trajectories and hence lead to different established model control limits to detect process deviations. The results demonstrate that OPLS was able to detect all process deviations and provided a good process understanding of the root causes for these deviations. PCA and PLS on the other hand were shown to provide different interpretations for several of these process deviations, or in some cases they were unable to detect actual process deviations. Hence, the use of OPLS in BSPC can lead to better fault detection and root cause analysis as compared to existing benchmark methods and may therefore be used to complement the existing toolbox.

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. We asked to which degree different lengths of sorafenib treatment would influence liver regeneration after hepatic resection in rats. METHODS: Fischer-344 rats received intragastric injections of sorafenib (5-15 mg/kg/d), underwent a two-thirds partial hepatectomy (PH), and were sacrificed at different time points thereafter. Sorafenib treatment was stopped 0, 3, or 14 d after PH. Serum levels of aminotransferases and labeling indices of S-phase nuclei (bromodeoxyuridine and MIB-5) were analyzed, body and liver weights measured, and levels of phospho-ERK determined by Western blot. RESULTS: Sorafenib increased aminotransferases and the number of S-phase nuclei at baseline, but decreased liver weights and levels of phospho-ERK 24 h after PH. The number of S-phase nuclei and mitotic indices decreased 48 h after PH and increased 7 d after PH in animals on sorafenib treatment. Relative liver weights were restored 5 d after PH in control rats, at 7 d in animals receiving sorafenib prior to surgery, at 10 d in rats where sorafenib was stopped 3 d after surgery, and after 14 d in rats on continuous treatment. CONCLUSIONS: In this rat model, the regenerating liver adapted to the proliferation-inhibitory effect of sorafenib during continuous treatment. Sorafenib given after hepatic resection did not completely inhibit liver regeneration, but it prolonged the regenerative phase in proportion to the length of treatment.

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. To do this we isolated sub-cellular fractions of rat livers from a previous experiment where we have shown anti-carcinogenic effects of statins. The levels of Q(8), Q(9) and Q(10) were analysed with liquid chromatography-mass spectrometry. The Q(9)-levels, constituting the major part of Q in rats, were not significantly affected in any of the sub-cellular compartments. The levels of Q(10), constituting a minor part of Q in rats but the major part of Q in humans, were significantly decreased by about 60% in the statin treated rats. The decrease was present in all sub-cellular compartments, but was most pronounced in the cytosol. There was a significant correlation between extra-mitochondrial Q(10) levels and inhibited carcinogenesis. No such correlation was observed with extra-mitochondrial Q(9). The reduced Q(10)-levels might be explained by the reduced availability of isoprene units during statin treatment, shifting the synthesis towards isoforms with shorter side-chains. In line with this hypothesis there were increased levels of Q(8)-levels during statin treatment. The results support our previous suggestion that at least part of the anti-carcinogenic effect of statins in our rat model is mediated by effects on synthesis of Q. We also demonstrate a shift in the Q-synthesis pathway towards isoforms with shorter side-chains during statin treatment. The ratio between the different Q-isoforms might be used as a more sensitive marker of statin-induced inhibition of Q than measuring total Q levels.

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. These compounds suppress cancer via different mechanisms. In the case of selenium the induction of glutathione peroxidase 4 and inhibition of lipid peroxidation might be a part of the anticarcinogenic effect. In the case of statins, the inhibition of ubiquinone synthesis, as well as of the selenium-containing enzyme thioredoxin reductase 1 (TrxR1) might explain their anticarcinogenic properties. Interestingly, also in the case of selenium the inhibited carcinogenesis was associated with reduced TrxR activity, indicating an important role for this enzyme in carcinogenesis.

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. AIM: To characterize the expression pattern of hepcidin and the iron-sensing pathway of hepcidin regulation during liver regeneration. METHODS: Rats were subjected to PH or sham operation. Liver weights, number of S-phase nuclei, and serum levels of iron and IL-6 were determined. Messenger-RNA levels of hepcidin, ferritin, hemojuvelin, transferrin receptor 1 and 2, HFE, divalent metal transporter 1, ferroportin, and ceruloplasmin were determined with qPCR at different time points. Protein levels of STAT3 and SMAD4 were determined with western blot. RESULTS: During the acute-phase response, IL-6 release induced STAT3 protein and hepcidin mRNA, whereas mRNA levels of proteins in the iron-sensing pathway (HFE, hemojuvelin, and transferrin receptor 2) decreased. The mRNA levels of proteins involved in cellular iron uptake were increased and cellular iron export unchanged. During liver regeneration >24 h after PH, gene expressions in the iron-sensing pathway were continuously suppressed and hepcidin mRNA levels declined 3-7 days after surgery. CONCLUSIONS: Hepcidin gene expression peaks during the acute-phase response, but a sustained down-regulation of the iron-sensing pathway of hepcidin regulation gradually reduces hepcidin gene expression until regeneration is complete, thereby promoting iron mobilization to the regenerating liver.

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. METHODS: Human liver biopsies from a study where patients had been randomised to statin treatment or placebo were analysed. In addition we used liver tissue from a human liver bank where statin treated subjects were compared with non-treated. We also used tissue from a rat liver cancer model in which we have previously shown anti-carcinogenic effects of statins. Real-time PCR and activity assay were used to determine TrxR-levels and activity in tissue extracts. RESULTS: In humans 80 mg atorvastatin treatment for 4 weeks (n = 6) was associated with 85% lower levels of TrxR1 and TrxR2 compared to placebo-treated patients (n = 8) (p = 0.03). In liver biopsies from a human donor liver bank 3 statin treated subjects had 90% lower expression of TrxR1 than 15 non-treated subjects (p = 0.04). Statin treatment was associated with 45% lower expression and activity of TrxR1 in a rat model for liver cancer (p = 0.03). There was a clear correlation between inhibition of carcinogenesis and decreased TrxR1-levels (p = 0.003). CONCLUSION: Statin treatment decreases the hepatic expression of TrxR1 in humans and rats. Suppression of TrxR1 expression could explain possible anti-carcinogenic effects of statins. In addition, decreased levels of TrxR1 during statin treatment may shed light on the mechanism of other side-effects of statins.

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. Despite its efficacy in reducing tumour growth, 5 µg/mL sodium selenite treatment did not affect the gain of liver mass or the rate of cell proliferation after partial hepatectomy. In the regenerating livers, the activity of the cytosolic selenoenzyme thioredoxin reductase (TrxR1) was briefly and transiently increased, an increase further potentiated by sodium selenite. TrxR1 was selectively over expressed in proliferating liver tumours in relation to the surrounding liver tissue in the tumour model, as shown using immunohistochemistry analyses. We suggest that sodium selenite is a suitable candidate for liver cancer prevention in patients with chronic liver diseases that are dependent on sustained liver regeneration due to its differential effects on neoplastic and regenerative cell proliferation. Furthermore, the over expression of TrxR1 in liver neoplasia can only partly be explained by increased growth.

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. (1) In human HCC cell lines (HCC-1.2, HCC-3, and SNU398) linoleic acid peroxide (LOOH) and other prooxidants enhanced the expression of VEGF and IL-8. LOOH up-regulated AP-1 activation. Selenium inhibited these effects. This inhibition was mediated by glutathione peroxidase 4 (GPx4), which preferentially degrades lipid peroxides. Selenium enhanced GPx4 expression and total GPx activity, while knock-down of GPx4 by small interfering RNA (siRNA) increased VEGF, and IL-8 expression. (2) These results were confirmed in a rat hepatocarcinogenesis model. Selenium treatment during tumor promotion increased hepatic GPx4 expression and reduced the expression of VEGF and of the AP-1 component c-fos as well as nodule growth. (3) In HCC patients, increased levels of LOOH-related antibodies (LOOH-Ab) were found, suggesting enhanced LOOH formation. LOOH-Ab correlated with serum VEGF and IL-8 and with AP-1 activation in HCC tissue. In contrast, selenium inversely correlated with VEGF, IL-8, and HCC size (the latter only for tumors smaller than 3 cm). CONCLUSION: Reduced selenium levels result in accumulation of lipid peroxides. This leads to enhanced AP-1 activation and consequently to elevated expression of VEGF and IL-8, which accelerate the growth of HCC. Selenium supplementation could be considered for investigation as a strategy for chemoprevention or additional therapy of early HCC in patients with low selenium levels.

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.

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. Selenium levels were monitored in serum and liver tissue over the 10-week period, and the kinetics of induction of the redox-active cytosolic selenoenzyme thioredoxin reductase were followed. Selenite exposure via drinking water caused a dose-dependent increase in blood and liver selenium levels, with plateaus at 6 and 8 weeks, respectively. These plateaus were reached at the same level of selenium regardless of dose, and no further accumulation was observed. A selenium-dependent increase in the activity of TrxR1 in parallel with the increase in liver selenium levels was also seen, and the induction of TrxR1 mRNA was seen only during the first three days of treatment, when the levels of selenium in the liver were increasing. Sodium selenite at 1 and 5 µg/mL did not affect body weight or relative liver mass. We concluded that long-term treatment with selenite did not cause accumulation of selenium and that the activity of TrxR1 in the liver rose with the selenium levels. We therefore suggest that sodium selenite at doses up to 5 µg/mL could be used for long-term tumour prevention.

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. RESULTS: Lovastatin treatment reduced the volume fraction of liver nodules by 50% and the cell proliferation within the liver nodules was reduced to one third. Ubiquinone (Q10) treatment reversed the statin-induced inhibition of cell proliferation. Lathosterol levels were reduced significantly in the statin-treated rats, indicating inhibition of the mevalonate pathway, but cholesterol levels were not affected. CONCLUSION: Lovastatin inhibits carcinogenesis in a rat model for liver cancer, despite unaffected cholesterol levels. The statin-induced inhibition of cell proliferation may, at least in part, be explained by the inhibition of ubiquinone synthesis.

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. In this study, (i) the understanding of their meaning is improved, (ii) their utility further corroborated, and (iii) the scope of their applicability is broadened. Notably, the rigidity and flexibility scales are benchmarked against previous amino acid description precedence and found to contribute (1) new information, and (2) direct interpretation. The suggested description extensions were tested using empirical data from peptide description and in quantitative structure-activity relationships (QSAR).

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. Selenite at 5 microM caused the lowest mean survival of primary tumor cells in the panel of all tested drugs (28.95% CI 18.60-39.30%). The cells showed a significant (p<0.05) correlation in the resistance to all tested conventional AML drugs whereas selenite did not, indicating sensitivity to selenite also in multi drug resistant cells. Exposure to selenite also resulted in an increased mRNA expression of the antioxidant proteins TrxR1 and Grx, while staining for TrxR1 showed decreased protein levels. The results strongly suggest a great potential for selenite in the treatment of multi drug resistant AML.

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. A Likert-type questionnaire was used containing 26 items with five response alternatives; totally disagree, partly disagree, doubtful, partly agree and totally agree. The main data collection comprised 238 telephone interviews. The factor analysis revealed four factors with an eigenvalue >1.0. Cronbach's alpha coefficient was 0.89, which indicates high reliability. The duration of the telephone interview was approximately 10-20 minutes. The relatives appreciated the opportunity to evaluate the care, and a majority stated that they preferred a telephone interview to answering in writing. The questionnaire is considered reliable, valid and useful for identifying areas in need of quality improvement interventions.

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. METHODS: HCCs were induced in rats by the Solt and Farber protocol of chemical hepatocarcinogenesis, and to evaluate the effects of iron loading, one group of animals were supplemented with dietary iron during tumour progression. Tissue iron contents were determined, labelling indices of S-phase nuclei were calculated, and mRNA levels of iron-regulatory genes were quantitated. Protein levels of ferroportin1 were determined with Western blot. RESULTS: HCCs displayed reduced amount of tissue iron and lack of histologically stainable iron. HCCs expressed significantly higher mRNA levels of genes involved in iron uptake (transferrin receptor-1, divalent metal ion transporter-1), ferroxidase activity (Ferritin-H), and iron extrusion (ferroportin1). The protein levels of ferroportin1 in iron-deficient HCCs were similar as in control livers, and did not increase in HCCs exposed to iron. Hepcidin mRNA levels were decreased in iron-deficient HCCs, rose in response to iron loading and correlated to the tissue iron content. CONCLUSIONS: Taken together, the altered expressions of iron-regulatory genes in HCCs possibly reflect an increased demand for bioavailable iron and a high iron turnover in neoplastic cells.

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. The method extensions are illustrated using two example QSAR data sets containing many X- and Y-variables.