Prognostic significance of age in patients with acute ischaemic stroke treated with intravenous thrombolysis

Aim of the study. To assess the influence of age on long-term functional outcome in patients with acute ischaemic stroke (AIS) treated with intravenous thrombolysis (IVT).Material and methods. We performed retrospective analysis of 362 AIS patients treated with IVT or IVT and subsequent mechanical thrombectomy in the University Hospital in Krakow, Poland. Patients were categorised into four subgroups by age: (I) below the age of 60, (II) 60 to 69, (III) 70 to 79, and (IV) 80 or more. The outcomes were assessed with modified Rankin scale (mRS) 90 days after stroke onset, and defined as favourable (mRS 0–2), poor (mRS 3–5), or death (mRS = 6).Results. Patients aged 80 or more compared to those below 60 were more often women (72.64% vs. 26.76%, < 0.001), more often suffered from hypertension (94.34% vs. 60.56%, p < 0.001), ischaemic heart disease (27.36% vs. 8.45%, p = 0.002), atrial fibrillation (49.06% vs. 5.63%, p < 0.001), and premorbid disability (pre-stroke mRS ≥ 1: 17.92% vs. 1.41%, p < 0.001), less often were active smokers (0% vs. 27.14%, p < 0.001), more often had cardioembolic aetiology (50.00% vs. 16.90%, p < 0.001), and less often other stroke aetiology (1.89% vs. 15.49%, < 0.008), had shorter time from stroke onset to IVT (125 [93–180] vs. 140 [110–186] min, p < 0.008), less often underwent mechanical thrombectomy (18.87% vs. 46.48%, p < 0.001), had higher CRP levels (10.3 [3.2–39.8] vs. 4.3 [2.1–9.6] mg/L, p = 0.003), higher maximal systolic blood pressure within 24 hours after IVT (153 [140–170] vs. 138 [120–145] mmHg, p < 0.001), and higher creatinine concentration (88 [68–108] vs. 77 [67–87] μmol/l, p = 0.004), less often had a favourable outcome (48.04% vs. 85.51%, odds ratio [OR] 0.16, 95%CI: 0.07–0.34, p < 0.001), and had a greater risk of death (26.47% vs. 5.80%, OR 5.85, 95%CI: 1.95–17.59, p < 0.001) within three months of stroke onset. Multivariable logistic regression analysis showed that the independent predictors of worse outcome in patients aged 80 or more were NIHSS score after IVT (OR 0.64, 95%CI: 0.53–0.78, p < 0.001), pre-stroke mRS score ≥ 1 (OR 0.10, 95%CI: 0.02–0.61, p = 0.012), and CRP levels (OR 0.96, 95%CI: 0.93–0.99, p = 0.007).Conclusions. AIS patients treated with reperfusion therapy and aged 80 or more have around a six times higher risk of an unfavourable outcome or death within three months of stroke onset compared to those aged below 60. Higher NIHSS score after IVT, any signs of disability before stroke as measured with mRS, and higher CRP levels are independent risk factors for worse prognosis in the elderly

MET receptor is a potential therapeutic target in high grade cervical cancer

Cervical cancer is one of the leading causes of death among women suffering from tumors. Current treatment options are insufficient. Here, we investigated the MET receptor as a potential molecular target in advanced cervical cancer. Downregulation of MET receptor expression via RNA interference in different cervical carcinoma cell lines dramatically decreased tumor growth and forced tumor differentiation in vivo. MET receptor silencing also led to a dramatic decrease in cell size and a decrease in proliferation rate under normal and stress conditions. MET receptor downregulation also resulted in decreased cyclin D1 and c-myc levels but did not increase apoptosis. Subsequent experiments showed that downregulation of the MET receptor decreased the expression of a key regulator of the epithelial-to-mesenchymal transition, SLUG. and increased the expression of E-cadherin, a hallmark of the epithelial phenotype. Moreover, MET downregulation impairs expression and signaling of CXCR4 receptor, responsible for invasive phenotype. Taken together, our results strongly suggest that the MET receptor influences the oncogenic properties of cervical carcinoma cells in vitro and in vivo. These findings highlight a unique role of the MET receptor in cervical carcinoma cells and indicate the MET receptor as a potential therapeutic target for advanced cervical carcinoma

Inhibition of rhabdomyosarcoma's metastatic behavior through downregulation of MET receptor signaling.

Rhabdomyosarcoma (RMS) is a soft tissue sarcoma usually diagnosed in children. In advanced and metastatic stages the prognosis is often poor. RMS cell lines were used for evaluation of the role of MET receptor inhibition on chemotaxis and invasion. In vivo studies were performed using NOD-SCID xenograft model. This study shows that blocking of MET expression has strong influence on metastatic behavior of RMS. MET negative cells possess a reduced potential to migrate and to invade. Downregulation of MET suppressed the ability of RMS cells to populate bone marrow. Inhibition of MET negative tumor cells engraftment into bone marrow was observed. MET negative tumors were also two to four times smaller than their wild type counterparts. Since MET receptor plays a very important role in facilitating metastasis of RMS cells, blocking of HGF-MET axis might be considered as a therapeutic option for RMS patients, at more advanced and metastatic stages

Multifunctional protein APPL2 contributes to survival of human glioma cells

Some endocytic proteins have recently been shown to play a role in tumorigenesis. In this study, we demonstrate that APPL2, an adapter protein with known endocytic functions, is upregulated in 40% cases of glioblastoma multiforme, the most common and aggressive cancer of the central nervous system. The silencing of APPL2 expression by small interfering RNAs (siRNAs) in glioma cells markedly reduces cell survival under conditions of low growth factor availability and enhances apoptosis (measured by executor caspase activity). Long‐term depletion of APPL2 by short hairpin RNAs (shRNAs), under regular growth factor availability, suppresses the cell transformation abilities, assessed by inhibited colony formation in soft agar and by reduced xenograft tumor growth in vivo. At the molecular level, the negative effect of APPL2 knockdown on cell survival is not due to the alterations in AKT or GSK3β activities which were reported to be modulated by APPL proteins. Instead, we attribute the reduced cell survival upon APPL2 depletion to the changes in gene expression, in particular to the upregulation of apoptosis‐related genes, such as UNC5B (a proapoptotic dependence receptor) and HRK (harakiri, an activator of apoptosis, which antagonizes anti‐apoptotic function of Bcl2). In support of this notion, the loss of glioma cell survival upon APPL2 knockdown can be rescued either by an excess of netrin‐1, the prosurvival ligand of UNC5B or by simultaneous silencing of HRK. Consistently, APPL2 overexpression reduces expression of HRK and caspase activation in cells treated with apoptosis inducers, resulting in the enhancement of cell viability. This prosurvival activity of APPL2 is independent of its endosomal localization. Cumulatively, our data indicate that a high level of APPL2 protein might enhance glioblastoma growth by maintaining low expression level of genes responsible for cell death induction

A proposed integrated approach for the preclinical evaluation of phage therapy in Pseudomonas infections

Bacteriophage therapy is currently resurging as a potential complement/alternative to antibiotic treatment. However, preclinical evaluation lacks streamlined approaches. We here focus on preclinical approaches which have been implemented to assess bacteriophage efficacy against Pseudomonas biofilms and infections. Laser interferometry and profilometry were applied to measure biofilm matrix permeability and surface geometry changes, respectively. These biophysical approaches were combined with an advanced Airway Surface Liquid infection model, which mimics in vitro the normal and CF lung environments, and an in vivo Galleria larvae model. These assays have been implemented to analyze KTN4 (279,593 bp dsDNA genome), a type-IV pili dependent, giant phage resembling phiKZ. Upon contact, KTN4 immediately disrupts the P. aeruginosa PAO1 biofilm and reduces pyocyanin and siderophore production. The gentamicin exclusion assay on NuLi-1 and CuFi-1 cell lines revealed the decrease of extracellular bacterial load between 4 and 7 logs and successfully prevents wild-type Pseudomonas internalization into CF epithelial cells. These properties and the significant rescue of Galleria larvae indicate that giant KTN4 phage is a suitable candidate for in vivo phage therapy evaluation for lung infection applications

Course of fatigue among patients previously hospitalised due to COVID-19

Introduction. Discrepancies exist regarding the clinical course and prognostic factors for post-COVID fatigue. Therefore, our aim was to assess the timely course of fatigue and its possible predictors in patients previously hospitalised due to SARS-CoV-2 infection. Material and methods. Patients and employees of the University Hospital in Krakow were assessed with the use of a validated neuropsychological questionnaire. Included were participants aged 18 or more, previously hospitalised due to COVID-19, who completed questionnaires only once > 3 months after the onset of infection. Individuals were retrospectively asked about the presence of eight symptoms of chronic fatigue syndrome at four timepoints: before COVID-19, within 0–4 weeks, 4–12 weeks, and > 12 weeks post-infection. Results. We enrolled 204 patients [40.2% women, median age 58 (46–66) years] evaluated after a median of 187 (156–220) days from the first positive nasal swab test for SARS-CoV-2. The most common comorbidities were hypertension (44.61%), obesity (36.27%), smoking (28.43%), and hypercholesterolemia (21.08%); none of the patients required mechanical ventilation during hospitalisation. Before COVID-19, 43.62% of patients reported at least one symptom of chronic fatigue. Within 4, 4–12, and > 12 weeks after COVID-19, the prevalence of chronic fatigue was 76.96%, 75.49%, and 66.17%, respectively (all p < 0.001). The frequency of chronic fatigue symptoms decreased within > 12 weeks following the onset of infection but did not return to baseline values, except for self-reported lymph node enlargement. In a multivariable linear regression model, the number of fatigue symptoms was predicted by female sex [β 0.25 (0.12; 0.39), p < 0.001 and 0.26 (0.13; 0.39), p < 0.001 for weeks 0–12 and > 12, respectively], and age [for < 4 weeks, β –0.12 (–0.28; –0.01), p = 0.029]. Conclusions. Most patients previously hospitalised due to COVID-19 suffer from fatigue > 12 weeks after infection onset. The presence of fatigue is predicted by female sex and – only for the acute phase — age

Sex-related patient-reported brain fog symptoms in non-hospitalised COVID-19 patients

Introduction. Previous studies on the prognostic role of sex in post-COVID-associated brain fog have yielded divergent results. Moreover, limited evidence exists regarding the evolution of brain fog symptoms over time, especially in ambulatory patients and separately for women and men. Therefore, the aim of the current study was to assess brain fog symptoms in nonhospitalised patients with COVID-19, according to their sex. Material and methods. We created a neuropsychological questionnaire including eight questions on the presence of brain fog symptoms in the following four time periods: before COVID-19, and 0–4, 4–12, and > 12 weeks post-infection. The validity and reliability of the questionnaire were assessed. In this cross-sectional study, questionnaires were filled out anonymously and retrospectively once only by patients or through a survey link posted online. Included were patients ≥ 18 years, with > 3 months since the SARS-CoV-2 infection onset confirmed by RT-PCR from a nasopharyngeal swab. Results. The study included 303 patients (79.53% women, 47.52% medical personnel). Median time between COVID-19 onset and questionnaire completion was 208 (IQR 161–248) days. Women, compared to men, reported a higher prevalence of problems with writing, reading, and counting (< 4 weeks, OR 3.05, 95% CI: 1.38–6.72; 4–12 weeks, OR 2.51, 95% CI: 1.02–6.14; > 12 weeks, OR 3.74, 95% CI: 1.12–12.56) and thoughts communication (< 4 weeks, OR 2.53, 95% CI: 1.41–4.54; 4–12 weeks, OR 3.74, 95% CI: 1.93–7.24; > 12 weeks, OR 2.00, 95% CI: 1.01–3.99). The difference between the two sexes in answering questions in an understandable/unambiguous manner was statistically significant between four and 12 weeks after infection (OR 2.63, 95% CI: 1.36–5.10), while a sex difference in recalling new information was found below 12 weeks (OR 2.54, 95% CI: 1.44–4.48 and OR 2.43, 95% CI: 1.37–4.31 for < 4 and 4–12 weeks, respectively). No sex differences in reporting problems with multitasking, remembering information from the past, determining the current date, or field orientation were noted. Conclusions. Non-hospitalised women and men retrospectively report a different course of COVID-19-associated brain fog

Usefulness of assessment of fractional flow reserve and coronary flow velocity reserve in determination of the significance of borderline stenoses in the anterior descending artery in patients with multivessel disease

Introduction. Assessment of the significance of borderline stenosis in the area of the anterior descending artery in patients with multivessel coronary artery disease is a challenge. Currently, ractional flow reserve (FFR) and coronary flow reverse (CFR) methods are available. Aim. The aim of the study was to compare the usefulness of fractional flow reverse (FFR) and CFR methods in the assessment of left anterior descending artery (LAD) borderline stenosis in patients with multivessel coronary disease (MVD) and isolated LAD stenosis. Material and methods. We examined 100 patients with suspected ischemic heart disease. The examination revealed MVD disease with borderline stenosis of the LAD in 23 patients. Significant changes were confirmed with FFR and CFR. Results. Abnormal FFR (82% vs. 22%; p &lt; 0.001) and abnormal CFR (32% vs. 12%; p = 0.029) were significantly more commonly observed in patients with MVD. The mean FFR (0.76 vs. 0.84; p &lt; 0.001), the mean CFR (2.13 vs. 2.31; p = 0.075). Positive CFR and FFR values were found in 7 MVD patients and in 3 patients with single-vessel lesions (32% vs. 4%; p &lt; 0.001). Negative CFR and positive FFR values were noted in 11 patients with MVD and 14 with lesions only in LAD (50% vs. 18%; p &lt; 0.001). Positive CFR and negative FFR 0 vs 6 patients (0% vs. 8%; p &lt; 0.001). Negative CFR and negative FFR were obtained in 4 patients from the MVD group and in 55 patients from the group of borderline stenosis only in LAD (18% vs. 71%; p &lt; 0.001). MACE was observed significantly more frequently in the MVD group than in the group of patients with borderline lesions only in LAD (47% vs. 6%; p = 0.004). Conclusions. Positive FFR and CFR results correlate with more frequent MACE episodes.Introduction. Assessment of the significance of borderline stenosis in the area of the anterior descending artery in patients with multivessel coronary artery disease is a challenge. Currently, ractional flow reserve (FFR) and coronary flow reverse (CFR) methods are available. Aim. The aim of the study was to compare the usefulness of fractional flow reverse (FFR) and CFR methods in the assessment of left anterior descending artery (LAD) borderline stenosis in patients with multivessel coronary disease (MVD) and isolated LAD stenosis. Material and methods. We examined 100 patients with suspected ischemic heart disease. The examination revealed MVD disease with borderline stenosis of the LAD in 23 patients. Significant changes were confirmed with FFR and CFR. Results. Abnormal FFR (82% vs. 22%; p < 0.001) and abnormal CFR (32% vs. 12%; p = 0.029) were significantly more commonly observed in patients with MVD. The mean FFR (0.76 vs. 0.84; p < 0.001), the mean CFR (2.13 vs. 2.31; p = 0.075). Positive CFR and FFR values were found in 7 MVD patients and in 3 patients with single-vessel lesions (32% vs. 4%; p < 0.001). Negative CFR and positive FFR values were noted in 11 patients with MVD and 14 with lesions only in LAD (50% vs. 18%; p < 0.001). Positive CFR and negative FFR 0 vs 6 patients (0% vs. 8%; p < 0.001). Negative CFR and negative FFR were obtained in 4 patients from the MVD group and in 55 patients from the group of borderline stenosis only in LAD (18% vs. 71%; p < 0.001). MACE was observed significantly more frequently in the MVD group than in the group of patients with borderline lesions only in LAD (47% vs. 6%; p = 0.004). Conclusions. Positive FFR and CFR results correlate with more frequent MACE episodes