The Hippo signaling pathway and its two downstream effectors, the YAP and TAZ transcriptional coactivators, are drivers of tumor growth in experimental models. Studying mouse models, we show that YAP and TAZ can also exert a tumor-suppressive function. We found that normal hepatocytes surrounding liver tumors displayed activation of YAP and TAZ and that deletion of Yap and Taz in these peritumoral hepatocytes accelerated tumor growth. Conversely, experimental hyperactivation of YAP in peritumoral hepatocytes triggered regression of primary liver tumors and melanoma-derived liver metastases. Furthermore, whereas tumor cells growing in wild-type livers required YAP and TAZ for their survival, those surrounded by Yap- and Taz-deficient hepatocytes were not dependent on YAP and TAZ. Tumor cell survival thus depends on the relative activity of YAP and TAZ in tumor cells and their surrounding tissue, suggesting that YAP and TAZ act through a mechanism of cell competition to eliminate tumor cells.

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The Hippo signaling pathway is widely considered a master regulator of organ growth because of the prominent overgrowth phenotypes caused by experimental manipulation of its activity. Contrary to this model, we show here that removing Hippo transcriptional output did not impair the ability of the mouse liver and Drosophila eyes to grow to their normal size. Moreover, the transcriptional activity of the Hippo pathway effectors Yap/Taz/Yki did not correlate with cell proliferation, and hyperactivation of these effectors induced gene expression programs that did not recapitulate normal development. Concordantly, a functional screen in Drosophila identified several Hippo pathway target genes that were required for ectopic overgrowth but not normal growth. Thus, Hippo signaling does not instruct normal growth, and the Hippo-induced overgrowth phenotypes are caused by the activation of abnormal genetic programs.

The Hippo tumor-suppressor pathway regulates organ growth, cell proliferation, and stem cell biology. Defects in Hippo signaling and hyperactivation of its downstream effectors—Yorkie (Yki) in Drosophila and YAP/TAZ in mammals—result in progenitor cell expansion and overgrowth of multiple organs and contribute to cancer development. Deciphering the mechanisms that regulate the activity of the Hippo pathway is key to understanding its function and for therapeutic targeting. However, although the Hippo kinase cascade and several other upstream inputs have been identified, the mechanisms that regulate Yki/YAP/TAZ activity are still incompletely understood. To identify new regulators of Yki activity, we screened in Drosophila for suppressors of tissue overgrowth and Yki activation caused by overexpression of atypical protein kinase C (aPKC), a member of the apical cell polarity complex. In this screen, we identified mutations in the heterogeneous nuclear ribonucleoprotein Hrb27C that strongly suppressed the tissue defects induced by ectopic expression of aPKC. Hrb27C was required for aPKC-induced tissue growth and Yki target gene expression but did not affect general gene expression. Genetic and biochemical experiments showed that Hrb27C affects Yki phosphorylation. Other RNA-binding proteins known to interact with Hrb27C for mRNA transport in oocytes were also required for normal Yki activity, although they suppressed Yki output. Based on the known functions of Hrb27C, we conclude that Hrb27C-mediated control of mRNA splicing, localization, or translation is essential for coordinated activity of the Hippo pathway.

Objective: Most current algorithms for detecting Atrial Fibrillation (AF) rely on Heart Rate Variability (HRV), and only a few studies analyse the variability of Photopletysmography (PPG) waveform. This study aimed to compare morphological features of the PPG curve in patients with AF to those presenting a normal sinus rhythm (NSR) and evaluate their usefulness in AF detection.&#xD;Approach: 10-minute PPG signals were obtained from patients with persistent/paroxysmal AF and NSR. Nine morphological parameters (1/ΔT, Pulse Width [PW], Augmentation Index [AI], b/a, e/a, [b-e]/a, Crest Time [CT], Inflection Point Area [IPA], Area and five HRV parameters (Heart rate [HR], Shannon entropy [ShE], root mean square of the successive differences [RMSSD], number of pairs of consecutive systolic peaks [R-R] that differ by more than 50 ms [NN50], standard deviation of the R-R intervals [SDNN]) were calculated.&#xD;Main Results: Eighty subjects, including 33 with AF and 47 with NSR were recruited. In univariate analysis five morphological features (1/ΔT, p<0.001; b/a, p<0.001; [b-e]/a, p<0.001; CT, p=0.011 and Area, p<0.001) and all HRV parameters (p=0.01 for HR and p<0.001 for others) were significantly different between the study groups. In the stepwise multivariate model (Area under the curve [AUC] = 0.988 [0.974-1.000]), three morphological parameters (PW, p<0.001; e/a, p=0.011; (b-e)/a, p<0.001) and three of HRV parameters (ShE, p=0.01; NN50, p<0.001, HR, p = 0.01) were significant. &#xD;Significance: There are significant differences between AF and NSR, PPG waveform, which are useful in AF detection algorithm. Moreover adding those features to HRV-based algorithms may improve their specificity and sensitivity.&#xD;

Cardiovascular diseases (CVDs) are major concerns in the healthcare system. An individual diagnostic approach and personalized therapy are key areas of an effective therapeutic process. The major aims of this study were: (1) to assess leading patient problems related to symptoms, diagnosis, and treatment of CVDs, (2) to examine patients’ opinions about the healthcare system in Poland, and (3) to provide a proposal of practical solutions. The 27-point author’s questionnaire was distributed in the Cardiology Department of the Tertiary Care Centre between 2nd September–13th November 2021. A total of 132 patients were recruited, and 82 (62.12%; nmale = 37, 45.12%; nfemale = 45, 54.88%) was finally included. The most common CVDs were arrhythmias and hypertension (both n = 43, 52.44%). 23 (28.05%) patients had an online appointment. Of the patients, 66 (80.49%) positively assessed and obtained treatment, while 11 (13.41%) patients declared they received a missed therapy. The participants identified: (1) waiting time (n = 31; 37.80%), (2) diagnostic process (n = 18; 21.95%), and (3) high price with limited availability of drugs (n = 12; 14.63%) as the areas that needed the strongest improvement. Younger patients more often negatively assessed doctor visits (30–40 yr.; p = 0.02) and hospital interventions (40–50 yr.; p = 0.008). Older patients (50–60 years old) less often negatively assessed the therapeutic process (p = 0.01). The knowledge of the factors determining patient adherence to treatment and satisfaction by Medical Professionals is crucial in providing effective treatment. Areas that require the strongest improvement are: (1) waiting time for an appointment and diagnosis, (2) limited availability and price of drugs, and (3) prolonged, complicated diagnostic process. Providing practical solutions is a crucial aspect of improving CVDs therapy.

Presented studies covered determination of minor pressure losses and values of minor loss coefficients for two selected installation valves: water control globe valve and angle valve, both DN 15. The tested valves were installed on three pipes, including PP 20x3.4 mm, PEX-Al-PEX 16x2.0 mm and Cu 15x1.0 mm. In order to reflect the real operating conditions of the angle valve, the elastic PVC pipe was used. Our researches were performed on the laboratory installation, for the variable flow rate. The obtained results of laboratory studies showed the clear dependence between minor pressure loss and minor loss coefficients of studied valves, and water flow rate (Reynolds number), degree of valves’ closure and, in some cases, manner of valves installation and material of pipes. The greatest values of minor pressure loss coefficients, of mean values relevantly statistically grater, were determined for the tested valves installed on the PEX-Al-PEX pipeline.

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