Analysis of gene expression to predict dynamics of future hypertension incidence in type 2 diabetic patients

BACKGROUND: The main focus of the Genetic Analysis Workshop 19 (GAW19) is identification of genes related to the occurrence of hypertension in the cohort of patients with type 2 diabetes mellitus (T2DM). The aim of our study was to predict dynamics of the future hypertension incidence, based on gene expression profiles, systolic and diastolic blood pressure changes in time, sex, baseline age, and cigarette smoking status. We analyzed data made available to GAW19 participants, which included gene expression profiles of peripheral blood mononuclear cells (PBMCs) from the diabetic members of 20 Mexican American families. METHODS: On the basis of mid blood pressure measurements at several time points, the coefficient of regression (slope) was calculated for each individual. We corrected the slope value in patients treated with antihypertensive medications. Feature preprocessing methods were used to remove highly correlated probes and linear dependencies between them. Subsequently, multiple linear regression model was used to associate gene expression with the regression coefficient calculated for each T2DM patient. Tenfold cross-validation was used to validate the model. We used linear mixed effects model and kinship coefficients to account for the family structure. All calculations were performed in R. RESULTS: This analysis allowed us to identify 6 well-annotated genes: RTP4, FXYD6, GDF11, IFNAR1, NOX3, and HLA-DQ2, associated with dynamics of future hypertension incidence. Two of them, IFNAR1 and NOX3 were previously implicated in pathogenesis of hypertension. CONCLUSIONS: There is no obvious mechanism that links all detected genes with dynamics of hypertension incidence. Identification of possible connection with hypertension needs further investigation

Dysregulation of transcription factor activity during formation of cancer-associated fibroblasts

The reciprocal interactions between cancer cells and the quiescent fibroblasts leading to the activation of cancer-associated fibroblasts (CAFs) serve an important role in cancer progression. Here, we investigated the activation of transcription factors (TFs) in prostate fibroblasts (WPMY cell line) co-cultured with normal prostate or tumorous cells (RWPE1 and RWPE2 cell lines, respectively). After indirect co-cultures, we performed mRNA-seq and predicted TF activity using mRNA expression profiles with the Systems EPigenomics Inference of Regulatory Activity (SEPIRA) package and the GTEx and mRNA-seq data of 483 cultured fibroblasts. The initial differential expression analysis between time points and experimental conditions showed that co-culture with normal epithelial cells mainly promotes an inflammatory response in fibroblasts, whereas with the cancerous epithelial, it stimulates transformation by changing the expression of the genes associated with microfilaments. TF activity analysis revealed only one positively regulated TF in the RWPE1 co-culture alone, while we observed dysregulation of 45 TFs (7 decreased activity and 38 increased activity) uniquely in co-culture with RWPE2. Pathway analysis showed that these 45 dysregulated TFs in fibroblasts co-cultured with RWPE2 cells may be associated with the RUNX1 and PTEN pathways. Moreover, we showed that observed dysregulation could be associated with FER1L4 expression. We conclude that phenotypic changes in fibroblast responses to co-culturing with cancer epithelium result from orchestrated dysregulation of signaling pathways that favor their transformation and motility rather than proinflammatory status. This dysregulation can be observed both at the TF and transcriptome levels

Narodowy Rejestr Chorych na Cukrzycę w Polsce : program pilotażowy

Wstęp. Pilotażowy projekt Rejestru Dorosłych Chorych na Cukrzycę w Polsce został przeprowadzony w latach 2006–2009. Został on sfinansowany z funduszy Ministerstwa Zdrowia. Celem projektu była ocena jakości opieki diabetologicznej w kilka lat po przystąpieniu Polski do Unii Europejskiej. Materiał i metody. Kwestionariusze dotyczące danych pacjentów z cukrzycą były wypełniane przez lekarzy diabetologów w 39 różnych ośrodkach diabetologicznych w Polsce. Dane zawarte w kwestionariuszach zawierały pytania o: wiek, płeć, BMI, typ i czas trwania cukrzycy, rodzaj leczenia hipoglikemizującego, HbA1c, profile glikemii, lipidogram, ciśnienie tętnicze, powikłania cukrzycy, choroby towarzyszące i ich leczenie oraz inne aspekty opieki. Kwestionariusze były analizowane w centralnym ośrodku. Wyniki. Uzyskano dane 7606 pacjentów: 15,0% z typem 1 cukrzycy (T1DM), 80,9% z typem 2 cukrzycy (T2DM), 1,9% z innymi typami cukrzycy i 2,2% z cukrzycą ciążową. Grupa chorych z T1DM i T2DM charakteryzowała się odpowiednio: liczebnością 1134 (52,4% kobiet) i 6119 (55,5% kobiet), średnim wiekiem 40,9 i 63,8 lat, średnim czasem trwania cukrzycy 14,6 i 9,7 lat. Średni poziom HbA1c wynosił dla T1DM i T2DM odpowiednio 7,69 i 7,25%. Parametry gospodarki lipidowej dla T1DM i T2DM wynosiły: cholesterol całkowity 4,84 i 5,06 mmol/l; LDL-cholesterol 2,73 i 2,90 mmol/l; HDL-cholesterol 1,58 i 1,30 mmol/l; triglicerydy 1,26 i 1,95 mmol/l; ciśnienie tętnicze 127,4/77,7 i 139,8/81,8 mmHg. Odsetek pacjentów spełniających kryteria wyrównania wynosił odpowiednio dla: HbA1c £ 7,0% i £ 6,5%: T1DM 39,4 i 22,6%, T2DM 52,1 i 32,8%; cholesterol całkowity < 4,5 mmol/l: T1DM 40,1%, T2DM 32,6%; triglicerydy < 1,7 mmol/l: T1D 82,1%, T2D 53,2%; ciśnienie tętnicze < 130/80 mm Hg: T1DM 31,9%, T2DM 12,9%. Częstość występowania mikronaczyniowych powikłań cukrzycy wynosił odpowiednio dla chorych z T1DM i T2DM: retinopatia 38,4 i 23,4%; nefropatia 15,2 i 8,5%; neuropatia obwodowa 25.3 i 25.4%; neuropatia autonomiczna 9,6 i 5,4%. Wnioski. Dane uzyskane w Rejestrze obrazują obecny stan opieki diabetologicznej w Polsce, który wykazuje tendencję do poprawy w porównaniu do badania DEPAC przeprowadzonego w krajach Europy środkowo-wschodniej, w tym w Polsce w okresie przystąpienia do Unii Europejskiej (2004). Pomimo tego trendu większość pacjentów wciąż nie spełnia kryteriów wyrównania cukrzycy rekomendowanych przez krajowe i międzynarodowe zalecenia. (Diabet. Klin. 2012; 1, 1: 3–11)Background. Over the years 2006–2009 a pilot project of the Polish Diabetes Registry for Adults financed by the Polish Ministry of Health was performed. The objective was to assess outpatient diabetes care a few years after joining the European Union. Material and methods. Questionnaires for randomly enrolled patients were completed by diabetologists in 39 outpatient diabetes centers in different parts of Poland. Data concerning age, sex, BMI, diabetes type and duration, hypoglycemic treatment, glycated haemoglobin (HbA1c), lipids levels, blood pressure (BP), diabetes complications, concomitant diseases and their treatment, and other aspects of medical care were collected. The questionnaires were analysed centrally. Results. Data on 7606 individuals were available: 15.0% with type 1 diabetes (T1DM); 80.9% with type 2 diabetes (T2DM); 1.9% with other types of diabetes; and 2.2% with gestational diabetes. T1DM and T2DM cohorts consisted of 1134 (52.4% women) and 6119 (55.5% women) patients, mean age 40.9 and 63.8 years, mean diabetes duration 14.6 and 9.7 years, respectively. Mean HbA1c for T1DM and T2DM was 7.69 and 7.25%. Lipid parameters for T1DM and T2DM were as followed: mean total cholesterol (TC) 4.84 and 5.06 mmol/l; mean LDL-cholesterol (LDL) 2.73 and 2.90 mmol/l; mean HDL-cholesterol (HDL) 1.58 and 1.30 mmol/l; mean triglycerides (TG) 1.26 and 1.95 mmol/l; mean blood pressure (BP) 127.4//77.7 and 139.8/81.8 mmHg. The following proportion of the patients within target were recorded: for HbA1c (£ 7.0% and £ 6.5%): T1DM 39.4 and 22.6%, T2DM 52.1 and 32.8%; for TC levels (< 4.5 mmol/l):T1DM 40.1%, T2DM 32.6%; for TG levels (< 1.7 mmol/l):T1DM 82.1%, T2DM 53.2%; for BP (< 130/80 mm Hg):T1DM 31.9%, T2DM 12.9%, respectively. Prevalence of microvascular complications among T1DM and T2DM was as followed: retinopathy 38,4 and 23,4%; nephropathy 15,2 and 8,5%; peripheral neuropathy 25.3 and 25.4%; autonomic neuropathy 9,6 and 5,4%. Conclusions. The data show the current quality of diabetes care in Poland, which seems to show some improvement as compared to the DEPAC survey performed at the accession to EU (2004). Nevertheless, the current Registry also indicates that most patients still do not meet the criteria of diabetes control defined by the local and international guidelines. (Diabet. Klin. 2012; 1, 1: 3–11

Decreased expression of the high mobility group box 1 (HMGB1) gene in peripheral blood in patients with mild or moderate clostridioides difficile infection

Cytokines are mediators of inflammation induced in the course of Clostridioides difficile infection (CDI). High Mobility Group Box 1 (HMGB1) is a cytokine playing an important role in the pathogenesis of numerous inflammatory and autoimmune diseases. The aim of the study was to assess the HMGB1 gene expression in the course of CDI. We have performed a prospective case-control study- including 55 adult patients, among them 27 with CDI, who were hospitalized from October 2018 to February 2020 and 28 healthy volunteers. We assessed: a complete blood count with differential leukocyte count, blood creatinine, albumin, and C-reactive protein (CRP) levels. Then, the expression of the HMGB1 gene was evaluated using quantitative Real-Time PCR. Patients with CDI were found to have a significant increase in white blood cells (WBC), neutrophil count, and CRP levels, they also exhibited decreased levels of albumin compared with controls. The HMGB1 gene expression was significantly lower among patients with CDI compared with the control group and significantly, inversely correlated with CRP level in blood. In conclusion, we have observed a decreased expression of the HMGB1 gene in peripheral blood of patients with mild or moderate CDI, which hypothetically could reflect their diminished capability to fight the pathogen

Low expression of miR-375 and miR-190b differentiates grade 3 patients with endometrial cancer

Endometrial cancer (EC) is treated according to the stage and prognostic risk factors. Most EC patients are in the early stages and they are treated surgically. However some of them, including those with high grade (grade 3) are in the intermediate and high intermediate prognostic risk groups and may require adjuvant therapy. The goal of the study was to find differences between grades based on an miRNA gene expression profile. Tumor samples from 24 patients with grade 1 (n = 10), 2 (n = 7), and 3 (n = 7) EC were subjected to miRNA profiling using next generation sequencing. The results obtained were validated using the miRNA profile of 407 EC tumors from the external Cancer Genome Atlas (TCGA) cohort. We obtained sets of differentially expressed (DE) miRNAs with the largest amount between G2 to G1 (50 transcripts) and G3 to G1 (40 transcripts) patients. Validation of our results with external data (TCGA) gave us a reasonable gene overlap of which we selected two miRNAs (miR-375 and miR190b) that distinguish the high grade best from the low grade EC. Unsupervised clustering showed a high degree of heterogeneity within grade 2 samples. MiR-375 as well as 190b might be useful to create grading verification test for high grade EC. One of the possible mechanisms that is responsible for the high grade is modulation by virus of host morphology or physiology

The Polish Diabetes Registry for Adults — a pilot study

Background. Over the years 2006–2009 a pilot project of the Polish Diabetes Registry for Adults financed by the Polish Ministry of Health was performed. The objective was to assess outpatient diabetes care a few years after joining the European Union.Material and methods. Questionnaires for randomly enrolled patients were completed by diabetologists in 39 outpatient diabetes centers in different parts of Poland. Data concerning age, sex, BMI, diabetes type and duration, hypoglycemic treatment, glycated haemoglobin (HbA1c), lipids levels, blood pressure (BP), diabetes complications, concomitant diseases and their treatment, and other aspects of medical care were collected. The questionnaires were analysed centrally.Results. Data on 7606 individuals were available: 15.0% with type 1 diabetes (T1DM); 80.9% with type 2 diabetes (T2DM); 1.9% with other types of diabetes; and 2.2% with gestational diabetes. T1DM and T2DMcohorts consisted of 1134 (52.4% women) and 6119 (55.5% women) patients, mean age 40.9 and 63.8 years, mean diabetes duration 14.6 and 9.7 years, respectively. Mean HbA1c for T1DM and T2DM was 7.69 and 7.25%. Lipid parameters for T1DM and T2DM were as followed: mean total cholesterol (TC) 4.84 and 5.06 mmol/l; mean LDL-cholesterol (LDL) 2.73 and 2.90 mmol/l; mean HDL-cholesterol (HDL) 1.58 and 1.30 mmol/l; mean triglycerides (TG) 1.26 and 1.95 mmol/l; mean blood pressure (BP) 127.4//77.7 and 139.8/81.8 mmHg. The following proportionof the patients within target were recorded: for HbA1c (£ 7.0% and £ 6.5%): T1DM 39.4 and 22.6%, T2DM 52.1 and 32.8%; for TC levels (&lt; 4.5 mmol/l):T1DM 40.1%, T2DM 32.6%; for TG levels (&lt; 1.7 mmol/l):T1DM 82.1%, T2DM 53.2%; for BP (&lt; 130/80 mm Hg):T1DM 31.9%, T2DM 12.9%, respectively. Prevalence of microvascular complications among T1DM and T2DM was as followed: retinopathy 38,4 and 23,4%; nephropathy 15,2 and 8,5%; peripheral neuropathy 25.3 and 25.4%; autonomic neuropathy 9,6 and 5,4%.Conclusions. The data show the current quality of diabetes care in Poland, which seems to show some improvement as compared to the DEPAC survey performed at the accession to EU (2004). Nevertheless, the current Registry also indicates that most patients still do not meet the criteria of diabetes control defined by the local and international guidelines. (Diabet. Klin. 2012; 1, 1: 3–11

Cranial irradiation in childhood acute lymphoblastic leukemia Is related to subclinical left ventricular dysfunction and reduced large artery compliance in cancer survivors

Long-term survivors of acute lymphoblastic leukemia (ALL), the most common childhood malignancy, are at remarkably increased risk of heart failure (HF) in middle age, most likely due anthracycline cardiotoxicity. The role of cranial radiation therapy (CRT) in the development of left ventricular (LV) dysfunction, a predecessor of overt HF, remains unclear. Our aim was to compare LV function and systemic arterial properties according to past CRT in young adult survivors of anthracycline-treated ALL.We studied young adult survivors of childhood ALL at a median of 16 years from diagnosis treated with anthracycline-based chemotherapy, with (n = 12) or without (n = 30) CRT. In addition to fractional shortening (FS) and ejection fraction (EF), LV function was quantified by tissue Doppler imaging of the mitral annulus. Aortic strain/distensibility and arterial compliance were derived from echocardiography and simultaneously recorded pulse pressure. Despite similar FS and EF, peak mitral annular systolic velocity (median (interquartile range): 9.0 (7.5–10.0) vs. 10.0 (8.8–11.5) cm/s, p = 0.05), and early diastolic velocity (13.8 (13.0–14.8) vs. 15.5 (14.0–17.3), p = 0.01) were decreased after chemotherapy combined with CRT compared to chemotherapy without CRT. Systemic arterial compliance was lower in post-CRT subjects (1.0 (0.8–1.2 vs. 1.4 (1.1–1.7) mL/mmHg, p = 0.002). Aortic strain and distensibility were similar regardless of prior CRT. In conclusion, lower arterial compliance and subclinical LV dysfunction may be possible late consequences of past CRT in adult survivors of childhood ALL. Whether arterial stiffening is associated with future HF development in CRT-exposed ALL survivors remains to be investigated

Influence of rs1080985 single nucleotide polymorphism of the CYP2D6 gene on response to treatment with donepezil in patients with Alzheimer's disease

BACKGROUND: Recent data indicate that the rs1080985 single nucleotide polymorphism of the cytochrome P450 (CYP) 2D6 gene may affect the response to treatment with donepezil in patients with Alzheimer’s disease. There is also evidence that the common apolipoprotein E (APOE) polymorphism may affect the response to treatment with donepezil in Alzheimer’s disease. We investigated the association between response to donepezil and the rs1080985 single nucleotide polymorphism, the minor allele (G) of which was previously reported to be associated with a poor response to this drug in patients with Alzheimer’s disease. The common APOE polymorphism was also assessed for its relevance to the outcome of this treatment. METHODS: Analysis of CYP2D6 and APOE polymorphisms was undertaken in 88 naive Caucasian patients with Alzheimer’s disease. All patients received treatment with donepezil for at least 10 months, and the response to treatment was then assessed according to the National Institute for Health and Clinical Excellence criteria. RESULTS: No significant differences were observed in distribution of the CYP2D6 rs1080985 single nucleotide polymorphism or common APOE polymorphism between responders (68.2%) and nonresponders (31.8%) to treatment with donepezil. CONCLUSION: Our results suggest that neither the CYP2D6 nor the APOE polymorphism influences the response to treatment with donepezil in a Polish population with Alzheimer’s disease