Publications by authors named "Piotr Kozlowski"

207 Publications

A data-driven T relaxation analysis approach for myelin water imaging: Spectrum analysis for multiple exponentials via experimental condition oriented simulation (SAME-ECOS).

Magn Reson Med 2021 Sep 7. Epub 2021 Sep 7.

Physics & Astronomy, University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: The decomposition of multi-exponential decay data into a T spectrum poses substantial challenges for conventional fitting algorithms, including non-negative least squares (NNLS). Based on a combination of the resolution limit constraint and machine learning neural network algorithm, a data-driven and highly tailorable analysis method named spectrum analysis for multiple exponentials via experimental condition oriented simulation (SAME-ECOS) was proposed.

Theory And Methods: The theory of SAME-ECOS was derived. Then, a paradigm was presented to demonstrate the SAME-ECOS workflow, consisting of a series of calculation, simulation, and model training operations. The performance of the trained SAME-ECOS model was evaluated using simulations and six in vivo brain datasets. The code is available at https://github.com/hanwencat/SAME-ECOS.

Results: Using NNLS as the baseline, SAME-ECOS achieved over 15% higher overall cosine similarity scores in producing the T spectrum, and more than 10% lower mean absolute error in calculating the myelin water fraction (MWF), as well as demonstrated better robustness to noise in the simulation tests. Applying to in vivo data, MWF from SAME-ECOS and NNLS was highly correlated among all study participants. However, a distinct separation of the myelin water peak and the intra/extra-cellular water peak was only observed in the mean T spectra determined using SAME-ECOS. In terms of data processing speed, SAME-ECOS is approximately 30 times faster than NNLS, achieving a whole-brain analysis in 3 min.

Conclusion: Compared with NNLS, the SAME-ECOS method yields much more reliable T spectra in a dramatically shorter time, increasing the feasibility of multi-component T decay analysis in clinical settings.
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http://dx.doi.org/10.1002/mrm.29000DOI Listing
September 2021

Impact of a Single Nucleotide Change or Non-Nucleoside Modifications in G-Rich Region on the Quadruplex-Duplex Hybrid Formation.

Biomolecules 2021 08 18;11(8). Epub 2021 Aug 18.

Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704 Poznan, Poland.

In this paper, a method to discriminate between two target RNA sequences that differ by one nucleotide only is presented. The method relies on the formation of alternative structures, i.e., quadruplex-duplex hybrid (QDH) and duplex with dangling ends (Dss), after hybridization of DNA or RNA G-rich oligonucleotides with target sequences containing 5'-GGGCUGG-3' or 5'-GGGCGGG-3' fragments. Using biophysical methods, we studied the effect of oligonucleotide types (DNA, RNA), non-nucleotide modifications (aliphatic linkers or abasic), and covalently attached G4 ligand on the ability of G-rich oligonucleotides to assemble a G-quadruplex motif. We demonstrated that all examined non-nucleotide modifications could mimic the external loops in the G-quadruplex domain of QDH structures without affecting their stability. Additionally, some modifications, in particular the presence of two abasic residues in the G-rich oligonucleotide, can induce the formation of non-canonical QDH instead of the Dss structure upon hybridization to a target sequence containing the GGGCUGG motif. Our results offer new insight into the sequential requirements for the formation of G-quadruplexes and provide important data on the effects of non-nucleotide modifications on G-quadruplex formation.
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http://dx.doi.org/10.3390/biom11081236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392043PMC
August 2021

Influence of Vibroacoustic Therapy on Local Status and Rehabilitation of Post-TKR and Post-THR patients.

Ortop Traumatol Rehabil 2021 Apr;23(2):101-113

Klinika Ortopedii i Ortopedii Dziecięcej Centralnego Szpitala Klinicznego w Łodzi, Polska / Department of Orthopaedics and Pediatric Orthopaedics, Central Teaching Hospital of Medical University in Lodz, Poland.

Background: Rehabilitation following major joint replacement surgery is an extremely important part of complementary treatment after the surgical procedure. To obtain the best final treatment outcome possible, apart from improvements in surgical technique, new methods of rehabilitation are still being sought and implemented to increase its effectiveness, safety and patient comfort. One such technique is vibroacoustic therapy, a method of treatment based on the direct transmission of audible sound vibrations through a sound transmitter to the patient's body. The present study assessed the effectiveness of vibroacoustic therapy in early postoperative rehabilitation of post-TKR and post-THR patients.

Material And Methods: The study involved 60 post-TKR and post-THR patients divided into two groups depending on the type of surgery. Each group was further divided into an experimental group treated with the VITAFON-2 apparatus and a control group treated with a placebo apparatus; all patients also underwent routine kinesiotherapy that is offered at the hospital. Vibroa-coustic treatment was carried out and evaluated during the first 4 days following surgery. Symptom intensity, range of motion of the operated joints, oedema in the operated limb and haematoma absorption were assessed.

Results: Postoperative vibroacoustic therapy performed during the first 4 post-operative days reduced pain more significantly than kinesiotherapy alone. It also clinically improved the absorption of post-traumatic haematomas in post-TKR patients insignificantly better than kinesiotherapy. In post-THR patients who had undergone an anterolateral approach procedure, phoning (vibroacoustic stimulation) significantly sped up the rate of recovery of normal internal rotation angles in the operated joints.

Conclusions: 1. Vibroacoustic therapy applied topically in post-TKR patients exerts a significant positive effect on reducing pain intensity. 2. Topical vibroacoustic therapy does not significantly reduce the oedema around the operated hip and knee joints or increase their range of motion. 3. Vibroacoustic therapy accelerates the absorption of postoperative subcutaneous haematomas in a clinically visible manner.
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http://dx.doi.org/10.5604/01.3001.0014.8139DOI Listing
April 2021

Novel fluorescent-based reporter cell line engineered for monitoring homologous recombination events.

PLoS One 2021 30;16(4):e0237413. Epub 2021 Apr 30.

Institute of Biomedicine and Molecular Genetics (IBGM) of Valladolid, Valladolid, Spain.

Homologous recombination (HR) faithfully restores DNA double-strand breaks. Defects in this HR repair pathway are associated with cancer predisposition. In genetic engineering, HR has been used extensively to study gene function and it represents an ideal method of gene therapy for single gene disorders. Here, we present a novel assay to measure HR in living cells. The HR substrate consisted of a non-fluorescent 3' truncated form of the eGFP gene and was integrated into the AAVS1 locus, known as a safe harbor. The donor DNA template comprised a 5' truncated eGFP copy and was delivered via AAV particles. HR mediated repair restored full-length eGFP coding sequence, resulting in eGFP+ cells. The utility of our assay in quantifying HR events was validated by exploring the impact of the overexpression of HR promoters and the siRNA-mediated silencing of genes known to play a role in DNA repair on the frequency of HR. We conclude that this novel assay represents a useful tool to further investigate the mechanisms that control HR and test continually emerging tools for HR-mediated genome editing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087102PMC
September 2021

Temperature dependence and histological correlation of inhomogeneous magnetization transfer and myelin water imaging in ex vivo brain.

Neuroimage 2021 08 20;236:118046. Epub 2021 Apr 20.

University of British Columbia MRI Research Centre, 2221 Wesbrook Mall, M10 Purdy Pavilion, Vancouver, BC V6T 2B5, Canada; Radiology, University of British Columbia, 2775 Laurel Street, 11th Floor, Vancouver, BC V5Z 1M9, Canada; ICORD (International Collaboration on Repair Discoveries), 818 W. 10th Ave., Vancouver, BC V5Z 1M9, Canada. Electronic address:

Purpose: The promise of inhomogeneous magnetization transfer (ihMT) as a new myelin imaging method was studied in ex vivo human brain tissue and in relation to myelin water fraction (MWF). The temperature dependence of both methods was characterized, as well as their correspondence with a histological measure of myelin content. Unfiltered and filtered ihMT protocols were studied by adjusting the saturation scheme to preserve or attenuate signal from tissue with short dipolar relaxation time T.

Methods: ihMT ratio (ihMTR) and MWF maps were acquired at 7 T from formalin-fixed human brain samples at 22.5 °C, 30 °C and 37 °C. The impact of temperature on unfiltered ihMTR, filtered ihMTR and MWF was investigated and compared to myelin basic protein staining.

Results: Unfiltered ihMTR exhibited no temperature dependence, whereas filtered ihMTR increased with increasing temperature. MWF decreased at higher temperature, with an increasing prevalence of areas where the myelin water signal was unreliably determined, likely related to a reduction in T peak separability at higher temperatures ex vivo. MWF and ihMTR showed similar per-sample correlation with myelin staining at room temperature. At 37 C, filtered ihMTR was more strongly correlated with myelin staining and had increased dynamic range compared to unfiltered ihMTR.

Conclusions: Given the temperature dependence of filtered ihMT, increased dynamic range, and strong myelin specificity that persists at higher temperatures, we recommend carefully controlled temperatures close to 37 °C for filtered ihMT acquisitions. Unfiltered ihMT may also be useful, due to its independence from temperature, higher amplitude values, and sensitivity to short T components. Ex vivo myelin water imaging should be performed at room temperature, to avoid fitting issues found at higher temperatures.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118046DOI Listing
August 2021

Spinal Perineural Cysts among European Patients.

J Neurol Surg A Cent Eur Neurosurg 2021 Sep 1;82(5):463-467. Epub 2021 Apr 1.

Radiology Department, Lublin Cancer Hospital of Saint John from Dukla, Lublin, Poland.

Background:  A perineural (Tarlov) cyst is a fluid-filled lesion occurring between the perineurium and the endoneurium of spinal nerve roots. The aim of the study was to evaluate the prevalence and morphology of perineural cysts, detected incidentally in patients with symptomatic degenerative disk disease.

Materials/methods:  The study was based on the retrospective data gathered during magnetic resonance imaging (MRI) examinations.

Results And Conclusions:  Out of 3,128 spinal MRI examinations, perineural cysts were detected in 286 patients (9%). The cysts were most commonly observed in the sacral region, followed by thoracic, cervical, and lumbar regions. Cysts were more common in women than in men and the average age of patients was 54.8 years. In the majority, a single cyst was found. The average longest dimension of the lesion was 11.72 mm.
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http://dx.doi.org/10.1055/s-0040-1722194DOI Listing
September 2021

The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer.

Nat Commun 2021 03 26;12(1):1920. Epub 2021 Mar 26.

Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.

Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC-dependent promoters. High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3K-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC-overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens. Lastly, we provide evidence that AAMDC can interact with the RabGTPase-activating protein RabGAP1L, and that AAMDC, RabGAP1L, and Rab7a colocalize in endolysosomes. The discovery of the RabGAP1L-AAMDC assembly platform provides insights for the design of selective blockers to target malignancies having the AAMDC amplification.
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http://dx.doi.org/10.1038/s41467-021-22101-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998036PMC
March 2021

A pan-cancer atlas of somatic mutations in miRNA biogenesis genes.

Nucleic Acids Res 2021 01;49(2):601-620

Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.

It is a well-known and intensively studied phenomenon that the levels of many miRNAs are differentiated in cancer. miRNA biogenesis and functional expression are complex processes orchestrated by many proteins cumulatively called miRNA biogenesis proteins. To characterize cancer somatic mutations in the miRNA biogenesis genes and investigate their potential impact on the levels of miRNAs, we analyzed whole-exome sequencing datasets of over 10 000 cancer/normal sample pairs deposited within the TCGA repository. We identified and characterized over 3600 somatic mutations in 29 miRNA biogenesis genes and showed that some of the genes are overmutated in specific cancers and/or have recurrent hotspot mutations (e.g. SMAD4 in PAAD, COAD and READ; DICER1 in UCEC; PRKRA in OV and LIN28B in SKCM). We identified a list of miRNAs whose level is affected by particular types of mutations in either SMAD4, SMAD2 or DICER1 and showed that hotspot mutations in the RNase domains in DICER1 not only decrease the level of 5p-miRNAs but also increase the level of 3p-miRNAs, including many well-known cancer-related miRNAs. We also showed an association of the mutations with patient survival. Eventually, we created an atlas/compendium of miRNA biogenesis alterations providing a useful resource for different aspects of biomedical research.
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http://dx.doi.org/10.1093/nar/gkaa1223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826265PMC
January 2021

Performance of In Silico Prediction Tools for the Detection of Germline Copy Number Variations in Cancer Predisposition Genes in 4208 Female Index Patients with Familial Breast and Ovarian Cancer.

Cancers (Basel) 2021 Jan 1;13(1). Epub 2021 Jan 1.

Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, 50931 Cologne, Germany.

The identification of germline copy number variants (CNVs) by targeted next-generation sequencing (NGS) frequently relies on in silico CNV prediction tools with unknown sensitivities. We investigated the performances of four in silico CNV prediction tools, including one commercial (Sophia Genetics DDM) and three non-commercial tools (ExomeDepth, GATK gCNV, panelcn.MOPS) in 17 cancer predisposition genes in 4208 female index patients with familial breast and/or ovarian cancer (BC/OC). CNV predictions were verified via multiplex ligation-dependent probe amplification. We identified 77 CNVs in 76 out of 4208 patients (1.81%); 33 CNVs were identified in genes other than , mostly in , , and and less frequently in , , , , , , and . The Sophia Genetics DDM software showed the highest sensitivity; six CNVs were missed by at least one of the non-commercial tools. The positive predictive values ranged from 5.9% (74/1249) for panelcn.MOPS to 79.1% (72/91) for ExomeDepth. Verification of in silico predicted CNVs is required due to high frequencies of false positive predictions, particularly affecting target regions at the extremes of the GC content or target length distributions. CNV detection should not be restricted to due to the relevant proportion of CNVs in further BC/OC predisposition genes.
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http://dx.doi.org/10.3390/cancers13010118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794674PMC
January 2021

{PVW}-Polyoxometalates Functionalized with Phthalocyaninato Y and Yb Moieties.

Inorg Chem 2021 Jan 12;60(1):80-86. Epub 2020 Nov 12.

Leibniz Institute of Surface Engineering (IOM), Permoserstraße 15, 04318 Leipzig, Germany.

A tris(alkoxo)pyridine-augmented Wells-Dawson polyoxometalate (BuN)[] (WD = PVWO(OCH)C, Py = CHN) was functionalized with phthalocyaninato metal moieties ( where M = Y or Yb and Pc = CHN) to afford (BuN)[H()] compounds. High-resolution mass spectrometry was used to detect and identify the hybrid assembly. The magnetism studies reveal substantial differences between M = Yb (monomeric, single-ion paramagnetism) and M = Y (containing dimers, radical character). The results of electronic paramagnetic resonance spectroscopy, SQUID magnetometry, and magnetochemical calculations indicate the presence of molecular charge transfer from the moiety to the polyoxometalate and of molecular charge transfer from the moiety of one molecule to the polyoxometalate unit of another molecule. These compounds with identified V ions represent unique examples of transition-metal/lanthanide complex-POM hybrid compounds with nonphotoinduced charge transfer between electron donor and acceptor centers.
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http://dx.doi.org/10.1021/acs.inorgchem.0c02257DOI Listing
January 2021

Pan-cancer analysis of somatic mutations in miRNA genes.

EBioMedicine 2020 Nov 7;61:103051. Epub 2020 Oct 7.

Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland. Electronic address:

Background: miRNAs are considered important players in oncogenesis, serving either as oncomiRs or suppressormiRs. Although the accumulation of somatic alterations is an intrinsic aspect of cancer development and many important cancer-driving mutations have been identified in protein-coding genes, the area of functional somatic mutations in miRNA genes is heavily understudied.

Methods: Here, based on the analysis of large genomic datasets, mostly the whole-exome sequencing of over 10,000 cancer/normal sample pairs deposited within the TCGA repository, we undertook an analysis of somatic mutations in miRNA genes.

Findings: We identified and characterized over 10,000 somatic mutations and showed that some of the miRNA genes are overmutated in Pan-Cancer and/or specific cancers. Nonrandom occurrence of the identified mutations was confirmed by a strong association of overmutated miRNA genes with KEGG pathways, most of which were related to specific cancer types or cancer-related processes. Additionally, we showed that mutations in some of the overmutated genes correlate with miRNA expression, cancer staging, and patient survival.

Interpretation: Our study is the first comprehensive Pan-Cancer study of cancer somatic mutations in miRNA genes. It may help to understand the consequences of mutations in miRNA genes and the identification of miRNA functional mutations. The results may also be the first step (form the basis and provide the resources) in the development of computational and/or statistical approaches/tools dedicated to the identification of cancer-driver miRNA genes.

Funding: This work was supported by research grants from the Polish National Science Centre 2016/22/A/NZ2/00184 and 2015/17/N/NZ3/03629.
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http://dx.doi.org/10.1016/j.ebiom.2020.103051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648123PMC
November 2020

Summary of Mutations and Precise Estimation of Breast and Ovarian Cancer Risks Associated with the Mutations.

Genes (Basel) 2020 07 15;11(7). Epub 2020 Jul 15.

Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Z. Noskowskiego St. 12/14, 61-704 Poznan, Poland.

Over the last two decades, numerous mutations/pathogenic variants (PVs) have been found in patients with breast cancer (BC) and ovarian cancer (OC). However, their role in BC and OC susceptibility remains controversial, and strong evidence-based guidelines for carriers are not yet available. Herein, we present a comprehensive catalog of PVs identified in large cumulative cohorts of ~48,700 BC and ~20,800 OC cases (retrieved from 123 studies examining the whole coding sequence of ). Using these resources, we compared the frequency of PVs in the cases and ~134,100 controls from the gnomAD database and estimated the effect of the PVs on BC and OC risks. The analysis revealed that is a BC moderate-risk gene (odds ratio (OR) = 2.90, 95% CIs:2.25-3.75, < 0.0001) but not an OC risk gene (OR = 1.36, 95% CIs:0.87-2.11, = 0.1733). In addition, the mutational spectrum outlined in this study allowed us to determine recurrent PVs and evaluate the variant-specific risk for the most frequent PVs. In conclusion, these precise estimates improve the understanding of the role of PVs in BC and OC predisposition and support the need for diagnostic testing in BC patients.
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http://dx.doi.org/10.3390/genes11070798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397132PMC
July 2020

TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study.

Genet Med 2020 09 28;22(9):1489-1497. Epub 2020 May 28.

Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland.

Purpose: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations.

Methods: Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2.

Results: Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizure-free survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2.

Conclusion: TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.
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http://dx.doi.org/10.1038/s41436-020-0823-4DOI Listing
September 2020

Vascular-Cognitive Impairment following High-Thoracic Spinal Cord Injury Is Associated with Structural and Functional Maladaptations in Cerebrovasculature.

J Neurotrauma 2020 09 1;37(18):1963-1970. Epub 2020 Jul 1.

International Collaboration on Repair Discoveries, Vancouver, British Columbia, Canada.

Individuals living with chronic spinal cord injury (SCI) often exhibit impairments in cognitive function, which impede their rehabilitation and transition into the community. Although a number of clinical studies have demonstrated the impact of impaired cardiovascular control on cognitive impairment, the mechanistic understanding of this deleterious relationship is still lacking. The present study investigates whether chronic disruption of cardiovascular control following experimental SCI results in cerebrovascular decline and vascular cognitive impairment. Fourteen weeks following a high thoracic SCI (at the third thoracic segment), rats were subjected to a battery of and physiological assessments, cognitive-behavioral tests, and immunohistochemical approaches to investigate changes in cerebrovascular structure and function in the middle cerebral artery (MCA). We show that in the MCA of rats with SCI, there is a 55% (SCI vs. control: 13.4 ± 1.9% vs. 29.63 ± 2.8%, respectively) reduction in the maximal vasodilator response to carbachol, which is associated with reduced expression of endothelial marker cluster of differentiation 31 (CD31) and transient receptor potential cation channel 4 (TRPV 4) channels. Compared with controls, MCAs in rats with SCI were found to have 50% (SCI vs. control: 1.5 ± 0.2 vs. 1 ± 0.1 a.u., respectively) more collagen 1 in the media of vascular wall and 37% (SCI vs. control: 30.5 ± 2.9% vs. 42.0 ± 4.0%, respectively) less distensibility at physiological intraluminal pressure. Further, the cerebral blood flow (CBF) in the hippocampus was reduced by 32% in the SCI group (SCI vs. control: 44.3 ± 4.5 mL/100 g/min vs. 65.0 ± 7.2 mL/100 g/min, respectively) in association with impairment of short-term memory based on a novel object recognition test. There were no changes in the sympathetic innervation of the vasculature and passive structure in the SCI group. Chronic experimental SCI is associated with structural alterations and endothelial dysfunction in cerebral arteries that likely contribute to significantly reduced CBF and vascular cognitive impairment.
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http://dx.doi.org/10.1089/neu.2019.6913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470217PMC
September 2020

BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of ~30,000 cases.

J Ovarian Res 2020 May 2;13(1):50. Epub 2020 May 2.

Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14 Street, 61-704, Poznan, Poland.

Background: It is estimated that more than 20% of ovarian cancer cases are associated with a genetic predisposition that is only partially explained by germline mutations in the BRCA1 and BRCA2 genes. Recently, several pieces of evidence showed that mutations in three genes involved in the homologous recombination DNA repair pathway, i.e., BRIP1, RAD51C, and RAD51D, are associated with a high risk of ovarian cancer. To more precisely estimate the ovarian cancer risk attributed to BRIP1, RAD51C, and RAD51D mutations, we performed a meta-analysis based on a comparison of a total of ~ 29,400 ovarian cancer patients from 63 studies and a total of ~ 116,000 controls from the gnomAD database.

Results: The analysis allowed precise estimation of ovarian cancer risks attributed to mutations in BRIP1, RAD51C, and RAD51D, confirming that all three genes are ovarian cancer high-risk genes (odds ratio (OR) = 4.94, 95%CIs:4.07-6.00, p < 0.0001; OR = 5.59, 95%CIs:4.42-7.07, p < 0.0001; and OR = 6.94, 95%CIs:5.10-9.44, p < 0.0001, respectively). In the present report, we show, for the first time, a mutation-specific risk analysis associated with distinct, recurrent, mutations in the genes.

Conclusions: The meta-analysis provides evidence supporting the pathogenicity of BRIP1, RAD51C, and RAD51D mutations in relation to ovarian cancer. The level of ovarian cancer risk conferred by these mutations is relatively high, indicating that after BRCA1 and BRCA2, the BRIP1, RAD51C, and RAD51D genes are the most important ovarian cancer risk genes, cumulatively contributing to ~ 2% of ovarian cancer cases. The inclusion of the genes into routine diagnostic tests may influence both the prevention and the potential treatment of ovarian cancer.
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http://dx.doi.org/10.1186/s13048-020-00654-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196220PMC
May 2020

AthCNV: A Map of DNA Copy Number Variations in the Arabidopsis Genome.

Plant Cell 2020 06 7;32(6):1797-1819. Epub 2020 Apr 7.

Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704 Poznan, Poland

Copy number variations (CNVs) greatly contribute to intraspecies genetic polymorphism and phenotypic diversity. Recent analyses of sequencing data for >1000 Arabidopsis () accessions focused on small variations and did not include CNVs. Here, we performed genome-wide analysis and identified large indels (50 to 499 bp) and CNVs (500 bp and larger) in these accessions. The CNVs fully overlap with 18.3% of protein-coding genes, with enrichment for evolutionarily young genes and genes involved in stress and defense. By combining analysis of both genes and transposable elements (TEs) affected by CNVs, we revealed that the variation statuses of genes and TEs are tightly linked and jointly contribute to the unequal distribution of these elements in the genome. We also determined the gene copy numbers in a set of 1060 accessions and experimentally validated the accuracy of our predictions by multiplex ligation-dependent probe amplification assays. We then successfully used the CNVs as markers to analyze population structure and migration patterns. Finally, we examined the impact of gene dosage variation triggered by a CNV spanning the gene on expression at both the transcript and protein levels. The catalog of CNVs, CNV-overlapping genes, and their genotypes in a top model dicot will stimulate the exploration of the genetic basis of phenotypic variation.
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http://dx.doi.org/10.1105/tpc.19.00640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268809PMC
June 2020

MRI of the Prostate With and Without Endorectal Coil at 3 T: Correlation With Whole-Mount Histopathologic Gleason Score.

AJR Am J Roentgenol 2020 07 11;215(1):133-141. Epub 2020 Mar 11.

Department of Radiology, University of British Columbia, Vancouver General Hospital, 899 W 12th Ave, Vancouver, BC V5Z 1M9, Canada.

The purpose of this article is to prospectively compare image quality and diagnostic accuracy of clinically significant prostate cancer with and without endorectal coil (ERC) at 3 T using a combination of T2-weighted and diffusion-weighted MRI. Twenty-three patients with biopsy-proven prostate cancer underwent MRI with and without ERC at the same visit. Patients subsequently underwent radical prostatectomy. Specimens were assessed by whole-mount histopathologic examination. Two radiologists reviewed MR images for image quality (5-point scale) and disease using Prostate Imaging Reporting and Data Systems version 2 (PI-RADSv2). Sensitivity, specificity, and area under the ROC curve (AUC) were calculated with and without ERC. Additionally, apparent diffusion coefficient (ADC) was correlated with Gleason score and ADC values of each lesion were compared with and without ERC. Image quality was comparable with and without ERC (3.8 vs 3.5). Twenty-nine cancer foci larger than 0.5 cm in diameter were found in 23 patients on histopathologic examination; 18 tumors had a Gleason score of 7 or greater. Two radiologists recorded AUC for tumors with a Gleason score of 7 or greater as 0.96 and 0.96 with ERC and 0.88 and 0.91 without ERC. All 13 tumors with a Gleason score of 3 + 4 were detected with ERC, but only 9 were detected without ERC. One of five tumors with Gleason scores less than 3 + 4 was missed with and without ERC. ADC significantly correlated with Gleason score. There was no significant difference in the ADC of a lesion on MRI with and without an ERC. MRI with and without ERC was equally accurate at showing prostate cancers with Gleason scores of 4 + 3 or greater. However, MRI with ERC was superior at showing cancer with a Gleason score of 3 + 4. There was no significant difference in ADC values between scores acquired with or without an ERC.
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http://dx.doi.org/10.2214/AJR.19.22094DOI Listing
July 2020

Carfilzomib-induced hemolysis is noticeably common but rarely shows features of thrombotic microangiopathy: A retrospective study.

Eur J Haematol 2020 Jun 15;104(6):588-593. Epub 2020 Mar 15.

Division of Hematology, Department of Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.

Objective: Hemolysis is a sporadically reported but potentially serious side effect of the proteasome inhibitor carfilzomib. We aimed to investigate the frequency of hemolysis in an unselected cohort.

Methods: We performed a retrospective, single-center study of the incidence of hemolysis in patients treated with carfilzomib, based mainly on consecutive haptoglobin levels. The patients were diagnosed with myeloma (n = 20), AL amyloidosis (n = 3), and light-chain deposition disease (n = 1). Carfilzomib treatment was applied after a median of 3 (range: 1-7) therapy lines.

Results: Haptoglobin levels were normal/increased before, generally suppressed during, and normalized after treatment with carfilzomib. Very low haptoglobin (<0.1 g/L) implying the presence of hemolysis was observed in 16 of 24 (67%) patients during carfilzomib therapy. Hemolysis was mild in 11 of 16 (69%) affected patients, whereas 5 of 16 (31%) required transfusion. Severe hemolysis was explained by thrombotic microangiopathy (TMA) in one patient who died of the complication. Mechanisms were unclear in the remaining 15 patients.

Conclusions: Hemolysis was surprisingly common but mostly mild during carfilzomib treatment. However, the possibility of TMA should be kept in mind in this setting. Hypothetically, non-TMA hemolysis could be attributed to the accumulation of globin chains due to the suppression of eukaryotic translation initiation inhibition by carfilzomib.
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http://dx.doi.org/10.1111/ejh.13401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318150PMC
June 2020

Multi-spin echo T relaxation imaging with compressed sensing (METRICS) for rapid myelin water imaging.

Magn Reson Med 2020 09 17;84(3):1264-1279. Epub 2020 Feb 17.

Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: Myelin water imaging (MWI) provides a valuable biomarker for myelin, but clinical application has been restricted by long acquisition times. Accelerating the standard multi-echo T acquisition with gradient echoes (GRASE) or by 2D multi-slice data collection results in image blurring, contrast changes, and other issues. Compressed sensing (CS) can vastly accelerate conventional MRI. In this work, we assessed the use of CS for in vivo human MWI, using a 3D multi spin-echo sequence.

Methods: We implemented multi-echo T relaxation imaging with compressed sensing (METRICS) and METRICS with partial Fourier acceleration (METRICS-PF). Scan-rescan data were acquired from 12 healthy controls for assessment of repeatability. MWI data were acquired for METRICS in 9 m:58 s and for METRICS-PF in 7 m:25 s, both with 1.5 × 2 × 3 mm voxels, 56 echoes, 7 ms ΔTE, and 240 × 240 × 170 mm FOV. METRICS was compared with a novel multi-echo spin-echo gold-standard (MSE-GS) MWI acquisition, acquired for a single additional subject in 2 h:2 m:40 s.

Results: METRICS/METRICS-PF myelin water fraction had mean: repeatability coefficient 1.5/1.1, coefficient of variation 6.2/4.5%, and intra-class correlation coefficient 0.79/0.84. Repeatability metrics comparing METRICS with METRICS-PF were similar, and both sequences agreed with reference values from literature. METRICS images and quantitative maps showed excellent qualitative agreement with those of MSE-GS.

Conclusion: METRICS and METRICS-PF provided highly repeatable MWI data without the inherent disadvantages of GRASE or 2D multi-slice acquisition. CS acceleration allows MWI data to be acquired rapidly with larger FOV, higher estimated SNR, more isotropic voxels and more echoes than with previous techniques. The approach introduced here generalizes to any multi-component T mapping application.
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http://dx.doi.org/10.1002/mrm.28199DOI Listing
September 2020

Self-assembled monolayers of polyoxovanadates with phthalocyaninato lanthanide moieties on gold surfaces.

Chem Commun (Camb) 2019 Nov;55(90):13554-13557

Leibniz Institute of Surface Engineering (IOM), Permoserstraße 15, 04318 Leipzig, Germany.

The two first representatives of phthalocyaninato (Pc) lanthanide-ligated polyoxovanadate cages {[V12O32(Cl)](LnPc)n}n-5 (n = 1 or 2, Ln = Yb3+) were synthesised and fully characterised. These magnetic complexes form two-dimensional self-assembled monolayers exhibiting electrical conductivity on gold substrate surfaces, as assessed by using an EGaIn tip.
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http://dx.doi.org/10.1039/c9cc06852jDOI Listing
November 2019

An Overview of Circular RNAs and Their Implications in Myotonic Dystrophy.

Int J Mol Sci 2019 Sep 6;20(18). Epub 2019 Sep 6.

Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704 Poznan, Poland.

Circular RNAs (circRNAs) are a class of single-stranded covalently closed RNA rings. Biogenesis of circRNAs, which may occur co-transcriptionally and post-transcriptionally via a back-splicing mechanism, requires the presence of complementary and/or inverted repeat sequences in introns flanking back-spliced exons and is facilitated by RNA-binding proteins. CircRNAs are abundant across eukaryotes; however, their biological functions remain largely speculative. Recently, they have been emerging as new members of a gene regulatory network and contributing factors in various human diseases including cancer, neurological, muscular and cardiovascular disorders. In this review, we present an overview of the current knowledge about circRNAs biogenesis and their aberrant expression in various human disorders. In particular, we focus on the latest discovery of circRNAs global upregulation in myotonic dystrophy type 1 (DM1) skeletal muscles and the role these prospective biomarkers might have for prognosis and therapeutic response in DM1.
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http://dx.doi.org/10.3390/ijms20184385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769675PMC
September 2019

Global Increase in Circular RNA Levels in Myotonic Dystrophy.

Front Genet 2019 18;10:649. Epub 2019 Jul 18.

Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.

Splicing aberrations induced as a consequence of the sequestration of muscleblind-like splicing factors on the dystrophia myotonica protein kinase transcript, which contains expanded CUG repeats, present a major pathomechanism of myotonic dystrophy type 1 (DM1). As muscleblind-like factors may also be important factors involved in the biogenesis of circular RNAs (circRNAs), we hypothesized that the level of circRNAs would be decreased in DM1. To test this hypothesis, we selected 20 well-validated circRNAs and analyzed their levels in several experimental systems (e.g., cell lines, DM muscle tissues, and a mouse model of DM1) using droplet digital PCR assays. We also explored the global level of circRNAs using two RNA-Seq datasets of DM1 muscle samples. Contrary to our original hypothesis, our results consistently showed a global increase in circRNA levels in DM1, and we identified numerous circRNAs that were increased in DM1. We also identified many genes (including muscle-specific genes) giving rise to numerous (>10) circRNAs. Thus, this study is the first to show an increase in global circRNA levels in DM1. We also provided preliminary results showing the association of circRNA level with muscle weakness and alternative splicing changes that are biomarkers of DM1 severity.
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http://dx.doi.org/10.3389/fgene.2019.00649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689976PMC
July 2019

Rapid myelin water imaging for the assessment of cervical spinal cord myelin damage.

Neuroimage Clin 2019 17;23:101896. Epub 2019 Jun 17.

Physics and Astronomy, University of British Columbia, 6224 Agricultural Road, Vancouver, BC V6T 1Z1, Canada; Radiology, University of British Columbia, 2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada; International Collaboration on Repair Discoveries, University of British Columbia, 818 West 10th Avenue, Vancouver, BC V5Z 1M9, Canada; Medicine (Neurology), University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.

Background: Rapid myelin water imaging (MWI) using a combined gradient and spin echo (GRASE) sequence can produce myelin specific metrics for the human brain. Spinal cord MWI could be similarly useful, but technical challenges have hindered routine application. GRASE rapid MWI was recently successfully implemented for imaging of healthy cervical spinal cord and may complement other advanced imaging methods, such as diffusion tensor imaging (DTI) and quantitative T (qT).

Objective: To demonstrate the feasibility of cervical cord GRASE rapid MWI in multiple sclerosis (MS), primary lateral sclerosis (PLS) and neuromyelitis optica spectrum disorder (NMO), with comparison to DTI and qT metrics.

Methods: GRASE MWI, DTI and qT data were acquired in 2 PLS, 1 relapsing-remitting MS (RRMS), 1 primary-progressive MS (PPMS) and 2 NMO subjects, as well as 6 age (±3 yrs) and sex matched healthy controls (HC). Internal cord structure guided template registrations, used for region of interest (ROI) analysis. Z score maps were calculated for the difference between disease subject and mean HC metric values.

Results: PLS subjects had low myelin water fraction (MWF) in the lateral funiculi compared to HC. RRMS subject MWF was heterogeneous within the cord. The PPMS subject showed no trends in ROI results but had a region of low MWF Z score corresponding to a focal lesion. The NMO subject with a longitudinally extensive transverse myelitis lesion had low values for whole cord mean MWF of 12.8% compared to 24.3% (standard deviation 2.2%) for HC. The NMO subject without lesions also had low MWF compared to HC. DTI and qT metrics showed similar trends, corroborating the MWF results and providing complementary information.

Conclusion: GRASE is sufficiently sensitive to detect decreased myelin within MS spinal cord plaques, NMO lesions, and PLS diffuse spinal cord injury. Decreased MWF in PLS is consistent with demyelination secondary to motor neuron degeneration. GRASE MWI is a feasible method for rapid assessment of myelin content in the cervical spinal cord and provides complementary information to that of DTI and qT measures.
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http://dx.doi.org/10.1016/j.nicl.2019.101896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611998PMC
June 2020

Somatic Mutations in miRNA Genes in Lung Cancer-Potential Functional Consequences of Non-Coding Sequence Variants.

Cancers (Basel) 2019 Jun 8;11(6). Epub 2019 Jun 8.

Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan 61-704, Poland.

A growing body of evidence indicates that miRNAs may either drive or suppress oncogenesis. However, little is known about somatic mutations in miRNA genes. To determine the frequency and potential consequences of miRNA gene mutations, we analyzed whole exome sequencing datasets of 569 lung adenocarcinoma (LUAD) and 597 lung squamous cell carcinoma (LUSC) samples generated in The Cancer Genome Atlas (TCGA) project. Altogether, we identified 1091 somatic sequence variants affecting 522 different miRNA genes and showed that half of all cancers had at least one such somatic variant/mutation. These sequence variants occurred in most crucial parts of miRNA precursors, including mature miRNA and seed sequences. Due to our findings, we hypothesize that seed mutations may affect miRNA:target interactions, drastically changing the pool of predicted targets. Mutations may also affect miRNA biogenesis by changing the structure of miRNA precursors, DROSHA and DICER cleavage sites, and regulatory sequence/structure motifs. We identified 10 significantly overmutated hotspot miRNA genes, including the miR-379 gene in LUAD enriched in mutations in the mature miRNA and regulatory sequences. The occurrence of mutations in the hotspot miRNA genes was also shown experimentally. We present a comprehensive analysis of somatic variants in miRNA genes and show that some of these genes are mutational hotspots, suggesting their potential role in cancer.
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http://dx.doi.org/10.3390/cancers11060793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627760PMC
June 2019

[Epidemiology and diagnosis of breast cancer].

Pol Merkur Lekarski 2019 May;46(275):195-204

Human Anatomy Department, Medical University, Lublin, Poland; Radiology Department, St. John's Cancer Center, Lublin, Poland.

Breast cancer is the most common cancer in women. Family history of breast cancer, age at menarche, number of pregnancies and births, history of breast biopsies, use of hormone replacement therapy and time from the last menstrual period are the key events to note. In addition, a high percentage of cases has been demonstrated in women with a genetically conditioned cancer, i.e. mutations in genes BRCA1, BRCA2, syndromes of Li-Fraumeni, Cowden and Peutz-Jeghers. Over 90% of cases are local or regional when detected. The diagnostics approach consists of self-control, breast palpation by the doctor, breast imaging usually with ultrasound, mammography and magnetic resonance. To confirm the diagnosis, a fine-, core-needle or mammotome biopsy is performed. The final diagnosis is based on a wide panel of immunohistochemical and cytogenetic tests. Histological examination provides accurate assessment of the tumor type, grade, estrogen and progesterone hormone receptor status, HER2 overexpression and Ki67 proliferation index. The data makes possible to qualify to one of four groups of breast cancer biological subtypes, which allows individualized treatment of the patient.
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May 2019

is A Low/Moderate Breast Cancer Risk Gene: Evidence Based on An Association Study of the Central European p.Q564X Recurrent Mutation.

Cancers (Basel) 2019 May 28;11(6). Epub 2019 May 28.

Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61704 Poznan, Poland.

In addition to several well-established breast cancer (BC) susceptibility genes, the contribution of other candidate genes to BC risk remains mostly undefined. is a potentially predisposing BC gene, however, the rarity of its mutations and an insufficient family/study size have hampered corroboration and estimation of the associated cancer risks. To clarify the role of mutations in BC predisposition, a comprehensive case-control association study of a recurring nonsense mutation c.1690C>T (p.Q564X) was performed, comprising ~14,000 unselected BC patients and ~5900 controls from Polish and Belarusian populations. For comparisons, two variants of unknown significance were also genotyped. We detected the highest number of variants in BC cases in any individual -specific study, including 38 p.Q564X mutations. The p.Q564X was associated with a moderately increased risk of BC (OR = 2.30, = 0.04). The estimated risk was even higher for triple-negative BC and bilateral BC. As expected, the two tested variants of unknown significance did not show significant associations with BC risk. Our study provides substantial evidence for the association of a deleterious mutation with BC as a low/moderate risk allele. The p.Q564X was shown to be a Central European recurrent mutation with potential relevance for future genetic testing.
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http://dx.doi.org/10.3390/cancers11060740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627038PMC
May 2019

Survival in adult acute lymphoblastic leukaemia (ALL): A report from the Swedish ALL Registry.

Eur J Haematol 2019 Aug 6;103(2):88-98. Epub 2019 Jun 6.

Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Objectives: As new, effective therapies emerge for acute lymphoblastic leukaemia (ALL), the results of clinical trials need to relate to standard of care.

Methods: We used the population-based Swedish ALL Registry to evaluate characteristics, treatment and long-term outcome in 933 patients with diagnosis between 1997 and 2015.

Results: The median age was 53 years. The frequency of Philadelphia (Ph)-positive leukaemia was 34% of examined B-ALL with a peak incidence at 50-59 years. Five-year overall survival (OS) improved between 1997-2006 and 2007-2015; in patients 18-45 years from 50% (95% CI 43-57) to 65% (95% CI 58-72), 46-65 years from 25% (95% CI 18-32) to 46% (95% CI 37-55) and >65 years from 7% (95% CI 2.6-11) to 11% (95% CI 5.9-16) (P < 0.05). Men with Ph-neg B-ALL 46-65 years had inferior OS compared with women (P < 0.01). Standardised mortality ratio was 5.7 (95% CI 5.0-6.3) for patients who survived 5 years from diagnosis. In multivariable analysis, Ph-positive disease was not associated with impaired prognosis but with lower risk of death in 2007-2015.

Conclusions: In a population-based cohort, OS has improved in adult ALL, especially for Ph-positive disease but for middle-aged men with Ph-negative B-ALL outcome was poor. Cure without late toxicity or relapse is still desired.
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http://dx.doi.org/10.1111/ejh.13247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851994PMC
August 2019

Obesity as a tumour development triggering factor.

Ann Agric Environ Med 2019 Mar 17;26(1):13-23. Epub 2019 Jan 17.

Human Anatomy Department, Medical University, Lublin, Poland.

Introduction: The overweight and obesity epidemic represents a rapidly growing threat to the health of populations in an increasing number of countries. Nearly one-third of the world's population has excess adipose tissue. Nowadays, obesity occurrence is so common that it is replacing more traditional problems, such as an undernutrition and infectious diseases, as the most significant causes of ill health. If the current trend continues, almost half of the world's adult population will be overweight or obese by 2030.

Objective: The aim of this study is to show the connection between recent trends in body mass index, and the globally changing cancer profile.

State Of Knowledge: A range of clinical and epidemiological studies have shown the relationship between excess body fat and the most frequently occurring malignancies. Obesity is associated with many cancers, such as: breast, colorectal, liver, lung, kidney, oesophageal, pancreatic, endometrium, ovarian, prostate, thyroid, and gallbladder cancer.

Conclusions: In the light of this information, the study supports the claimed statement that obesity is one of the major health problems of the 21st century. Considering the increase in the number of obese people worldwide, it is necessary to develop a strategy allowing to prevent it. Fighting against unhealthy lifestyle in order to reduce overweight and obesity in society may have an essential impact on decreasing the number of incidences of cancer.
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http://dx.doi.org/10.26444/aaem/100664DOI Listing
March 2019

Large-scale meta-analysis of mutations identified in panels of breast/ovarian cancer-related genes - Providing evidence of cancer predisposition genes.

Gynecol Oncol 2019 05 4;153(2):452-462. Epub 2019 Feb 4.

Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland. Electronic address:

Objective: Germline mutations occurring in the highly penetrant genes BRCA1 and BRCA2 are responsible for only certain cases of familial breast cancer (BC) and ovarian cancer (OC). Thus, the use of NGS multi-gene panel (MGP) testing has recently become very popular.

Methods: To estimate a reliable BC and OC risk associated with pathogenic variants in the selected candidate BC/OC predisposition genes, a comprehensive meta-analysis of 48 MGP-based studies analyzing BC/OC patients was conducted. The role of 37 genes was evaluated, comparing, in total, the mutation frequency in ~120,000 BC/OC cases and ~120,000 controls, which guaranteed strong statistical support with high confidence for most analyzed genes.

Results: We characterized the strategies of MGP analyses and the types and localizations of the identified mutations and showed that 13 and 11 of the analyzed genes were significantly associated with an increased BC and OC risk, respectively. The risk attributed to some of these genes (e.g., CDKN2A and PALB2 for BC) was similar to that observed for BRCA2. The analysis also showed a substantial difference in the profile of genes contributing to either BC or OC risk, including genes specifically associated with a high risk of OC but not BC (e.g., RAD51C, and RAD51D).

Conclusions: Our study provides strong statistical proof, defines the risk for many genes often considered candidates for BC/OC predisposition and excludes the role of other genes frequently analyzed in the MGPs. In the context of clinical diagnostics, the results support the knowledge-based interpretation of identified mutations.
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http://dx.doi.org/10.1016/j.ygyno.2019.01.027DOI Listing
May 2019

Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice.

Brain 2019 02;142(2):412-425

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy in which brainstem spreading depolarization may play a pivotal role, as suggested by animal studies. However, patiotemporal details of spreading depolarization occurring in relation to fatal seizures have not been investigated. In addition, little is known about behavioural and neurophysiological features that may discriminate spontaneous fatal from non-fatal seizures. Transgenic mice carrying the missense mutation S218L in the α1A subunit of Cav2.1 (P/Q-type) Ca2+ channels exhibit enhanced excitatory neurotransmission and increased susceptibility to spreading depolarization. Homozygous Cacna1aS218L mice show spontaneous non-fatal and fatal seizures, occurring throughout life, resulting in reduced life expectancy. To identify characteristics of fatal and non-fatal spontaneous seizures, we compared behavioural and electrophysiological seizure dynamics in freely-behaving homozygous Cacna1aS218L mice. To gain insight on the role of brainstem spreading depolarization in SUDEP, we studied the spatiotemporal distribution of spreading depolarization in the context of seizure-related death. Spontaneous and electrically-induced seizures were investigated by video monitoring and electrophysiological recordings in freely-behaving Cacna1aS218L and wild-type mice. Homozygous Cacna1aS218L mice showed multiple spontaneous tonic-clonic seizures and died from SUDEP in adulthood. Death was preceded by a tonic-clonic seizure terminating with hindlimb clonus, with suppression of cortical neuronal activity during and after the seizure. Induced seizures in freely-behaving homozygous Cacna1aS218L mice were followed by multiple spreading depolarizations and death. In wild-type or heterozygous Cacna1aS218L mice, induced seizures and spreading depolarization were never followed by death. To identify temporal and regional features of seizure-induced spreading depolarization related to fatal outcome, diffusion-weighted MRI was performed in anaesthetized homozygous Cacna1aS218L and wild-type mice. In homozygous Cacna1aS218L mice, appearance of seizure-related spreading depolarization in the brainstem correlated with respiratory arrest that was followed by cardiac arrest and death. Recordings in freely-behaving homozygous Cacna1aS218L mice confirmed brainstem spreading depolarization during spontaneous fatal seizures. These data underscore the value of the homozygous Cacna1aS218L mouse model for identifying discriminative features of fatal compared to non-fatal seizures, and support a key role for cortical neuronal suppression and brainstem spreading depolarization in SUDEP pathophysiology.
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http://dx.doi.org/10.1093/brain/awy325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351775PMC
February 2019
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