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[This corrects the article DOI: 10.1371/journal.pone.0185475.].

The great amount of gene expression data has brought a big challenge for the discovery of Gene Regulatory Network (GRN). For network reconstruction and the investigation of regulatory relations, it is desirable to ensure directness of links between genes on a map, infer their directionality and explore candidate biological functions from high-throughput transcriptomic data. To address these problems, we introduce a Boolean Function Network (BFN) model based on techniques of hidden Markov model (HMM), likelihood ratio test and Boolean logic functions. BFN consists of two consecutive tests to establish links between pairs of genes and check their directness. We evaluate the performance of BFN through the application to S. cerevisiae time course data. BFN produces regulatory relations which show consistency with succession of cell cycle phases. Furthermore, it also improves sensitivity and specificity when compared with alternative methods of genetic network reverse engineering. Moreover, we demonstrate that BFN can provide proper resolution for GO enrichment of gene sets. Finally, the Boolean functions discovered by BFN can provide useful insights for the identification of control mechanisms of regulatory processes, which is the special advantage of the proposed approach. In combination with low computational complexity, BFN can serve as an efficient screening tool to reconstruct genes relations on the whole genome level. In addition, the BFN approach is also feasible to a wide range of time course datasets.

Abstract Background Patients with chronic thromboembolic pulmonary hypertension (CTEPH) in countries with limited resources have, to date, been poorly represented in registries. Objective This work assesses the epidemiology, diagnosis, hemodynamic and functional parameters, and treatment of CTEPH in Russia, Kazakhstan, Turkey, Lebanon, and Saudi Arabia. Methods A prospective, cohort, phase IV, observational registry with 3-year follow-up (n = 212) in patients aged ≥ 18 years diagnosed with CTEPH was created. Clinical, hemodynamic, and functional parameters were obtained at an initial visit, follow-up visits, and a final visit at the end of 3 years’ observation or end of follow-up. Data were recorded on electronic case report forms. Parameters evaluated included 6-minute walking distance (6MWD), use of pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), pulmonary hypertension (PH)-targeted therapy, and survival. All statistical analyses were exploratory and descriptive, and were performed in the overall population. Results The most common symptoms were typical of those expected for CTEPH. Almost 90% of patients underwent right heart catheterization at diagnosis or initial study visit. In total, 66 patients (31%) underwent PEA before the initial visit; 95 patients (45%) were considered operable, 115 (54%) were inoperable, and two (1%) had no operability data. Only 26 patients (12%) had been assessed for BPA at their initial visit. PH-targeted therapy was documented at diagnosis for 77 patients (36%), most commonly a phosphodiesterase type 5 inhibitor (23%). Use of PH-targeted therapy increased to 142 patients (67%) at the initial visit, remaining similar after 3 years. Use of riociguat increased from 6% of patients at diagnosis to 38% at 3 years. Between baseline and end of observation, results for patients with paired data showed an increase in 6MWD. Survival at the end of observation was 88%. Conclusions These data highlight the current diagnosis and management of CTEPH in the participating countries. They show that early CTEPH diagnosis remains challenging, and use of off-label PH-targeted therapy is common. ClinicalTrials.gov: NCT02637050; registered December 2015. Graphical Abstract

Introduction: The predictive value of the risk stratification scales in elderly patients with IPAH might differ from that in younger patients. It is unknown whether young and older IPAH patients have the same survival dependence on PAH-specific therapy numbers. The aim of this study was to evaluate the prognostic relevance of risk stratification scales and PAH medication numbers in elderly IPAH patients in comparison with young IPAH patients. Materials and methods: A total of 119 patients from a prospective single-center PAH registry were divided into group I < 60 years old (n = 89) and group II ≥ 60 years old (n = 30). ESC/ERS, REVEAL, and REVEAL 2.0 risk stratification scores were assessed at baseline, as well as H2FpEF score and survival at follow-up. Results: During a mean follow-up period of 2.9 years (1.63; 6.0), 42 (35.3%) patients died; at 1, 2, 3, 5, 7, and 10 years, survival was 95%, 88.6%, 78.5%, 61.7%, 48.5%, and 33.7%, respectively. No survival differences were observed between the two groups, despite the use of monotherapy in the elderly patients. The best predictive REVEAL value in elderly patients (IPAH patients ≥ 60 years) was AUC 0.73 (0.56–0.91), p = 0.03; and in patients with LHD comorbidities in the entire cohort, it was AUC 0.73 (0.59–0.87), p < 0.009. Factors independently associated with death in the entire cohort were CKD (p = 0.01, HR 0.2), the right-to-left ventricle dimension ratio (p = 0.0047, HR 5.97), and NT-proBNP > 1400 pg/mL (p = 0.008, HR 3.18). Conclusion: Risk stratification in the elderly IPAH patients requires a fundamentally different approach than that of younger patients, taking into account the initial limitations in physical performance and comorbidities that interfere with current assessment scores. The REVEAL score reliably stratifies patients at any age and LHD comorbidities. The initial monotherapy seems to be reasonable in patients over 60 years. Selection tools for initial combination PAH therapy in older IPAH patients with comorbidities need to be validated in prospective observational studies.

IntroductionPatients with glioma (GM) are at a high risk of venous thromboembolism (VTE). The role of microvesiculation in the cancer-associated thrombosis mechanisms has been previously demonstrated. This study aimed to evaluate the relative abundance of extracellular vesicles (EVs) and thrombin generation (TG) in combination with standard laboratory tests in patients with newly diagnosed GM as potential prognostic markers in VTE.Materials and MethodsIn the present study, 11 patients with newly diagnosed GM and 10 healthy volunteers were analyzed. EVs were counted and their cellular origin was determined (CytoFlex B4-R2-V2, Beckman Coulter, United States), as well as thrombin generation test (TGT) (Diagnostica Stago SAS, France) was performed.ResultsIn patients with GM, the relative abundance of the CD41 + EVs (platelet-derived)—and CD105 + EVs (endothelial-derived) was significantly higher than in the control group (44.3 [40.5; 52.4] vs. 27.2 [22.9; 31.0]%, p = 0.002, and 5.4 [4.8; 7.8] vs. 1.9 [1.5; 2.8]%, p = 0.0003, respectively). The D-dimer level was higher in patients with GM compared with the control group (0.46 [0.38; 1.85] vs. 0.36 [0.27; 0.40] μg/ml FEU, p = 0.03, respectively). There was a trend toward an increase in the peak thrombin and velocity index (VI) in the GM group (p = 0.06). During the follow-up period, two patients (18%) developed thrombosis, had tumor sizes of more than 5 cm, thrombocytopenia, increased VI, and D-dimer.ConclusionAnalysis of platelet-derived EVs, platelet count, and TGT in combination with D-dimer assessment could improve the stratification of patients prone to VTE, which needs to be confirmed in a larger sample.

Immune checkpoint inhibitors are promising agents for anticancer therapy. But despite their high efficacy in the treatment of solid tumors, there is still a problem with immune-related adverse events, especially cardiovascular complications with a very high mortality rate. Myocarditis or ischemic heart disease progression is not the only possible cause of cardiovascular death in patients treated with checkpoint inhibitors. We report a case of a patient with mucinous carcinoma of the lung, with a previous history of hypertension and moderate left ventricular dysfunction. The patient was prescribed atezolizumab, but the first atezolizumab infusion resulted in the patient cardiovascular death. Postmortem histopathological evaluation of myocardium revealed several possible reasons for hemodynamic instability: tumor embolism of the coronary arteries, micrometastases of mucinous carcinoma in the myocardium, and myocarditis diagnosed by both Dallas and immunohistochemistry criteria. In addition, testing for expression of PD-L1 detected the high levels of membranous and cytoplasmic PD-L1 protein even in the myocardium area free from tumor cells. The present clinical case demonstrates a problem of cardiovascular death in patients treated with checkpoint inhibitors and actualizes the need for future research of potential risk factors for cardiovascular complications.