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1.	Abulmeaty, M. M. A., et al. (författare) Impact of Vitamin D Supplementation on Bone Mineral Density and All-Cause Mortality in Heart Transplant Patients 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:10 Tidskriftsartikel (refereegranskat)abstract Vitamin D (VD) deficiency is frequently reported in heart transplant (HT) recipients and routinely supplemented. However, the efficacy of VD supplementation on bone mineral density (BMD) and its association with all-cause mortality is underinvestigated. The VD levels and BMD were studied for two years, and the association of VD and BMD with all-cause mortality risk was investigated. Ninety-six HT patients (38.18 & PLUSMN; 12.10 years old; 74% men) were followed up during VD, Ca, and Mg supplementation. Anthropometric measurements, BMD by Dual-energy X-ray absorptiometry (DEXA) scan, VD concentrations, and related biochemical parameters were analyzed before, 1 year, and 2 years after HT. Despite significant improvement of VD3 and 25-hydroxy VD (25OHVD) levels especially in the men, BMD parameters were insignificantly changed. After 2 years, the all-cause mortality rate was 15.6%. High pretransplant levels of 25OHVD failed to improve the survival probability. Cox's regression showed a 32.7% increased hazard ratio for each unit increase in body mass index (95% CI: 1.015-1.733, p = 0.038), in the VD-deficient group rather than in the VD-sufficient one. In conclusion, VD supplementation improves the biochemical status, especially in VD-deficient HT. However, its impact on the BMD and mortality was not as usually expected. Further investigation of the disturbed VD metabolism in HT is warranted.
2.	Asik, RM, et al. (författare) Alzheimer's Disease: A Molecular View of β-Amyloid Induced Morbific Events 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:9 Tidskriftsartikel (refereegranskat)abstract Amyloid-β (Aβ) is a dynamic peptide of Alzheimer’s disease (AD) which accelerates the disease progression. At the cell membrane and cell compartments, the amyloid precursor protein (APP) undergoes amyloidogenic cleavage by β- and γ-secretases and engenders the Aβ. In addition, externally produced Aβ gets inside the cells by receptors mediated internalization. An elevated amount of Aβ yields spontaneous aggregation which causes organelles impairment. Aβ stimulates the hyperphosphorylation of tau protein via acceleration by several kinases. Aβ travels to the mitochondria and interacts with its functional complexes, which impairs the mitochondrial function leading to the activation of apoptotic signaling cascade. Aβ disrupts the Ca2+ and protein homeostasis of the endoplasmic reticulum (ER) and Golgi complex (GC) that promotes the organelle stress and inhibits its stress recovery machinery such as unfolded protein response (UPR) and ER-associated degradation (ERAD). At lysosome, Aβ precedes autophagy dysfunction upon interacting with autophagy molecules. Interestingly, Aβ act as a transcription regulator as well as inhibits telomerase activity. Both Aβ and p-tau interaction with neuronal and glial receptors elevate the inflammatory molecules and persuade inflammation. Here, we have expounded the Aβ mediated events in the cells and its cosmopolitan role on neurodegeneration, and the current clinical status of anti-amyloid therapy.
3.	Baker, Jacqueline Roshelli, et al. (författare) Prediagnostic blood selenium status and mortality among patients with colorectal cancer in western european populations 2021 Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 9:11 Tidskriftsartikel (refereegranskat)abstract A higher selenium (Se) status has been shown to be associated with lower risk for colorectal cancer (CRC), but the importance of Se in survival after CRC diagnosis is not well studied. The associations of prediagnostic circulating Se status (as indicated by serum Se and selenoprotein P (SELENOP) measurements) with overall and CRC-specific mortality were estimated using multi-variable Cox proportional hazards regression among 995 CRC cases (515 deaths, 396 from CRC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Se and SELENOP serum concentrations were measured on average 46 months before CRC diagnosis. Median follow-up time was 113 months. Participants with Se concentrations in the highest quintile (≥100 µg/L) had a multivariable-adjusted hazard ratio (HR) of 0.73 (95% CI: 0.52–1.02; Ptrend = 0.06) for CRC-specific mortality and 0.77 (95% CI: 0.57–1.03; Ptrend = 0.04) for overall mortality, compared with the lowest quintile (≤67.5 µg/L). Similarly, participants with SELENOP concentrations in the highest (≥5.07 mg/L) compared with the lowest quintile (≤3.53 mg/L) had HRs of 0.89 (95% CI: 0.64–1.24; Ptrend = 0.39) for CRC-specific mortality and 0.83 (95% CI: 0.62–1.11; Ptrend = 0.17) for overall mortal-ity. Higher prediagnostic exposure to Se within an optimal concentration (100–150 µg/L) might be associated with improved survival among CRC patients, although our results were not statistically significant and additional studies are needed to confirm this potential association. Our findings may stimulate further research on selenium’s role in survival among CRC patients especially among those residing in geographic regions with suboptimal Se availability.
4.	Bazaz, S, et al. (författare) Novel Orthogonally Hydrocarbon-Modified Cell-Penetrating Peptide Nanoparticles Mediate Efficient Delivery of Splice-Switching Antisense Oligonucleotides In Vitro and In Vivo 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:8 Tidskriftsartikel (refereegranskat)abstract Splice-switching therapy with splice-switching oligonucleotides (SSOs) has recently proven to be a clinically applicable strategy for the treatment of several mis-splice disorders. Despite this, wider application of SSOs is severely limited by the inherently poor bioavailability of SSO-based therapeutic compounds. Cell-penetrating peptides (CPPs) are a class of drug delivery systems (DDSs) that have recently gained considerable attention for improving the uptake of various oligonucleotide (ON)-based compounds, including SSOs. One strategy that has been successfully applied to develop effective CPP vectors is the introduction of various lipid modifications into the peptide. Here, we repurpose hydrocarbon-modified amino acids used in peptide stapling for the orthogonal introduction of hydrophobic modifications into the CPP structure during peptide synthesis. Our data show that α,α-disubstituted alkenyl-alanines can be successfully utilized to introduce hydrophobic modifications into CPPs to improve their ability to formulate SSOs into nanoparticles (NPs), and to mediate high delivery efficacy and tolerability both in vitro and in vivo. Conclusively, our results offer a new flexible approach for the sequence-specific introduction of hydrophobicity into the structure of CPPs and for improving their delivery properties.
5.	Blockhuys, Stephanie, 1983, et al. (författare) Evaluation of ATOX1 as a potential predictive biomarker for tetrathiomolybdate treatment of breast cancer patients with high risk of recurrence 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:12 Tidskriftsartikel (refereegranskat)abstract Copper plays a key role in cancer metastasis, which is the most common cause of cancer death. Copper depletion treatment with tetrathiomolybdate (TM) improved disease-free survival in breast cancer patients with high risk of recurrence in a phase II clinical trial. Because the copper metallochaperone ATOX1 was recently reported to drive breast cancer cell migration and breast cancer migration is a critical factor in metastasis, we tested if ATOX1 expression levels in primary tumor tissue could predict the TM treatment outcome of breast cancer patients at high risk of recurrence. We performed ATOX1 immunohistochemical staining of breast tumor material (before TM treatment) of 47 patients enrolled in the phase II TM clinical trial and evaluated ATOX1 expression levels in relation with patient outcome after TM treatment. Our results show that higher ATOX1 levels in the tumor cell cytoplasm correlate with a trend towards better event-free survival after TM treatment for triple-negative breast cancer patients and patients at stage III of disease. In conclusion, ATOX1 may be a potential predictive biomarker for TM treatment of breast cancer patients at high risk of recurrence and should be tested in a larger cohort of patients.
6.	Bompada, Pradeep, et al. (författare) Epigenome-Wide Histone Acetylation Changes in Peripheral Blood Mononuclear Cells in Patients with Type 2 Diabetes and Atherosclerotic Disease 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:12 Tidskriftsartikel (refereegranskat)abstract There is emerging evidence of an association between epigenetic modifications, glycemic control and atherosclerosis risk. In this study, we mapped genome-wide epigenetic changes in patients with type 2 diabetes (T2D) and advanced atherosclerotic disease. We performed chromatin immunoprecipitation sequencing (ChIP-seq) using a histone 3 lysine 9 acetylation (H3K9ac) mark in peripheral blood mononuclear cells from patients with atherosclerosis with T2D (n = 8) or without T2D (ND, n = 10). We mapped epigenome changes and identified 23,394 and 13,133 peaks in ND and T2D individuals, respectively. Out of all the peaks, 753 domains near the transcription start site (TSS) were unique to T2D. We found that T2D in atherosclerosis leads to an H3K9ac increase in 118, and loss in 63 genomic regions. Furthermore, we discovered an association between the genomic locations of significant H3K9ac changes with genetic variants identified in previous T2D GWAS. The transcription factor 7-like 2 (TCF7L2) rs7903146, together with several human leukocyte antigen (HLA) variants, were among the domains with the most dramatic changes of H3K9ac enrichments. Pathway analysis revealed multiple activated pathways involved in immunity, including type 1 diabetes. Our results present novel evidence on the interaction between genetics and epigenetics, as well as epigenetic changes related to immunity in patients with T2D and advanced atherosclerotic disease.
7.	Cheung, Pierre, et al. (författare) PET Imaging of GPR44 by Antagonist [C-11]MK-7246 in Pigs 2021 Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 9:4 Tidskriftsartikel (refereegranskat)abstract A validated imaging marker for beta-cell mass would improve understanding of diabetes etiology and enable new strategies in therapy development. We previously identified the membrane-spanning protein GPR44 as highly expressed and specific to the beta cells of the pancreas. The selective GPR44 antagonist MK-7246 was radiolabeled with carbon-11 and the resulting positron-emission tomography (PET) tracer [C-11]MK-7246 was evaluated in a pig model and in vitro cell lines. The [C-11]MK-7246 compound demonstrated mainly hepatobiliary excretion with a clearly defined pancreas, no spillover from adjacent tissues, and pancreatic binding similar in magnitude to the previously evaluated GPR44 radioligand [C-11]AZ12204657. The binding could be blocked by preadministration of nonradioactive MK-7246, indicating a receptor-binding mechanism. [C-11]MK-7246 showed strong potential as a PET ligand candidate for visualization of beta-cell mass (BCM) and clinical translation of this methodology is ongoing.
8.	Cheung, Pierre, et al. (författare) The Current State of Beta-Cell-Mass PET Imaging for Diabetes Research and Therapies 2021 Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 9:12 Tidskriftsartikel (refereegranskat)abstract Diabetes is a chronic metabolic disease affecting over 400 million people worldwide and one of the leading causes of death, especially in developing nations. The disease is characterized by chronic hyperglycemia, caused by defects in the insulin secretion or action pathway. Current diagnostic methods measure metabolic byproducts of the disease such as glucose level, glycated hemoglobin (HbA1c), insulin or C-peptide levels, which are indicators of the beta-cell function. However, they inaccurately reflect the disease progression and provide poor longitudinal information. Beta-cell mass has been suggested as an alternative approach to study disease progression in correlation to beta-cell function, as it behaves differently in the diabetes physiopathology. Study of the beta-cell mass, however, requires highly invasive and potentially harmful procedures such as pancreatic biopsies, making diagnosis and monitoring of the disease tedious. Nuclear medical imaging techniques using radiation emitting tracers have been suggested as strong non-invasive tools for beta-cell mass. A highly sensitive and high-resolution technique, such as positron emission tomography, provides an ideal solution for the visualization of beta-cell mass, which is particularly essential for better characterization of a disease such as diabetes, and for estimating treatment effects towards regeneration of the beta-cell mass. Development of novel, validated biomarkers that are aimed at beta-cell mass imaging are thus highly necessary and would contribute to invaluable breakthroughs in the field of diabetes research and therapies. This review aims to describe the various biomarkers and radioactive probes currently available for positron emission tomography imaging of beta-cell mass, as well as highlight the need for precise quantification and visualization of the beta-cell mass for designing new therapy strategies and monitoring changes in the beta-cell mass during the progression of diabetes.
9.	Coggi, D, et al. (författare) Relationship between Circulating PCSK9 and Markers of Subclinical Atherosclerosis-The IMPROVE Study 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:7 Tidskriftsartikel (refereegranskat)abstract (1) Background and purpose: circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key regulators of cholesterol metabolism. Despite this, its role as a player in atherosclerosis development is still matter of debate. Here, we investigated the relationships between this protein and several markers of subclinical atherosclerosis. (2) Methods: the IMPROVE study enrolled 3703 European subjects (54–79 years; 48% men; with ≥3 vascular risk factors), asymptomatic for cardiovascular diseases. PCSK9 levels were measured by ELISA. B-mode ultrasound was used to measure markers of carotid subclinical atherosclerosis. (3) Results: in the crude analysis, PCSK9 levels were associated with several baseline measures of carotid intima-media thickness (cIMT) (all p < 0.0001); with cIMT change over time (Fastest-IMTmax-progr) (p = 0.01); with inter-adventitia common carotid artery diameter (ICCAD) (p < 0.0001); and with the echolucency (Grey Scale Median; GSM) of both carotid plaque and plaque-free common carotid IMT (both p < 0.0001). However, after adjustment for age, sex, latitude, and pharmacological treatment, all the afore-mentioned correlations were no longer statistically significant. The lack of correlation was also observed after stratification for sex, latitude, and pharmacological treatments. (4) Conclusions: in subjects who are asymptomatic for cardiovascular diseases, PCSK9 plasma levels do not correlate with vascular damage and/or subclinical atherosclerosis of extracranial carotid arteries.
10.	Colombo, GI, et al. (författare) The Association between HDL-C and Subclinical Atherosclerosis Depends on CETP Plasma Concentration: Insights from the IMPROVE Study 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:3 Tidskriftsartikel (refereegranskat)abstract The impact of cholesteryl ester transfer protein (CETP) on atherosclerosis is highly debated. This study aimed to investigate the associations between plasma CETP or CETP genotypes and carotid intima-media thickness (cIMT) and the influence of high-density lipoprotein cholesterol (HDL-C) on these associations. Plasma CETP and HDL-C concentrations were measured in 552 subjects free of any pharmacological treatment from the IMPROVE cohort, which includes 3711 European subjects at high cardiovascular risk. CETP single-nucleotide polymorphisms (SNPs) and cIMT measures (cIMTmax; cIMTmean–max of bifurcations, common and internal carotids; plaque-free common carotid [PF CC]-IMTmean) were available for the full cohort. In drug-free subjects, plasma CETP correlated with HDL-C levels (r = 0.19, p < 0.0001), but not with cIMT variables. When stratified according to HDL-C quartiles, CETP positively correlated with cIMTmax and cIMTmean–max, but not with PF CC-IMTmean, in the top HDL-C quartile only. Positive associations between the CETP concentration and cIMTmax or cIMTmean–max were found in the top HDL-C quartile, whereas HDL-C levels were negatively correlated with cIMTmax and cIMTmean–max when the CETP concentration was below the median (HDL-C × CETP interaction, p = 0.001 and p = 0.003 for cIMTmax and cIMTmean–max, respectively). In the full cohort, three CETP SNPs (rs34760410, rs12920974, rs12708968) were positively associated with cIMTmax. rs12444708 exhibited a significant interaction with HDL-C levels in the prediction of cIMTmax. In conclusion, a significant interplay was found between plasma CETP and/or CETP genotype and HDL-C in the prediction of carotid plaque thickness, as indexed by cIMTmax. This suggests that the association of HDL-C with carotid atherosclerosis is CETP-dependent.
11.	Durual, S, et al. (författare) Pre-Treat Xenogenic Collagenous Blocks of Bone Substitutes with Saline Facilitate Their Manipulation and Guarantee High Bone Regeneration Rates, Qualitatively and Quantitatively 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:3 Tidskriftsartikel (refereegranskat)abstract Deproteinized bovine bone mineral particles embedded in collagen (DBBM-C) are widely used for bone regenerations with excellent, albeit sometimes variable clinical outcomes. Clinicians usually prepare DBBM-C by mixing with blood. Replacing blood by saline represents an alternative. We investigated if saline treatment could improve DBBM-C i. handling in vitro and ii. biological performances in a rabbit calvarial model. In vitro, DBBM-C blocks soaked in saline or blood were submitted to compression tests. In vivo, four poly ether ether ketone (PEEK)cylinders were placed on 16 rabbit skulls, filled with DBBM-C soaked in blood or saline for 2–4–8–12 weeks before histomorphometry. DBBM-C blocks were fully hydrated after 30 s in saline when 120 s in blood could not hydrate blocks core. Stiffness gradually decreased 2.5-fold after blood soaking whereas a six-fold decrease was measured after 30 s in saline. In vivo, saline treatment allowed 50% more bone regeneration during the first month when compared to blood soaking. This difference was then no longer visible. New bone morphology and maturity were equivalent in both conditions. DBBM-C saline-soaking facilitated its handling and accelerated bone regeneration of highly qualitative tissues when compared to blood treatment. Saline pretreatment thus may increase the clinical predictability of bone augmentation procedures.
12.	Elksnis, Andris, et al. (författare) Pharmacological Inhibition of NOX4 Improves Mitochondrial Function and Survival in Human Beta-Cells 2021 Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 9:12 Tidskriftsartikel (refereegranskat)abstract Previous studies have reported beneficial effects of NADPH oxidase 4 (NOX4) inhibition on beta-cell survival in vitro and in vivo. The mechanisms by which NOX4 inhibition protects insulin producing cells are, however, not known. The aim of the present study was to investigate the effects of a pharmacological NOX4 inhibitor (GLX7013114) on human islet and EndoC-beta H1 cell mitochondrial function, and to correlate such effects with survival in islets of different size, activity, and glucose-stimulated insulin release responsiveness. We found that maximal oxygen consumption rates, but not the rates of acidification and proton leak, were increased in islets after acute NOX4 inhibition. In EndoC-beta H1 cells, NOX4 inhibition increased the mitochondrial membrane potential, as estimated by JC-1 fluorescence; mitochondrial reactive oxygen species (ROS) production, as estimated by MitoSOX fluorescence; and the ATP/ADP ratio, as assessed by a bioluminescent assay. Moreover, the insulin release from EndoC-beta H1 cells at a high glucose concentration increased with NOX4 inhibition. These findings were paralleled by NOX4 inhibition-induced protection against human islet cell death when challenged with high glucose and sodium palmitate. The NOX4 inhibitor protected equally well islets of different size, activity, and glucose responsiveness. We conclude that pharmacological alleviation of NOX4-induced inhibition of beta-cell mitochondria leads to increased, and not decreased, mitochondrial ROS, and this was associated with protection against cell death occurring in different types of heterogeneous islets. Thus, NOX4 inhibition or modulation may be a therapeutic strategy in type 2 diabetes that targets all types of islets.
13.	Hallqvist, Andreas, 1973, et al. (författare) Optimizing the Schedule of PARP Inhibitors in Combination with 177Lu-DOTATATE: A Dosimetry Rationale. 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:11 Tidskriftsartikel (refereegranskat)abstract 177Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair 177Lu-induced DNA damage. To decrease the risk of side effects, the sequencing should be optimized according to the tumour-to-normal tissue enhanced dose ratio (TNED). The aim of this study was to investigate how to enhance 177Lu-DOTATATE by optimal timing of the addition of a PARP inhibitor. Biokinetic modelling was performed based on the absorbed dose to the bone marrow, kidneys and tumour; determined from SPECT/CT and planar images from 17 patients treated with 177Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during 177Lu-DOTATATE treatment, the concept of relative biological effectiveness (RBE) was used, and PARP inhibitor administration was simulated over different time intervals. The absorbed dose rate for the tumour tissue demonstrated an initial increase phase until 12 h after infusion followed by a slow decrease. In contrast, the bone marrow showed a rapid initial dose rate decrease. Twenty-eight days after infusion of 177Lu-DOTATATE, the full absorbed dose to the bone marrow and kidney was reached. Using an RBE value of 2 for both the tumour and normal tissues, the TNED was increased compared to 177Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of 177Lu-DOTATATE treatment and be continued for up to four weeks to optimize the TNED. Based on these results, a phase I trial assessing the combination of olaparib and 177Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267).
14.	Horn, Nina, et al. (författare) Atp7a-regulated enzyme metalation and trafficking in the menkes disease puzzle 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:4 Forskningsöversikt (refereegranskat)abstract Copper is vital for numerous cellular functions affecting all tissues and organ systems in the body. The copper pump, ATP7A is critical for whole-body, cellular, and subcellular copper homeostasis, and dysfunction due to genetic defects results in Menkes disease. ATP7A dysfunction leads to copper deficiency in nervous tissue, liver, and blood but accumulation in other tissues. Site-specific cellular deficiencies of copper lead to loss of function of copper-dependent enzymes in all tissues, and the range of Menkes disease pathologies observed can now be explained in full by lack of specific copper enzymes. New pathways involving copper activated lysosomal and steroid sulfatases link patient symptoms usually related to other inborn errors of metabolism to Menkes disease. Additionally, new roles for lysyl oxidase in activation of molecules necessary for the innate immune system, and novel adapter molecules that play roles in ERGIC trafficking of brain receptors and other proteins, are emerging. We here summarize the current knowledge of the roles of copper enzyme function in Menkes disease, with a focus on ATP7A-mediated enzyme metalation in the secretory pathway. By establishing mechanistic relationships between copper-dependent cellular processes and Menkes disease symptoms in patients will not only increase understanding of copper biology but will also allow for the identification of an expanding range of copper-dependent enzymes and pathways. This will raise awareness of rare patient symptoms, and thus aid in early diagnosis of Menkes disease patients.
15.	Isaguliants, M, et al. (författare) Prevalence and Risk Factors of Infection with High Risk Human Papilloma Viruses among HIV-Positive Women with Clinical Manifestations of Tuberculosis in a Middle-Income Country 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:6 Tidskriftsartikel (refereegranskat)abstract Women living with HIV-1 are at high risk of infection with human papillomavirus of high carcinogenic risk (HR HPVs). M. tuberculosis (TB) promotes HPV infection and increases the risk to develop HPV-associated cancer. Our knowledge of persisting HR HPVs genotypes, and of the factors promoting HR HPV infection in people living with HIV-1 with clinical TB manifestations is sparse. Here, we analyzed 58 women living with HIV-1 with clinical TB manifestations (WLWH with TB) followed up in specialized centers in Russia, a middle income country endemic for HIV-1 and TB, for the presence in cervical smears of DNA of twelve HR HPV genotypes. DNA encoding HPV16 E5, E6/E7 was sequenced. Sociodemographic data of patients was collected by questionnaire. All women were at C2-C3 stages of HIV-infection (by CDC). The majority were over 30 years old, had secondary education, were unemployed, had sexual partners, experienced 2–3 pregnancies and at least one abortion, and were smokers. The most prevalent was HPV16 detected in the cervical smears of 38% of study participants. Altogether 34.5% of study participants were positive for HR HPV types other than HPV16; however, but none of these types was seen in more than 7% of tested samples. Altogether, 20.7% of study participants were positive for several HR HPV types. Infections with HPVs other than HPV16 were common among WLWH with generalized TB receiving combined ART/TB-therapy, and associated with their ability to work, indirectly reflecting both their health and lifestyle. The overall prevalence of HR HPVs was associated with sexual activity of women reflected by the number of pregnancies, and of HPV 16, with young age; none was associated to CD4+-counts, route of HIV-infection, duration of life with HIV, forms of TB-infection, or duration of ART, characterizing the immune status. Thus, WLWH with TB—especially young—were predisposed to infection with HPV16, advancing it as a basis for a therapeutic HPV vaccine. Phylogenetic analysis of HPV16 E5, E6/E7 DNA revealed no common ancestry; sequences were similar to those of the European and American HPV16 strains, indicating that HPV vaccine for WLWH could be the same as HPV16 vaccines developed for the general population. Sociodemographic and health correlates of HR HPV prevalence in WLWH deserve further analysis to develop criteria/recommendations for prophylactic catch-up and therapeutic HPV vaccination of this highly susceptible and vulnerable population group.
16.	Keuenhof, Katharina, 1994, et al. (författare) High-resolution episcopic microscopy (Hrem) in multimodal imaging approaches 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:12 Tidskriftsartikel (refereegranskat)abstract High-resolution episcopic microscopy (HREM) is a three-dimensional (3D) episcopic imaging modality based on the acquisition of two-dimensional (2D) images from the cut surface of a block of tissue embedded in resin. Such images, acquired serially through the entire length/depth of the tissue block, are aligned and stacked for 3D reconstruction. HREM has proven to be specifically advantageous when integrated in correlative multimodal imaging (CMI) pipelines. CMI creates a composite and zoomable view of exactly the same specimen and region of interest by (sequentially) correlating two or more modalities. CMI combines complementary modalities to gain holistic structural, functional, and chemical information of the entire sample and place molecular details into their overall spatiotemporal multiscale context. HREM has an advantage over in vivo 3D imaging techniques on account of better histomorphologic resolution while simultaneously providing volume data. HREM also has certain advantages over ex vivo light microscopy modalities. The latter can provide better cellular resolution but usually covers a limited area or volume of tissue, with limited 3D structural context. HREM has predominantly filled a niche in the phenotyping of embryos and characterisation of anatomic developmental abnormalities in various species. Under the umbrella of CMI, when combined with histopathology in a mutually complementary manner, HREM could find wider application in additional nonclinical and translational areas. HREM, being a modified histology technique, could also be incorporated into specialised preclinical pathology workflows. This review will highlight HREM as a versatile imaging platform in CMI approaches and present its benefits and limitations. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
17.	Kumar, S, et al. (författare) In Vivo Lentiviral Gene Delivery of HLA-DR and Vaccination of Humanized Mice for Improving the Human T and B Cell Immune Reconstitution 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:8 Tidskriftsartikel (refereegranskat)abstract Humanized mouse models generated with human hematopoietic stem cells (HSCs) and reconstituting the human immune system (HIS-mice) are invigorating preclinical testing of vaccines and immunotherapies. We have recently shown that human engineered dendritic cells boosted bonafide human T and B cell maturation and antigen-specific responses in HIS-mice. Here, we evaluated a cell-free system based on in vivo co-delivery of lentiviral vectors (LVs) for expression of a human leukocyte antigen (HLA-DRA01/ HLA-DRB10401 functional complex, “DR4”), and a LV vaccine expressing human cytokines (GM-CSF and IFN-α) and a human cytomegalovirus gB antigen (HCMV-gB). Humanized NOD/Rag1null/IL2Rγnull (NRG) mice injected by i.v. with LV-DR4/fLuc showed long-lasting (up to 20 weeks) vector distribution and expression in the spleen and liver. In vivo administration of the LV vaccine after LV-DR4/fLuc delivery boosted the cellularity of lymph nodes, promoted maturation of terminal effector CD4+ T cells, and promoted significantly higher development of IgG+ and IgA+ B cells. This modular lentigenic system opens several perspectives for basic human immunology research and preclinical utilization of LVs to deliver HLAs into HIS-mice.
18.	Lam, Simon, et al. (författare) Systems Analysis Reveals Ageing-Related Perturbations in Retinoids and Sex Hormones in Alzheimer's and Parkinson's Diseases 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:10 Tidskriftsartikel (refereegranskat)abstract Neurodegenerative diseases, including Alzheimer's (AD) and Parkinson's diseases (PD), are complex heterogeneous diseases with highly variable patient responses to treatment. Due to the growing evidence for ageing-related clinical and pathological commonalities between AD and PD, these diseases have recently been studied in tandem. In this study, we analysed transcriptomic data from AD and PD patients, and stratified these patients into three subclasses with distinct gene expression and metabolic profiles. Through integrating transcriptomic data with a genome-scale metabolic model and validating our findings by network exploration and co-analysis using a zebrafish ageing model, we identified retinoids as a key ageing-related feature in all subclasses of AD and PD. We also demonstrated that the dysregulation of androgen metabolism by three different independent mechanisms is a source of heterogeneity in AD and PD. Taken together, our work highlights the need for stratification of AD/PD patients and development of personalised and precision medicine approaches based on the detailed characterisation of these subclasses.
19.	Larsson, Anders, et al. (författare) Strong Associations between Plasma Osteopontin and Several Inflammatory Chemokines, Cytokines, and Growth Factors 2021 Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 9:8, s. 908- Tidskriftsartikel (refereegranskat)abstract Osteopontin is a member of the proinflammatory cytokine network, a complex system that involves many chemokines, cytokines, and growth factors. The aim of the present study was to study the associations between osteopontin and a large number of chemokines, cytokines, and growth factors. We analyzed plasma and urine osteopontin in 652 men from the Uppsala Longitudinal Study of Adult Men (ULSAM) study cohort and compared the levels with the levels of eighty-five chemokines, cytokines, and growth factors. We found significant associations between plasma osteopontin and 37 plasma biomarkers in a model adjusted for age, and 28 of those plasma biomarkers were significant in a model also adjusting for cardiovascular risk factors. There were no significant associations after Bonferroni adjustment between urine osteopontin and any of the studied plasma cytokine biomarkers. This study shows that circulating osteopontin participates in a protein-protein interaction network of chemokines, cytokines, and growth factors. The network contains responses, pathways, and receptor binding interactions relating to cytokines, regulation of the immune system, and also regulation of apoptosis and intracellular signal transduction.
20.	Liao, ZH, et al. (författare) Cellular Senescence: Mechanisms and Therapeutic Potential 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:12 Tidskriftsartikel (refereegranskat)abstract Cellular senescence is a complex and multistep biological process which cells can undergo in response to different stresses. Referring to a highly stable cell cycle arrest, cellular senescence can influence a multitude of biological processes—both physiologically and pathologically. While phenotypically diverse, characteristics of senescence include the expression of the senescence-associated secretory phenotype, cell cycle arrest factors, senescence-associated β-galactosidase, morphogenesis, and chromatin remodelling. Persistent senescence is associated with pathologies such as aging, while transient senescence is associated with beneficial programmes, such as limb patterning. With these implications, senescence-based translational studies, namely senotherapy and pro-senescence therapy, are well underway to find the cure to complicated diseases such as cancer and atherosclerosis. Being a subject of major interest only in the recent decades, much remains to be studied, such as regarding the identification of unique biomarkers of senescent cells. This review attempts to provide a comprehensive understanding of the diverse literature on senescence, and discuss the knowledge we have on senescence thus far.
21.	Lin, T, et al. (författare) Neuronal Trafficking of the Amyloid Precursor Protein-What Do We Really Know? 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:7 Tidskriftsartikel (refereegranskat)abstract Alzheimer’s disease (AD) is the most common type of dementia, contributing to 60–80% of cases. It is a neurodegenerative disease that usually starts symptomless in the first two to three decades and then propagates into a long-term, irreversible disease, resulting in the progressive loss of memory, reasoning, abstraction and language capabilities. It is a complex disease, involving a large number of entangled players, and there is no effective treatment to cure it or alter its progressive course. Therefore, a thorough understanding of the disease pathology and an early diagnosis are both necessary. AD has two significant pathological hallmarks: extracellular senile plaques composed of amyloid β-peptide (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, and the aggregation of Aβ, which starts in earlier stages, is usually claimed to be the primary cause of AD. Secretases that cleave Aβ precursor protein (APP) and produce neurotoxic Aβ reside in distinct organelles of the cell, and current concepts suggest that APP moves between distinct intracellular compartments. Obviously, APP transport and processing are intimately related processes that cannot be dissociated from each other, and, thus, how and where APP is transported determines its processing fate. In this review, we summarize critical mechanisms underlying neuronal APP transport, which we divide into separate parts: (1) secretory pathways and (2) endocytic and autophagic pathways. We also include two lipoprotein receptors that play essential roles in APP transport: sorting-related receptor with A-type repeats and sortilin. Moreover, we consider here some major disruptions in the neuronal transport of APP that contribute to AD physiology and pathology. Lastly, we discuss current methods and technical difficulties in the studies of APP transport.
22.	Masini, D, et al. (författare) A Guide to the Generation of a 6-Hydroxydopamine Mouse Model of Parkinson's Disease for the Study of Non-Motor Symptoms 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:6 Tidskriftsartikel (refereegranskat)abstract In Parkinson’s disease (PD), a large number of symptoms affecting the peripheral and central nervous system precede, develop in parallel to, the cardinal motor symptoms of the disease. The study of these conditions, which are often refractory to and may even be exacerbated by standard dopamine replacement therapies, relies on the availability of appropriate animal models. Previous work in rodents showed that injection of the neurotoxin 6-hydroxydopamine (6-OHDA) in discrete brain regions reproduces several non-motor comorbidities commonly associated with PD, including cognitive deficits, depression, anxiety, as well as disruption of olfactory discrimination and circadian rhythm. However, the use of 6-OHDA is frequently associated with significant post-surgical mortality. Here, we describe the generation of a mouse model of PD based on bilateral injection of 6-OHDA in the dorsal striatum. We show that the survival rates of males and females subjected to this lesion differ significantly, with a much higher mortality among males, and provide a protocol of enhanced pre- and post-operative care, which nearly eliminates animal loss. We also briefly discuss the utility of this model for the study of non-motor comorbidities of PD.
23.	Mojumdar, Enamul Haque, et al. (författare) Probing skin barrier recovery on molecular level following acute wounds : An in vivo/ex vivo study on pigs 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:4 Tidskriftsartikel (refereegranskat)abstract Proper skin barrier function is paramount for our survival, and, suffering injury, there is an acute need to restore the lost barrier and prevent development of a chronic wound. We hypothesize that rapid wound closure is more important than immediate perfection of the barrier, whereas specific treatment may facilitate perfection. The aim of the current project was therefore to evaluate the quality of restored tissue down to the molecular level. We used Göttingen minipigs with a multi-technique approach correlating wound healing progression in vivo over three weeks, monitored by classical methods (e.g., histology, trans-epidermal water loss (TEWL), pH) and subsequent physicochemical characterization of barrier recovery (i.e., small and wide-angle X-ray diffraction (SWAXD), polarization transfer solid-state NMR (PTssNMR), dynamic vapor sorption (DVS), Fourier transform infrared (FTIR)), providing a unique insight into molecular aspects of healing. We conclude that although acute wounds sealed within two weeks as expected, molecular investigation of stratum corneum (SC) revealed a poorly developed keratin organization and deviations in lipid lamellae formation. A higher lipid fluidity was also observed in regenerated tissue. This may have been due to incomplete lipid conversion during barrier recovery as glycosphingolipids, normally not present in SC, were indicated by infrared FTIR spectroscopy. Evidently, a molecular approach to skin barrier recovery could be a valuable tool in future development of products targeting wound healing.
24.	Morettini, Micaela, et al. (författare) Hepatic and extrahepatic insulin clearance in mice with double deletion of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:8 Tidskriftsartikel (refereegranskat)abstract The aim of this study was to investigate whether incretins, at physiological levels, affect hepatic and/or extrahepatic insulin clearance. Hepatic and extrahepatic insulin clearance was studied in 31 double incretin receptor knockout (DIRKO) and 45 wild-type (WT) mice, which underwent an Intravenous Glucose Tolerance Test (IVGTT). A novel methodology based on mathematical modeling was designed to provide two sets of values (FEL-P1, CLP-P1; FEL-P2, CLP-P2 ) accounting for hepatic and extrahepatic clearance in the IVGTT first and second phases, respectively, plus the respective total clearances, CLT-P1 and CLT-P2 . A statistically significant difference between DIRKO and WT was found in CLT-P1 (0.61 [0.48–0.82] vs. 0.51 [0.46–0.65] (median [interquartile range]); p = 0.02), which was reflected in the peripheral component, CLP-P1 (0.18 [0.13–0.27] vs. 0.15 [0.11–0.22]; p = 0.04), but not in the hepatic component, FEL-P1 (29.7 [26.7–34.9] vs. 28.9 [25.7–32.0]; p = 0.18). No difference was detected between DIRKO and WT in CLT-P2 (1.38 [1.13–1.75] vs. 1.69 [1.48–1.87]; p = 0.10), neither in CLP-P2 (0.72 [0.64–0.81] vs. 0.79 [0.69–0.87]; p = 0.27) nor in FEL-P2 (37.8 [35.1–43.1] vs. 39.8 [35.8–44.2]; p = 0.46). In conclusion, our findings suggest that the higher insulin clearance observed in DIRKO compared with WT during the IVGTT first phase may be due to its extrahepatic component.
25.	Ntika, S, et al. (författare) Syndecan-1 Expression Is Increased in the Aortic Wall of Patients with Type 2 Diabetes but Is Unrelated to Elevated Fasting Plasma Glucagon-Like Peptide-1 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:6 Tidskriftsartikel (refereegranskat)abstract A reduced prevalence of a thoracic aortic aneurysm (thoracic AA) is observed in type 2 diabetes (T2D). Glucagon-like peptide-1 (GLP-1)/GLP-1-based anti-diabetic therapy has indicated protective effects in thoracic AA and regulates the processes controlling the vascular tissue expression of Syndecan-1 (Sdc-1). Sdc-1 expression on macrophages infiltrating the aortic tissue contributes to a counter-regulatory response to thoracic AA formation in animal models through the interplay with inflammation/proteolytic activity. We hypothesized that elevated fasting plasma GLP-1 (fpGLP-1) increases the aortic Sdc-1 expression in T2D, which may contribute to a reduced prevalence of thoracic AA. Consequently, we determined whether T2D/thoracic AA associates with an altered Sdc-1 expression in the aortic tissue and the possible associations with fpGLP-1 and inflammation/proteolytic activity. From a cohort of surgical patients with an aortic valve pathology, we compared different disease groups (T2D/thoracic AA) with the same sub-cohort group of controls (patients without T2D and thoracic AA). The MMP-2 activity and Sdc-1, GLP-1R and CD68 expression were analyzed in the aortic tissue. GLP-1, Sdc-1 and cytokines were analyzed in the plasma. The aortic Sdc-1 expression was increased in T2D patients but did not correlate with fpGLP-1. Thoracic AA was associated with an increased aortic expression of Sdc-1 and the macrophage marker CD68. CD68 was not detected in T2D. In conclusion, an increased aortic Sdc-1 expression may contribute to a reduced prevalence of thoracic AA in T2D.
26.	Perez-Ruiz, E, et al. (författare) Liquid Biopsy as a Tool for the Characterisation and Early Detection of the Field Cancerization Effect in Patients with Oral Cavity Carcinoma 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:10 Tidskriftsartikel (refereegranskat)abstract Oral squamous cell carcinoma (OSCC) constitutes approximately 25% of all head and neck cancer, for which the consumption of tobacco and alcohol are the main associated risk factors. The field cancerization effect of OSCC is one of the main reasons for the poor survival rates associated with this disease. Despite some advances, its ccharacterization and early diagnosis continue to challenge modern oncology, and the goal of improving the prognosis remains to be achieved. Among new early diagnostic tools for OSCC that have been proposed, liquid biopsy appears to be an ideal candidate, as studies have shown that the analysis of blood and saliva provides promising data for the early detection of relapses or second tumours.
27.	Rauch, L, et al. (författare) Bisphosphonates for the Treatment of Calcinosis Cutis-A Retrospective Single-Center Study 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:11 Tidskriftsartikel (refereegranskat)abstract (1) Background: Calcinosis cutis is a frequent symptom of autoimmune connective tissue diseases leading to pain, transcutaneous expulsion of calcified material and bacterial superinfection. There is a high need for new therapeutic options as no standardized treatment algorithm is established. While case reports indicate beneficial effects of bisphosphonates, standardized evaluation of treatment effects is missing. (2) Methods: In this retrospective analysis we evaluate the effects of intravenous pamidronate, a second-generation bisphosphonate, in seven patients with calcinosis cutis using consecutive clinical pictures, radiological examinations and patient’s subjective evaluation. (3) Results: 5/6 patients reported a reduction of pain, improvement of general condition and cessation of calcinosis progression. Regression of skin lesions was detectable in clinical pictures of 2/6 patients, while 1/6 patients had stable disease. Radiological examination revealed improvement or stable disease in 3/5 patients. Fever was the most common side effect. One out of seven patients developed osteonecrosis of the jaw. (4) Conclusions: Bisphosphonates appear to have beneficial effects in a subgroup of calcinosis cutis patients. While patient’s subjective evaluation was mainly positive, objective assessments showed improvement in approximately half of the cases. With regard to potential severe side effects, a careful risk-benefit evaluation is necessary before treatment initiation.
28.	Ruge, Toralph, et al. (författare) A comparison between endostatin and conventional biomarkers on 30-day mortality and renal replacement therapy in unselected intensive care patients 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:11 Tidskriftsartikel (refereegranskat)abstract Endostatin may predict mortality and kidney impairment in general populations as well as in critically ill patients. We decided to explore the possible role of endostatin as a predictor of 30-day mortality, acute kidney injury (AKI), and renal replacement therapy (RRT) in a cohort of unselected intensive care unit (ICU) patients. Endostatin and creatinine in plasma were analyzed and SAPS3 was determined in 278 patients on ICU arrival at admission to a Swedish medium-sized hospital. SAPS3 had the highest predictive value, 0.85 (95% C.I.: 0.8–0.90), for 30-day mortality. Endostatin, in combination with age, predicted 30-day mortality by 0.76 (95% C.I.: 0.70–0.82). Endostatin, together with age and creatinine, predicted AKI with 0.87 (95% C.I.: 0.83–0.91). Endostatin predicted AKI with [0.68 (0.62–0.74)]. Endostatin predicted RRT, either alone [0.82 (95% C.I.: 0.72–0.91)] or together with age [0.81 (95% C.I.: 0.71–0.91)]. The predicted risk for 30-day mortality, AKI, or RRT during the ICU stay, predicted by plasma endostatin, was not influenced by age. Compared to the complex severity score SAPS3, circulating endostatin, combined with age, offers an easily managed option to predict 30-day mortality. Additionally, circulating endostatin combined with creatinine was closely associated with AKI development.
29.	Schoch, Sarah, et al. (författare) In vitro nephrotoxicity studies of established and experimental platinum-based compounds 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:8 Tidskriftsartikel (refereegranskat)abstract Cisplatin is one of the most commonly used drugs for the treatment of various solid cancers. However, its efficacy is restricted by severe side effects, especially dose-limiting nephrotoxicity. New platinum-based compounds are designed to overcome this limitation. Previous investigations showed that the platinum(IV)–nitroxyl complex PN149 is highly cytotoxic in various tumor cell lines. In the present study, investigations with PN149 were extended to normal human kidney tubule epithelia. Coincident with higher intracellular platinum accumulation, the cytotoxicity of PN149 in the proximal tubule epithelial cell line ciPTEC was more pronounced compared to the established platinum chemotherapeutics cisplatin, carboplatin and oxaliplatin. Quantitative gene expression profiling revealed the induction of ROS-inducible and anti-oxidative genes, suggesting an oxidative stress response by PN149. However, in contrast to cisplatin, no pro-inflammatory response was observed. Genes coding for distinct DNA damage response factors and genes related to apoptosis were up-regulated, indicating the activation of the DNA damage response system and induction of the apoptotic cascade by PN149. Altogether, a comparable transcriptional response was observed for PN149 and the platinum chemotherapeutics. However, the lack of inflammatory activity, which is a possible cause contributing to toxicity in human renal proximal tubule epithelia, might indicate the reduced nephrotoxic potential of PN149.
30.	Sereti, Evangelia, et al. (författare) Study of the relationship between sigma receptor expression levels and some common sigma ligand activity in cancer using human cancer cell lines of the nci-60 cell line panel 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:1, s. 1-20 Tidskriftsartikel (refereegranskat)abstract Sigma (σ) receptors have attracted great interest since they are implicated in various cellular functions and biological processes and diseases, including various types of cancer. The receptor family consists of two subtypes: sigma-1 (σ1) and sigma-2 (σ2). Both σ receptor subtypes have been proposed as therapeutic targets for various types of cancers, and many studies have provided evidence that their selective ligands (agonists and antagonists) exhibit antiproliferative and cytotoxic activity. Still, the precise mechanism of action of both σ receptors and their ligands remains unclear and needs to be elucidated. In this study, we aimed to simultaneously determine the expression levels of both σ receptor subtypes in several human cancer cell lines. Additionally, we investigated the in vitro antiproliferative activity of some widely used σ1 and σ2 ligands against those cell lines to study the relationship between σ receptor expression levels and σ ligand activity. Finally, we ran the NCI60 COMPARE algorithm to further elucidate the cytotoxic mechanism of action of the selected σ ligands studied herein.
31.	Szczepanczyk, Michal, et al. (författare) Catalase Activity in Keratinocytes, Stratum Corneum, and Defatted Algae Biomass as a Potential Skin Care Ingredient 2021 Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 9:12 Tidskriftsartikel (refereegranskat)abstract The generation of reactive oxygen species presents a destructive challenge for the skin organ and there is a clear need to advance skin care formulations aiming at alleviating oxidative stress. The aim of this work was to characterize the activity of the antioxidative enzyme catalase in keratinocytes and in the skin barrier (i.e., the stratum corneum). Further, the goal was to compare the activity levels with the corresponding catalase activity found in defatted algae biomass, which may serve as a source of antioxidative enzymes, as well as other beneficial algae-derived molecules, to be employed in skin care products. For this, an oxygen electrode-based method was employed to determine the catalase activity and the apparent kinetic parameters for purified catalase, as well as catalase naturally present in HaCaT keratinocytes, excised stratum corneum samples collected from pig ears with various amounts of melanin, and defatted algae biomass from the diatom Phaeodactylum tricornutum. Taken together, this work illustrates the versatility of the oxygen electrode-based method for characterizing catalase function in samples with a high degree of complexity and enables the assessment of sample treatment protocols and comparisons between different biological systems related to the skin organ or algae-derived materials as a potential source of skin care ingredients for combating oxidative stress.
32.	Wilms, Torben, et al. (författare) High Levels of Low-Density Lipoproteins Correlate with Improved Survival in Patients with Squamous Cell Carcinoma of the Head and Neck 2021 Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 9:5 Tidskriftsartikel (refereegranskat)abstract Circulating lipoproteins as risk factors or prognostic indicators for various cancers have been investigated previously; however, no clear consensus has been reached. In this study, we aimed at evaluating the impact of serum lipoproteins on the prognosis of patients with squamous cell carcinoma of the head and neck (SCCHN). Levels of total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides and lipoprotein(a) were measured in serum samples from 106 patients and 28 healthy controls. We found that HDL was the only lipoprotein exhibiting a significant difference in concentration between healthy controls and patients (p = 0.012). Kaplan–Meier survival curves indicated that patients with high levels of total cholesterol or LDL had better overall survival than patients with normal levels (p = 0.028 and p = 0.007, respectively). Looking at patients without lipid medication (n = 89) and adjusting for the effects of TNM stage and weight change, multivariate Cox regression models indicated that LDL was an independent prognostic factor for both overall (p = 0.005) and disease-free survival (p = 0.013). In summary, our study revealed that high LDL level is beneficial for survival outcome in patients with SCCHN. Use of cholesterol-lowering medicines for prevention or management of SCCHN needs to be evaluated carefully.
33.	Xu, Jin, et al. (författare) Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort 2021 Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 9:11 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives.METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD.RESULTS: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046).CONCLUSIONS: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.
34.	Yang, Hong, et al. (författare) Combined Metabolic Activators Decrease Liver Steatosis by Activating Mitochondrial Metabolism in Hamsters Fed with a High-Fat Diet 2021 Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:10 Tidskriftsartikel (refereegranskat)abstract Although the prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase, there is no effective treatment approved for this condition. We previously showed, in high-fat diet (HFD)-fed mice, that the supplementation of combined metabolic activators (CMA), including nicotinamide riboside (NAD(+) precursor) and the potent glutathione precursors serine and N-acetyl-l-cysteine (NAC), significantly decreased fatty liver by promoting fat oxidation in mitochondria. Afterwards, in a one-day proof-of-concept human supplementation study, we observed that this CMA, including also L-carnitine tartrate (LCT), resulted in increased fatty acid oxidation and de novo glutathione synthesis. However, the underlying molecular mechanisms associated with supplementation of CMA have not been fully elucidated. Here, we demonstrated in hamsters that the chronic supplementation of this CMA (changing serine for betaine) at two doses significantly decreased hepatic steatosis. We further generated liver transcriptomics data and integrated these data using a liver-specific genome-scale metabolic model of liver tissue. We systemically determined the molecular changes after the supplementation of CMA and found that it activates mitochondria in the liver tissue by modulating global lipid, amino acid, antioxidant and folate metabolism. Our findings provide extra evidence about the beneficial effects of a treatment based on this CMA against NAFLD.

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