Publications by authors named "Wojciech Fendler"

195 Publications

Correction: Assessing Public Interest Based on Wikipedia's Most Visited Medical Articles During the SARS-CoV-2 Outbreak: Search Trends Analysis.

J Med Internet Res 2021 Apr 15;23(4):e29598. Epub 2021 Apr 15.

Management in Networked and Digital Societies, Kozminski University, Warszawa, Poland.

[This corrects the article DOI: 10.2196/26331.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/29598DOI Listing
April 2021

Remus: A Web Application for Prioritization of Regulatory Regions and Variants in Monogenic Diseases.

Front Genet 2021 5;12:638960. Epub 2021 Mar 5.

Department of Biostatistics and Translational Medicine, Medical University of Lodz, Łódź, Poland.

Background: Analysis of variants in distant regulatory elements could improve the current 25-50% yield of genetic testing for monogenic diseases. However, the vast size of the regulome, great number of variants, and the difficulty in predicting their phenotypic impact make searching for pathogenic variants in the regulatory genome challenging. New tools for the identification of regulatory variants based on their relevance to the phenotype are needed.

Methods: We used tissue-specific regulatory mapped by ENCODE and FANTOM, together with miRNA-gene interactions from miRTarBase and miRWalk, to develop Remus, a web application for the identification of tissue-specific regulatory regions. Remus searches for regulatory features linked to the known disease-associated genes and filters them using activity status in the target tissues relevant for the studied disorder. For user convenience, Remus provides a web interface and facilitates in-browser filtering of variant files suitable for sensitive patient data.

Results: To evaluate our approach, we used a set of 146 regulatory mutations reported causative for 68 distinct monogenic disorders and a manually curated a list of tissues affected by these disorders. In 89.7% of cases, Remus identified the regulator containing the pathogenic mutation. The tissue-specific search limited the number of considered variants by 82.5% as compared to a tissue-agnostic search.

Conclusion: Remus facilitates the identification of regulatory regions potentially associated with a monogenic disease and can supplement classical analysis of coding variations with the aim of improving the diagnostic yield in whole-genome sequencing experiments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2021.638960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978111PMC
March 2021

The Prognostic Value of Whole-Blood PSMB5, CXCR4, POMP, and RPL5 mRNA Expression in Patients with Multiple Myeloma Treated with Bortezomib.

Cancers (Basel) 2021 Feb 25;13(5). Epub 2021 Feb 25.

Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland.

Proteasome inhibitors, like bortezomib, play a key role in the treatment of multiple myeloma (MM); however, most patients eventually relapse and eventually show multiple drug resistance, and the molecular mechanisms of this resistance remain unclear. The aim of our study is to assess the expression of previously described genes that may influence the resistance to bortezomib treatment at the mRNA level (, , , , , , , and ) and prognosis of MM patients. mRNA expression was determined in 73 MM patients treated with bortezomib-based regimens (30 bortzomib-sensitive and 43 bortezomib-refractory patients) and 11 healthy controls. was significantly down-regulated in multiple myeloma patients as compared with healthy controls. Moreover, POMP was significantly up-regulated in MM patients refractory to bortezomib-based treatment. In multivariate analysis, high expression of and and autologous stem cell transplantation were independent predictors of progression-free survival, and high expression of and was associated with shorter overall survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13050951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956525PMC
February 2021

Assessing Public Interest Based on Wikipedia's Most Visited Medical Articles During the SARS-CoV-2 Outbreak: Search Trends Analysis.

J Med Internet Res 2021 04 12;23(4):e26331. Epub 2021 Apr 12.

Management in Networked and Digital Societies, Kozminski University, Warszawa, Poland.

Background: In the current era of widespread access to the internet, we can monitor public interest in a topic via information-targeted web browsing. We sought to provide direct proof of the global population's altered use of Wikipedia medical knowledge resulting from the new COVID-19 pandemic and related global restrictions.

Objective: We aimed to identify temporal search trends and quantify changes in access to Wikipedia Medicine Project articles that were related to the COVID-19 pandemic.

Methods: We performed a retrospective analysis of medical articles across nine language versions of Wikipedia and country-specific statistics for registered COVID-19 deaths. The observed patterns were compared to a forecast model of Wikipedia use, which was trained on data from 2015 to 2019. The model comprehensively analyzed specific articles and similarities between access count data from before (ie, several years prior) and during the COVID-19 pandemic. Wikipedia articles that were linked to those directly associated with the pandemic were evaluated in terms of degrees of separation and analyzed to identify similarities in access counts. We assessed the correlation between article access counts and the number of diagnosed COVID-19 cases and deaths to identify factors that drove interest in these articles and shifts in public interest during the subsequent phases of the pandemic.

Results: We observed a significant (P<.001) increase in the number of entries on Wikipedia medical articles during the pandemic period. The increased interest in COVID-19-related articles temporally correlated with the number of global COVID-19 deaths and consistently correlated with the number of region-specific COVID-19 deaths. Articles with low degrees of separation were significantly similar (P<.001) in terms of access patterns that were indicative of information-seeking patterns.

Conclusions: The analysis of Wikipedia medical article popularity could be a viable method for epidemiologic surveillance, as it provides important information about the reasons behind public attention and factors that sustain public interest in the long term. Moreover, Wikipedia users can potentially be directed to credible and valuable information sources that are linked with the most prominent articles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/26331DOI Listing
April 2021

Expression of Transcript Variants of and Genes among Patients with Chronic Rhinosinusitis with Nasal Polyps.

Diagnostics (Basel) 2021 Jan 16;11(1). Epub 2021 Jan 16.

Department of Clinical Genetics, Medical University of Lodz, 90-419 Lodz, Poland.

To date, there has been no reliable test to identify unfavorable course of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), especially in aspirin intolerant patients. The research aimed to analyze the expression of transcript variants of and genes in the pathobiology of the disease. The study was performed on 409 adult patients: 206 CRSwNP patients including 44 (21.36%) aspirin intolerant patients and 203 healthy volunteers in the control group. Transcript variants of the and genes named as follows: COX1.1 for NM_000962, COX1.2 for NM_080591, COX1.3 for NM_001271165.1, COX1.4 for NM_001271368.1, COX1.5 for NM_001271166.1, COX2.1 for NM_000963.3, COX2.2 for AY_151286 and COX2.3 for BQ_722004 were confirmed using direct sequencing and quantified using targeted qPCR. The coexistence of all examined transcript variants in the study and the control group and significant differences between both were found. In aspirin sensitive patients, the levels of COX1.2, COX1.3, COX1.4 and COX1.5 isoforms were higher compared to aspirin-tolerant patients. The severity of symptoms was bigger in patients with higher expressions of variants: COX1.1 (R with dCt = -0.134; = 0.0490), COX1.3 (R = -0.1429; = 0.0400) and COX1.5 (Rs = -0.1499; = 0.032). The expression of COX1.1 (Rs = -0.098; = 0.049) and COX1.5 (Rs = -0.141; = 0.043) isoforms increased with polyposis advancement in endoscopy. With the CT extent of sinuses opacification, COX1.1 isoform also significantly increased (Rs = -0.163; = 0.020). The isoforms COX1.3, COX1.4, COX1.5 and COX2.1 may promote milder CRSwNP course. On the contrary, the variants COX1.1, COX1.2 and COX2.2 may be involved in a more aggressive disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/diagnostics11010135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830232PMC
January 2021

Biological Activity of c-Peptide in Microvascular Complications of Type 1 Diabetes-Time for Translational Studies or Back to the Basics?

Int J Mol Sci 2020 Dec 20;21(24). Epub 2020 Dec 20.

Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland.

People with type 1 diabetes have an increased risk of developing microvascular complications, which have a negative impact on the quality of life and reduce life expectancy. Numerous studies in animals with experimental diabetes show that c-peptide supplementation exerts beneficial effects on diabetes-induced damage in peripheral nerves and kidneys. There is substantial evidence that c-peptide counteracts the detrimental changes caused by hyperglycemia at the cellular level, such as decreased activation of endothelial nitric oxide synthase and sodium potassium ATPase, and increase in formation of pro-inflammatory molecules mediated by nuclear factor kappa-light-chain-enhancer of activated B cells: cytokines, chemokines, cell adhesion molecules, vascular endothelial growth factor, and transforming growth factor beta. However, despite positive results from cell and animal studies, no successful c-peptide replacement therapies have been developed so far. Therefore, it is important to improve our understanding of the impact of c-peptide on the pathophysiology of microvascular complications to develop novel c-peptide-based treatments. This article aims to review current knowledge on the impact of c-peptide on diabetic neuro- and nephropathy and to evaluate its potential therapeutic role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21249723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766542PMC
December 2020

Serum microRNA as indicators of Wolfram syndrome's progression in neuroimaging studies.

BMJ Open Diabetes Res Care 2020 11;8(2)

Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland.

Introduction: Patients with the ultra-rare Wolfram syndrome (WFS) develop insulin-dependent diabetes and progressive neurodegeneration. The aim of the study was to quantify microRNAs (miRNAs) in sera from patients with WFS, correlate their expression with neurological imaging over time and compare miRNA levels with those observed in patients with type 1 diabetes mellitus (T1DM).

Research Design And Methods: We quantified miRNA expression (Qiagen, Germany) in two groups of patients: with WFS at study entry (n=14) and after 2 years of follow-up and in 15 glycated hemoglobin-matched (p=0.72) patients with T1DM.

Results: We observed dynamic changes in the expression of multiple miRNAs in patients with WFS parallel to disease progression and in comparison to the T1DM patients group. Among miRNAs that differed between baseline and follow-up WFS samples, the level of 5 increased over time (miR-375, miR-30d-5p, miR-30e-30, miR-145-5p and miR-193a-5p) and was inversely correlated with macular average thickness, while the expression of 2 (let-7g-5p and miR-22-3p) decreased and was directly correlated with neuroimaging indicators of neurodegeneration.

Conclusions: Our findings show for the first time that serum miRNAs can be used as easily accessible indicators of disease progression in patients with WFS, potentially facilitating clinical trials on mitigating neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjdrc-2020-001379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607591PMC
November 2020

Improved Estimation of Glycated Hemoglobin from Continuous Glucose Monitoring and Past Glycated Hemoglobin Data.

Diabetes Technol Ther 2021 Apr 9;23(4):293-305. Epub 2021 Mar 9.

Department of Biostatistics and Translational Medicine, Diabetology, Endocrinology and Nephrology, Medical University of Lodz, Lodz, Poland.

Accurate estimation of glycated hemoglobin (HbA1c) from continuous glucose monitoring (CGM) remains challenging in clinic. We propose two statistical models and validate them in real-life conditions against the current standard, glucose management indicator (GMI). Modeling utilized routinely collected data from patients with type 1 diabetes from central Poland (eligibility criteria: age >1 year, diabetes duration >3 months, and CGM use between 01/01/2015 and 12/31/2019). CGM records were extracted from dedicated Medtronic/Abbott databases and cross-referenced with HbA1c values; 28-day periods preceding HbA1c measurement with >75% of the sensor-active time were analyzed. We developed a mixed linear regression, including glycemic variability indices and patient's ID (glucose variability-based patient specific model, GV-PS) intended for closed-group use and linear regression using patient-specific error of GMI (proportional error-based patient agnostic model, PE-PA) for general use. Models were validated with either new HbA1cs from closed-group patients or separate patient-HbA1c pool. External validation was performed with data from clinical trials. Performance metrics included bias, its 95% confidence interval (95% CI), coefficient of determination (), and root mean square error (RMSE). We included 723 HbA1c-CGM pairs from 174 patients (mean age 9.9 ± 4.4 years and diabetes duration 3.7 ± 3.6 years). GMI yielded  = 0.58, with different bias between Medtronic and Abbott devices [0.120% vs. -0.152%,  < 0.0001], and overall 95% CI = -0.9% to +1%, RMSE = 0.47%. GV-PS successfully captured patient-specific variance (closed-group validation:  = 0.83, bias = 0.026%, 95% CI = -0.562% to 0.591%, RMSE = 0.31%). PE-PA performed similarly on new patients ( = 0.76, bias = -0.069%, 95% CI = -0.790% to 0.653%, RMSE = 0.37%). In external validation GMI, GV-PS, and PE-PA produced 73.8%, 87.5%, and 91.0% predictions within 0.5% (5.5 mmol/mol) from the true value. Constructed models performed better than GMI. PE-PA provided an accurate estimate of HbA1c with fast and straightforward implementation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/dia.2020.0433DOI Listing
April 2021

Hematopoietic Stem Cell Transplantation Positively Affects the Natural History of Cancer in Nijmegen Breakage Syndrome.

Clin Cancer Res 2021 Jan 20;27(2):575-584. Epub 2020 Oct 20.

Department Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland.

Purpose: Nijmegen breakage syndrome (NBS) is a DNA repair disorder with a high predisposition to hematologic malignancies.

Experimental Design: We describe the natural history of NBS, including cancer incidence, risk of death, and the potential effectiveness of hematopoietic stem cell transplantation (HSCT) in preventing both pathologies: malignancy and immunodeficiency.

Results: Among 241 patients with NBS enrolled in the study from 11 countries, 151 (63.0%) patients were diagnosed with cancer. Incidence rates for primary and secondary cancer, tumor characteristics, and risk factors affecting overall survival (OS) were estimated. The cumulative cancer incidence was 40.21% ± 3.5% and 77.78% ± 3.4% at 10 years and 20 years of follow-up, respectively. Most of the tumors = 95 (62.9%) were non-Hodgkin lymphomas. Overall, 20 (13.2%) secondary malignancies occurred at a median age of 18 (interquartile range, 13.7-21.5) years. The probability of 20-year overall survival (OS) for the whole cohort was 44.6% ± 4.5%. Patients who developed cancer had a shorter 20-year OS than those without malignancy (29.6% vs. 86.2%; < 10). A total of 49 patients with NBS underwent HSCT, including 14 patients transplanted before malignancy. Patients with NBS with diagnosed cancer who received HSCT had higher 20-year OS than those who did not (42.7% vs. 30.3%; = 0.038, respectively). In the group of patients who underwent preemptive transplantation, only 1 patient developed cancer, which is 6.7 times lower as compared with nontransplanted patients [incidence rate ratio 0.149 (95% confidence interval, 0.138-0.162); < 0.0001].

Conclusions: There is a beneficial effect of HSCT on the long-term survival of patients with NBS transplanted in their first complete remission of cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-2574DOI Listing
January 2021

Impact of factory-calibrated Freestyle Libre System with new glucose algorithm measurement accuracy and clinical performance in children with type 1 diabetes during summer camp.

Pediatr Diabetes 2021 Mar 20;22(2):261-270. Epub 2020 Oct 20.

Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.

Background: Factory-calibrated intermittently-scanned Continuous Glucose Monitoring (isCGM) device FreeStyle Libre (FSL) has recently received improvements in its glucose tracking algorithm and calibration procedures, which are claimed to have improved its accuracy.

Objective: To compare the accuracy of two generations of 14-days FSL devices (A in 2016, B in 2019) to self-monitored blood glucose measurements (SMBG) in children with type 1 diabetes in real-life conditions during a summer camp.

Materials And Methods: Two largely independent groups of youth with type 1 diabetes took part in summer camps. In 2016 they used FSL-A, in 2019 FSL-B. On scheduled days, participants performed supervised 8-point glucose profiles with FSL and SMBG. The accuracy vs SMBG was assessed with mean absolute relative difference (MARD) and clinical surveillance error grid (SEG).

Results: We collected 1655 FSL-SMBG measurement pairs from 78 FSL-A patients (age 13 ± 2.3 years old; HbA1c: 7.6 ± 0.8%) and 1796 from 58 in FSL-B group (age 13.8 ± 2.3 years old, HbA1c: 7.5 ± 1.1%)-in total 3451 measurements. FSL-B displayed lower MARD than FSL-A (11.3 ± 3.1% vs 13.7 ± 4.6%, P = .0003), lower SD of errors (20.2 ± 6.7 mg/dL vs 24.1 ± 9.6 mg/dL, P = .0090) but similar bias (-7.6 ± 11.8 mg/dL vs -6.5 ± 8 mg/dL, P = .5240). Both FSL-A and FSL-B showed significantly higher MARD when glycaemia was decreasing >2 mg/dL/min (FSL-A:22.3 ± 18.5%; FSL-B:17.9 ± 15.8%, P < .0001) compared with stable conditions (FSL-A: 11.4 ± 10.4%, FSL-B:10.1 ± 9.1%) and when the system could not define the glycaemic trend (FSL-A:16.5 ± 16.3%; FSL-B:15.2 ± 14.9%, P < .0001). Both generations demonstrated high percentage of A-class and B-class results in SEG (FSL-A: 96.4%, FSL-B: 97.6%) with a significant shift from B (decrease by 3.7%) to A category (increase by 3.9%) between generations (FSL-A: 16/80.4%; FSL-B:12.3/85.3%, P = .0012).

Conclusion: FSL-B demonstrated higher accuracy when compared to FSL-A However, when glycemia is decreasing or its trend is uncertain, the verification with a glucose meter is still advisable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pedi.13135DOI Listing
March 2021

NormiRazor: tool applying GPU-accelerated computing for determination of internal references in microRNA transcription studies.

BMC Bioinformatics 2020 Sep 29;21(1):425. Epub 2020 Sep 29.

Department of Biostatistics and Translational Medicine, Medical University of Lodz, 15 Mazowiecka St., Lodz, 92-215, Poland.

Background: Multi-gene expression assays are an attractive tool in revealing complex regulatory mechanisms in living organisms. Normalization is an indispensable step of data analysis in all those studies, since it removes unwanted, non-biological variability from data. In targeted qPCR assays it is typically performed with respect to prespecified reference genes, but the lack of robust strategy of their selection is reported in literature, especially in studies concerning circulating microRNAs (miRNA). Unfortunately, this problem impedes translation of scientific discoveries on miRNA biomarkers into widely available laboratory assays. Previous studies concluded that averaged expressions of multi-miRNA combinations are more stable references than single genes. However, due to the number of such combinations the computational load is considerable and may be hindering for objective reference selection in large datasets. Existing implementations of normalization algorithms (geNorm, NormFinder and BestKeeper) have poor performance and may require days to compute stability values for all potential reference as the evaluation is performed sequentially.

Results: We designed NormiRazor - an integrative tool which implements those methods in a parallel manner on a graphics processing unit (GPU) using CUDA platform. We tested our approach on publicly available miRNA expression datasets. As a result, the times of executions on 8 datasets containing from 50 to 400 miRNAs (subsets of GSE68314) decreased 18.7 ±0.6 (mean ±SD), 104.7 ±4.2 and 76.5 ±2.2 times for geNorm, BestKeeper and NormFinder with respect to previous Python implementation. To allow for easy access to normalization pipeline for biomedical researchers we implemented NormiRazor as an online platform where a user could normalize their datasets based on the automatically selected references. It is available at norm.btm.umed.pl, together with instruction manual and exemplary datasets.

Conclusions: NormiRazor allows for an easy, informed choice of reference genes for qPCR transcriptomic studies. As such it can improve comparability and repeatability of experiments and in longer perspective help translate newly discovered biomarkers into readily available assays.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12859-020-03743-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523363PMC
September 2020

Radiation-Induced Hypothyroidism in Patients with Oropharyngeal Cancer Treated with IMRT: Independent and External Validation of Five Normal Tissue Complication Probability Models.

Cancers (Basel) 2020 Sep 22;12(9). Epub 2020 Sep 22.

Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland.

We aimed to externally validate five normal tissue complication probability (NTCP) models for radiation-induced hypothyroidism (RIHT) in a prospectively recruited cohort of 108 patients with oropharyngeal cancer (OPC). NTCP scores were calculated using original published formulas. Plasma thyrotropin (TSH) level was additionally assessed in the short-term after RT. After a median of 28 months of follow-up, thirty one (28.7%) patients developed RIHT. Thyroid mean dose and thyroid volume were significant predictors of RIHT: odds ratio equal to 1.11 (95% CI 1.03-1.19) for mean thyroid dose and 0.87 (95%CI 0.81-0.93) for thyroid volume in univariate analyses. Two of the evaluated NTCP models, published by Rønjom et al. and by Boomsma et al., had satisfactory performance with accuracies of 0.87 (95%CI 0.79-0.93) and 0.84 (95%CI: 0.76-0.91), respectively. Three remaining models, by Cella et al., Bakhshandeh et al. and Vogelius et al., performed significantly worse, overestimating the risk of RIHT in this patient cohort. A short-term TSH level change relative to baseline was not indicative of RIHT development in the follow-up (OR 0.96, 95%CI: 0.65-1.42, = 0.825). In conclusion, the models by Rønjom et al. and by Boomsma et al. demonstrated external validity and feasibility for long-term prediction of RIHT in survivors of OPC treated with Intensity-Modulated Radiation Therapy (IMRT).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12092716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563778PMC
September 2020

The Value of Serum MicroRNA Expression Signature in Predicting Refractoriness to Bortezomib-Based Therapy in Multiple Myeloma Patients.

Cancers (Basel) 2020 Sep 9;12(9). Epub 2020 Sep 9.

Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland.

Bortezomib is the first-in-class proteasome inhibitor, commonly used in the treatment of multiple myeloma (MM). The mechanisms underlying acquired bortezomib resistance in MM are poorly understood. Several cell-free miRNAs have been found to be aberrantly regulated in MM patients. The aim of this pilot study was to identify a blood-based miRNA signature that predicts bortezomib-based therapy efficacy in MM patients. Thirty MM patients treated with bortezomib-based regimens were studied, including 19 with refractory disease and 11 who were bortezomib sensitive. Serum miRNA expression patterns were identified with miRCURY LNA miRNA miRNome PCR Panels I+II (Exiqon/Qiagen). Univariate analysis found a total of 21 miRNAs to be differentially expressed in patients with MM according to bortezomib sensitivity. Multivariate logistic regression was created and allowed us to discriminate refractory from sensitive patients with a very high AUC of 0.95 (95%CI: 0.84-1.00); sensitivity, specificity and accuracy were estimated as 0.95, 0.91, and 0.93. The model used expression of 3 miRNAs: miR-215-5p, miR-181a-5p and miR-376c-3p. This study is the first to demonstrate that serum expression of several miRNAs differs between patients who are bortezomib refractory and those who are sensitive which may prove useful in studies aimed at overcoming drug resistance in MM treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12092569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565855PMC
September 2020

Functional Radiogenetic Profiling Implicates ERCC6L2 in Non-homologous End Joining.

Cell Rep 2020 08;32(8):108068

Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland; Division of Molecular Pathology, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Bern Center for Precision Medicine, University of Bern, 3012 Bern, Switzerland. Electronic address:

Using genome-wide radiogenetic profiling, we functionally dissect vulnerabilities of cancer cells to ionizing radiation (IR). We identify ERCC6L2 as a major determinant of IR response, together with classical DNA damage response genes and members of the recently identified shieldin and CTC1-STN1-TEN1 (CST) complexes. We show that ERCC6L2 contributes to non-homologous end joining (NHEJ), and it may exert this function through interactions with SFPQ. In addition to causing radiosensitivity, ERCC6L2 loss restores DNA end resection and partially rescues homologous recombination (HR) in BRCA1-deficient cells. As a consequence, ERCC6L2 deficiency confers resistance to poly (ADP-ribose) polymerase (PARP) inhibition in tumors deficient for both BRCA1 and p53. Moreover, we show that ERCC6L2 mutations are found in human tumors and correlate with a better overall survival in patients treated with radiotherapy (RT); this finding suggests that ERCC6L2 is a predictive biomarker of RT response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2020.108068DOI Listing
August 2020

Clinical Role of Extraoral Bitter Taste Receptors.

Int J Mol Sci 2020 Jul 21;21(14). Epub 2020 Jul 21.

Department of Otolaryngology, Head and Neck Oncology, Medical University of Lodz, 90-419 Lodz, Poland.

Humans can recognise five basic tastes: sweet, sour, salty, bitter and umami. Sour and salty substances are linked to ion channels, while sweet, bitter and umami flavours are transmitted through receptors linked to the G protein (G protein-coupled receptors; GPCRs). There are two main types of GPCRs that transmit information about sweet, umami and bitter tastes-the Tas1r and families. There are about 25 functional genes coding bitter taste receptor proteins. They are found not only in the mouth and throat, but also in the intestines, brain, bladder and lower and upper respiratory tract. The determination of their purpose in these locations has become an inspiration for much research. Their presence has also been confirmed in breast cancer cells, ovarian cancer cells and neuroblastoma, revealing a promising new oncological marker. Polymorphisms of have been proven to have an influence on the course of chronic rhinosinusitis and upper airway defensive mechanisms. receptors mediate the bronchodilatory effect in human airway smooth muscle, which may lead to the creation of another medicine group used in asthma or chronic obstructive pulmonary disease. The discovery that functionally compromised receptors negatively impact glucose homeostasis has produced a new area of diabetes research. In this article, we would like to focus on what facts have been already established in the matter of extraoral receptors in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21145156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404188PMC
July 2020

Impact of processing method on donated human breast milk microRNA content.

PLoS One 2020 15;15(7):e0236126. Epub 2020 Jul 15.

Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.

Pasteurization of donated human milk preserves it for storage and makes it safe for feeding, but at the expense of its composition, nutritional values and functions. Here, we aimed to investigate the impact of Holder Pasteurization (HoP) and High Pressure Processing (HPP) methods on miRNA in human milk and to evaluate impact of these changes on miRNA functions. Milk samples obtained from women in 50th day of lactation (n = 3) were subjected either to HoP, HPP or remained unpasteurized as a control. Subsequently, miRNA was isolated from whole material and exosomal fraction and sequenced with Illumina NextSeq 500. Sequencing data were processed, read counts were mapped to miRNA and analyzed both quantitatively with DESeq2 and functionally with DIANA mirPath v.3. While HPP caused statistically insignificant decrease in number of miRNA reads compared to unprocessed material, HoP led to 82-fold decrease in whole material (p = 0.0288) and 302-fold decrease in exosomes (p = 0.0021) not leaving enough reads for further analysis. Changes in composition of miRNA fraction before and after HPP indicated uneven stability of individual miRNAs under high pressure conditions, with miR-30d-5p identified as relatively stable and miR-29 family as sensitive to HPP. Interestingly, about 2/3 of unprocessed milk miRNA content consists of only 10 distinct miRNAs with miR-148a-3p at the top. Functional analysis of most abundant human milk miRNAs showed their involvement in signaling pathways, cell communication, proliferation and metabolism that are obviously important in rapidly growing infants. Functions of miRNAs which suffered the greatest depletion during HPP were similar to roles of the majority of unprocessed human milk's miRNA, which indicates that those functions may be weakened although not completely lost. Our findings indicate that HPP is less detrimental to human milk miRNAs than HoP and should be considered in further research on recommended processing procedures for human milk banks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236126PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363072PMC
September 2020

Fetuin-A and Interleukine-8 in Children with the Clinical Remission of Type 1 Diabetes.

Iran J Immunol 2020 Jun;17(2):144-153

Department of Pediatrics, Silesian Medical University in Katowice, Katowice, Poland.

Background: Clinical partial remission (CPR) in most patients with type 1 diabetes (T1D) is observed shortly after clinical diagnosis. Increasing body weight and impaired insulin sensitivity may play a role in the pathogenesis of CPR. Several cytokines can also participate in the development of insulin resistance.

Objective: To evaluate the relationship between birth weight, body mass index, and the concentrations of IL-8 and Fetuin-A, and the presence of clinical partial remission in children at the T1D onset.

Methods: The study group consisted of 134 children with a newly diagnosed T1D in whom the presence of CPR was evaluated in a further 2-year course of diabetes. The control group included 47 children without glucose tolerance disorders. The concentrations of IL-8 and Fetuin-A were determined by the ELISA method.

Results: CPR occurred in 75.34% of T1D patients. At T1D onset, higher values of BMI SDS in the remitters as compared to the patients without remission were observed. At the T1D onset, the concentrations of Fetuin-A (p=0.031) and IL-8 (p=0.042) were significantly higher in patients compared to those without CPR.

Conclusion: Evaluation of Fetuin-A and IL-8 levels in patients with a newly diagnosed T1D can differentiate between patients with or without CPR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.22034/iji.2020.82797.1595DOI Listing
June 2020

Cytokine and Chemokine Profile in Patients with Multiple Myeloma Treated with Bortezomib.

Mediators Inflamm 2020 6;2020:1835836. Epub 2020 Jun 6.

Department of Hematology, Medical University of Lodz, Poland.

The aim of the study was to determine the levels of selected cytokines and chemokines in the serum of multiple myeloma (MM) patients treated with bortezomib-based regimens. A total of 71 MM patients were examined: 41 with primary refractory disease (17) or early relapse (28), and 30 who were bortezomib sensitive with no progression for at least six months. Patients who demonstrated CR or PR after bortezomib-based therapies longer than six months after treatment discontinuation were designated bortezomib sensitive. Serum cytokine levels were assayed with Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay on the MAGPIX Multiplex Reader and the Bio-Plex® 200 System (Bio-Rad). Higher levels of MIP-1 and lower levels of MIP-1 and IL-9 were associated with better responses to bortezomib-based treatment, and higher levels of IL-1ra and IL-8 were associated with bone involvement. MCP-1 was elevated in patients with hemoglobin < 10 g/dl compared to those without anemia. The levels of IL-8, MIP-1, and TNF- were significantly higher in patients with renal insufficiency. Only MIP-1 was elevated in patients with hypercalcemia compared to patients with normal calcium levels. In conclusion, distinct cytokines are involved in the pathogenesis of MM and may play a prominent role in the prediction of treatment response. However, a single measurement of serum cytokines should be interpreted with caution and further studies are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/1835836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294367PMC
June 2020

Klotho and fibroblast growth factors 19 and 21 serum concentrations in children and adolescents with normal body weight and obesity and their associations with metabolic parameters.

BMC Pediatr 2020 06 16;20(1):294. Epub 2020 Jun 16.

Department of Gastroenterology, Allergology and Pediatrics, Polish Mother's Memorial Hospital-Research Institute, 281/289 Rzgowska St, 93-338, Lodz, Poland.

Background: Fibroblast growth factor 19 (FGF19), fibroblast growth factor 21 (FGF21) and Klotho are regulators of energy homeostasis. However, in the pediatric population, the relationships between obesity, metabolic disorders and the aforementioned factors have not been clearly investigated. We analyzed the role of FGF19, FGF21 and Klotho protein in children with normal body weight as well as in overweight and obese subjects and explored their associations with insulin resistance (IR) and metabolic syndrome (MS) and its components.

Methods: This was a cross-sectional study conducted in a group of hospitalized children and adolescents. Laboratory investigations included serum analysis of FGF19, FGF21, and Klotho with ELISA kits as well as the analysis of the lipid profile and ALT serum concentrations. Moreover, each subject underwent an oral glucose tolerance test (OGTT) with fasting insulinemia measurement to detect glucose tolerance abnormalities and calculate the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index. Furthermore, the clinical analysis included blood pressure measurement, body fat percentage estimation and assessment of the prevalence of MS and its components.

Results: The study was conducted with 174 children/adolescents aged 6-17 years with normal body weight (N = 48), obesity (N = 92) and overweight (N = 34). Klotho concentration was significantly higher in the obese children [median 168.6 pg/ml (90.2 to 375.9)]) than in the overweight [131.3 pg/ml (78.0 to 313.0)] and normal-body-weight subjects [116.6 pg/ml (38.5 to 163.9)] (p = 0.0334) and was also significantly higher in insulin-resistant children than in insulin-sensitive children [185.3 pg/ml (102.1 to 398.2) vs 132.6 pg/ml (63.9 to 275.6), p = 0.0283]. FGF21 was elevated in patients with MS compared to the FGF21 levels in other subjects [136.2 pg/ml (86.5 to 239.9) vs 82.6 pg/ml (41.8 to 152.4), p = 0.0286]. The multivariable model showed that FGF19 was an independent predictor of IR after adjusting for pubertal stage and BMI Z-score.

Conclusions: Klotho levels were associated with body weight status in children and adolescents. Moreover, Klotho, FGF19 and FGF21 concentrations correlated with IR status and/or components of MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12887-020-02199-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296965PMC
June 2020

TP53-Deficient Angiosarcoma Expression Profiling in Rat Model.

Cancers (Basel) 2020 Jun 10;12(6). Epub 2020 Jun 10.

Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.

Sarcomas are a heterogeneous group of malignant tumors, that develop from mesenchymal cells. Sarcomas are tumors associated with poor prognosis and expected short overall survival. Efforts to improve treatment efficacy and treatment outcomes of advanced and metastatic sarcoma patients have not led to significant improvements in the last decades. In the rat model we therefore aimed to characterize specific gene expression pattern of angiosarcomas with a loss of TP53 function. The presence of metabolically active tumors in several locations including the brain, head and neck, extremities and abdomen was confirmed by magnetic resonance imaging (MRI) and positron emission tomography (PET) examinations. Limb angiosarcoma tumors were selected for microarray expression analysis. The most upregulated pathways in angiosarcoma vs all other tissues were related to cell cycle with mitosis and meiosis, chromosome, nucleosome and telomere maintenance as well as DNA replication and recombination. The downregulated genes were responsible for metabolism, including respiratory chain electron transport, tricarboxylic acid (TCA) cycle, fatty acid metabolism and amino-acid catabolism. Our findings demonstrated that the type of developing sarcoma depends on genetic background, underscoring the importance of developing more malignancy susceptibility models in various strains and species to simulate the study of the diverse genetics of human sarcomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12061525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352674PMC
June 2020

Metabolic bone markers can be related to preserved insulin secretion in children with newly diagnosed type 1 diabetes.

Pediatr Endocrinol Diabetes Metab 2020 ;26(1):10-16

Department of Paediatrics, Diabetology, Endocrinology, and Nephrology, Medical University of Lodz, Poland.

Introduction: Type 1 diabetes (T1D) may be associated with numerous complications including bone metabolism disorders. The aim of the study was to evaluate the bone metabolism markers twice in children with a newly diagnosed T1D and after an average of seven months of its duration in relation to parameters of the clinical course of diabetes.

Material And Methods: In 100 T1D patients and 52 control subjects, the following bone turnover markers were evaluated: osteocalcin - OC, osteoprotegerin - OPG, sRANKL, and deoxypyridoline in urine - DPD and DXA examination was also performed.

Results: Lower OC concentration at T1D onset in comparison to controls (p < 0.001) and its increase during follow-up (p < 0.001) was ob-served. The OPG concentration was elevated at T1D onset as compared to the control group (p = 0.024) and decreased thereafter (p < 0.001). The s-RANKL level increased during follow-up (p < 0.001) and was lower than in controls (p < 0.001). Urine DPD con-centration also increased during follow-up in the T1D patient group (p < 0.001) and was higher in comparison to the control group (p = 0.021). BMD-TBLH was higher in the control group as compared to patients both at T1D onset (p = 0.025) and in follow-up ob-servation (p = 0.034). Moreover, OPG correlated positively with glycated haemoglobin (HbA1c) (p = 0.004) and negatively with fasting C-peptide level (p = 0.046) and BMI Z-score (p = 0.003), whereas s-RANKL correlated positively with both fasting (p < 0.001) and stimulated C-peptide levels (p < 0.001).

Conclusions: Bone metabolism disorders observed at T1D onset in children and modified after reaching the metabolic control of the disease seem to be most strongly associated with preserved insulin secretion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5114/pedm.2020.94391DOI Listing
March 2021

Defining and Targeting Adaptations to Oncogenic KRAS Inhibition Using Quantitative Temporal Proteomics.

Cell Rep 2020 03;30(13):4584-4599.e4

Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address:

Covalent inhibitors of the KRAS oncoprotein have recently been developed and are being evaluated in clinical trials. Resistance to targeted therapies is common and may limit long-term efficacy of KRAS inhibitors (KRASi). To identify pathways of adaptation to KRASi and predict drug combinations that circumvent resistance, we use mass-spectrometry-based quantitative temporal proteomics to profile the proteomic response to KRASi in pancreatic and lung cancer 2D and 3D cellular models. We quantify 10,805 proteins, representing the most comprehensive KRASi proteome (https://manciaslab.shinyapps.io/KRASi/). Our data reveal common mechanisms of acute and long-term response between KRAS-driven tumors. Based on these proteomic data, we identify potent combinations of KRASi with phosphatidylinositol 3-kinase (PI3K), HSP90, CDK4/6, and SHP2 inhibitors, in some instances converting a cytostatic response to KRASi monotherapy to a cytotoxic response to combination treatment. Overall, using quantitative temporal proteomics, we comprehensively characterize adaptations to KRASi and identify combinatorial regimens with potential therapeutic utility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2020.03.021DOI Listing
March 2020

Validation of EORTC, CUETO, and EAU risk stratification in prediction of recurrence, progression, and death of patients with initially non-muscle-invasive bladder cancer (NMIBC): A cohort analysis.

Cancer Med 2020 06 26;9(11):4014-4025. Epub 2020 Mar 26.

Department of Urology, Copernicus Memorial Hospital, Medical University of Lodz, Lodz, Poland.

Brief Description: The results demonstrate that the European Organisation for Research and Treatment of Cancer (EORTC) scale provides the best recurrence and progression prediction in comparison with European Association of Urology (EAU) and Club Urologico Espanol de Tratamiento Oncologico (CUETO) risk scores among a mixed population of patients with non-muscle-invasive bladder who were treated with, or without, Bacillus Calmette-Guerin (BCG) and without any immediate postoperative chemotherapy. The study highlights the role of tumor diameter and extent in transition prediction. This retrospective cohort analysis of 322 patients with newly diagnosed non-muscle-invasive bladder cancer (NMIBC) assesses the concordance and accuracy of predicting recurrence and progression by EAU-recommended tools (EAU risk groups, EORTC, and CUETO). One-year and five-year c-indices ranged from 0.55 to 0.66 for recurrence and from 0.72 to 0.82 for progression. AUCROC of predictions ranged from 0.46 for 1-year recurrence risk based on CUETO groups, to 0.82 for 1-year progression risk based on EAU risk groups. Diameter (HR: 1.91; 95% CI: 1.39-2.61) and tumor extent (HR: 1.21; 95% CI: 1.01-1.46 for recurrence; HR: 3.1; 95% CI: 1.40-6.87 for progression) were shown to be significant predictors in multistate analysis. Lower accuracy of prediction was observed for patients treated with BCG maintenance immunotherapy. The EORTC model (overall c-index c = 0.64; 95% CI: 0.61-0.68) was superior to the EAU (P = .035; .62; 95% CI: 0.59-0.66) and CUETO (P < .001; c = 0.53; 95% CI: 0.50-0.56) models in predicting recurrence. The EORTC model (c = 0.82; 95% CI: 0.77-0.86) also performed better than CUETO (P = .008; c = 0.73; 95% CI: 0.66-0.81) but there was no sufficient evidence that it performed better than EAU (P = .572; c = 0.81; 95% CI: 0.77-0.84) for predicting progression. EORTC and CUETO gave similar predictions for progression in BCG-treated EAU high-risk patients (P = .48). We share anonymized individual patient data. In conclusion, despite moderate accuracy, EORTC provided the best recurrence and progression prediction for a mixed population of patients treated with, or without BCG, and without immediate postoperative chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286464PMC
June 2020

Detection screening and seasonality evaluation of hypoplastic left heart syndrome in the polish national registry for fetal cardiac anomalies from the years 2004 to 2016.

Prenat Diagn 2020 05 13;40(6):698-704. Epub 2020 Mar 13.

Department for Diagnoses and Prevention Fetal Malformations, Medical University of Lodz, Lodz, Poland.

Objectives: To evaluate the incidence of hypoplastic left heart syndrome (HLHS) and the efficiency of the screening program using data from the Polish National Registry for Fetal Cardiac Anomalies. To investigate whether HLHS incident rates in Poland are seasonally variable.

Methods: Data on 791 cases of HLHS from the Registry collected between 2004 and 2016 was analyzed.

Results: The median gestational age for the 734 cases of HLHS detected was 23 weeks. Comparing the age at time of HLHS detection between 2004 and 2016, a decrease from 26 to 20.8 weeks was observed. We noted a rapid increase in HLHS incidence during the initial years of the Registry data, the annual percentage change during that period was 22.0% and this trend lasted until 2010. In the following years, the Registry became representative of the general population which has an estimated incidence of HLHS of 20.93 cases per 100 000 live births. We observed no clear seasonal patterns of HLHS incidence in our population.

Conclusion: The Registry reached a plateau state in terms of diagnosing new cases of HLHS. No evidence of seasonality has been noted. The average gestational age of patients identified as having HLHS decreased significantly during the study period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.5677DOI Listing
May 2020

MiR-502 is the first reported miRNA simultaneously targeting two components of the classical non-homologous end joining (C-NHEJ) in pancreatic cell lines.

Heliyon 2020 Jan 18;6(1):e03187. Epub 2020 Jan 18.

University Medicine Greifswald, Department of Internal Medicine A, Greifswald, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Acquired inherited and/or somatic mutations drive its development. In order to prevent the formation of these mutations, precise and immediate repair of any DNA damage is indispensable. Non-homologous end-joining (NHEJ) is the key mechanism of DNA double-strand break repair. Here, we report that miR-502 targets two components in pancreatic cell lines, Ku70 and XLF of the C-NHEJ. Interestingly, we also observed an attenuated cell cycle response to gamma ionizing radiation (γ-IR) via diminished phosphorylation of checkpoint kinase 1 (Chk1) on serine 345 in these cell lines. Altogether, pancreatic cells showed increased susceptibility to γ-IR via direct inhibition of DNA double-strand break repair and attenuation of the cell cycle response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.heliyon.2020.e03187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002776PMC
January 2020

A systemic approach to screening high-throughput RT-qPCR data for a suitable set of reference circulating miRNAs.

BMC Genomics 2020 Jan 31;21(1):111. Epub 2020 Jan 31.

Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.

Background: The consensus on how to choose a reference gene for serum or plasma miRNA expression qPCR studies has not been reached and none of the potential candidates have yet been convincingly validated. We proposed a new in silico approach of finding a suitable reference for human, circulating miRNAs and identified a new set of endogenous reference miRNA based on miRNA profiling experiments from Gene Expression Omnibus. We used 3 known normalization algorithms (NormFinder, BestKeeper, GeNorm) to calculate a new normalization score. We searched for a universal set of endogenous miRNAs and validated our findings on 2 new datasets using our approach.

Results: We discovered and validated a set of 13 miRNAs (miR-222, miR-92a, miR-27a, miR-17, miR-24, miR-320a, miR-25, miR-126, miR-19b, miR-199a-3p, miR-30b, miR-30c, miR-374a) that can be used to create a reliable reference combination of 3 miRNAs. We showed that on average the mean of 3 miRNAs (p = 0.0002) and 2 miRNAs (p = 0.0031) were a better reference than single miRNA. The arithmetic means of 3 miRNAs: miR-24, miR-222 and miR-27a was shown to be the most stable combination of 3 miRNAs in validation sets.

Conclusions: No single miRNA was suitable as a universal reference in serum miRNA qPCR profiling, but it was possible to designate a set of miRNAs, which consistently contributed to most stable combinations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12864-020-6530-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995162PMC
January 2020

A cross-sectional study of patients referred for HNF1B-MODY genetic testing due to cystic kidneys and diabetes.

Pediatr Diabetes 2020 05 29;21(3):422-430. Epub 2020 Jan 29.

Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland.

Background/objectives: Patients referred for HNF1B testing present very heterogeneous phenotypes. Despite suggestive characteristics, many do not harbor mutations in HNF1B. Our objective was to evaluate the clinical characteristics of probands referred for HNF1B genetic testing through a nationwide monogenic diabetes screening program.

Methods: Probands tested for HNF1B mutations in the 2005-2018 period (N = 50) were identified in the Polish Monogenic Diabetes Registry, which prospectively recruits primarily pediatric patients and their families on a nationwide scale. Variants that had been reported pathogenic were reassessed using criteria of the American College of Medical Genetics and Genomics (ACMG). A structured medical interview was performed with all available individuals, their parents, and/or their physicians. For each patient, HNF1B score was calculated based on available clinical information.

Results: The study group numbered 36 unrelated probands (28% lost to follow-up): 14 with pathogenic or likely-pathogenic variants in HNF1B, one with a variant of uncertain significance, and 21 negative for HNF1B mutations. Presence of cystic kidneys (OR = 9.17, 95% CI:1.87-44.92), pancreatic abnormalities (OR = 15, 95% CI:1.55-145.23), elevated liver enzymes (OR = 15, 95% CI:1.55-145.23) best discriminated HNF1B-positive cases from the negative ones. Presence of impaired glucose tolerance coupled with kidney disease in the proband and one parent was also highly predictive for HNF1B mutations (OR = 11.11, 95% CI:1.13-109.36). HNF1B-score with recommended cutoff distinguished patients with and without HNF1B findings with 100% sensitivity and 47.6% specificity. Addition of four clinical variables to select patients based on HNF1B score improved specificity to 71.4% (95% CI:47.8%-88.7%) while retaining 100% sensitivity.

Conclusions: Detailed medical interview may enable more accurate patient selection for targeted genetic testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pedi.12959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217165PMC
May 2020

Clinical experience of narrow band imaging (NBI) usage in diagnosis of laryngeal lesions.

Otolaryngol Pol 2019 Aug;73(6):18-23

I Katedra Otolaryngologii, Klinika Otolaryngologii, Onkologii Głowy i Szyi Uniwersytet Medyczny w Łodzi.

Introduction: One of the most recent methods used in imaging of the larynx is narrow band imaging (NBI). NBI enables us to detect specific patterns of pathological angiogenesis suggestive of premalignant or neoplastic lesions. The aim of the study was to compare imaging of laryngeal lesions in white light endoscopy (WLE) and NBI in relation to histopathological examination.

Material And Methods: 333 patients with laryngeal lesions underwent endoscopic evaluation in WLE and NBI. Sensitivity, specificity, positive and negative predictive value (PPV, NPV) for WLE and NBI were calculated. The diagnostic value for WLE and NBI was evaluated for two assumptions (positive result is:1. severe dysplasia and cancer 2. only cancer) Results: Sensitivity, specificity, PPV, NPV of first assumption were respectively for white light compared to NBI: 95.4% vs 98.5%; 84.2% vs 98.5%; 79.6% vs 97.7% and 96.6% vs 99.0%. The values of second assumption were: 97.4% vs 100%; 79.3% vs 93.5%; 72.6% vs. 89.4% and 98.2% vs. 100.0%. Higher sensitivity was observed for the second assumption, while higher specifity was recorded for the first assumption. Specificity was significantly higher for NBI than for WLE (p<0.001).

Conclusions: NBI enables us to detect and differentiate laryngeal lesions, which are invisible in WLE. Endoscopic examination, especially in NBI-mode, is non-invasive, repeatable and remains a useful tool in the daily practice and diagnosis of patients with pathological lesions in the larynx.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5604/01.3001.0013.3401DOI Listing
August 2019

Analysis of the impact of bronchial asthma and hypersensitivity to aspirin on the clinical course of chronic sinusitis with nasal polyps.

Otolaryngol Pol 2019 Oct;73(5):37-43

I Katedra Otolaryngologii, Klinika Otolaryngologii i Laryngologii Onkologicznej, Uniwersytet Medyczny w Łodzi.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a disease with still not enough known pathogenesis despite the development of genetics, immunological and microbiological research. The number of patients with CRS has been constantly growing. The coexistence of CRS, bronchial asthma and aspirin intolerance (aspirin triad) is an adverse prognostic factor with higher risk of recurrences. The aim of study was to compare the severity of CRSwNP depending of coexistence of bronchial asthma and/or aspirin intolerance. The research was performed in the group of 204 patients operated 2009-2013 with 5 years follow-up. Higher nasal polyps growth in groups of patients with aspirin triad and CRSwNP and bronchial asthma in endoscopic examination (p=0,0005 and p=0,0030 respectively) and CT-scan according to Lund-Mackay point scale (p<0,0001 and p=0,0009) was showed. Also, these patients presented increased severity of nasal symptoms before surgical treatment according to VAS scale (p=0,0126 for CRSwNP with bronchial asthma; p=0,0390 for aspirin triad). Similarly, 6 months after surgery the same groups of patients presented higher severity of the disease symptoms (p<0,0001 for aspirin triad' patients; p=0,0174 for CRSwNP and bronchial asthma' patients) . Patients with aspirin triad had also statistically more surgeries in past (p=0,001), what proves that recurrences in this group are very likely to be observed in spite of the use of proper conservative treatment. No such differences have been shown in the group of patients with CRSwNP and isolated aspirin intolerance (without bronchial asthma). Allergy to inhaled allergens, hypersensitivity to aspirin are factors significantly worsening the course of CRSwNP. It would be advisable to consider, despite a lack of history of aspirin intolerance, a hypersensititvity to aspirin test in patients with particularly severe CRSwNP, especially those associated with bronchial asthma. It also seems reasonable to carry out such a test on every patient with newly diagnosed CRSwNP and bronchial asthma in order to be able to plan further treatment in this group of patients accordingly including biological treatment with antimonoclonal therapy against interleukin 4, 5 or13.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5604/01.3001.0013.5277DOI Listing
October 2019

Chip-Based Digital PCR Approach Provides A Sensitive and Cost-Effective Single-Day Screening Tool for Common Fetal Aneuploidies-A Proof of Concept Study.

Int J Mol Sci 2019 Nov 4;20(21). Epub 2019 Nov 4.

Department of Genetics, Polish Mother's Memorial Hospital Research Institute, 93-338 Lodz, Poland.

In the prenatal period, the copy number aberrations of chromosomes 13, 18, 21, X and Y account for over 80% of the clinically significant chromosome abnormalities. Classical cytogenetic analysis is the gold standard in invasive prenatal diagnostics but the long test waiting time affects its clinical utility. Several molecular rapid tests have been developed and employed in clinical practice, however all have substantial drawbacks. The aim of the study was to design and evaluate an optimized tool for rapid molecular detection of fetal aneuploidies. We established a novel single-day method using a chip-based platform, the QuantStudio 3D Digital PCR system. In order to assess the clinical usefulness of our screening test, we analyzed 133 prenatal samples. The difference in distributions of euploid and aneuploid samples identified the ploidy of each of the target chromosomes with high precision. The distribution of the chromosome ratio for euploid and aneuploid samples showed a statistically significant result ( = 0.003 for trisomy 13, = 0.001 for trisomies 18 and 21, Mann-Whitney test). Our results suggest that this novel chip-based approach provides a tool for rapid, technically simple, cost-effective screening for common fetal aneuploidies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20215486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862520PMC
November 2019