A Novel Irreversible TEAD Inhibitor, SWTX-143, Blocks Hippo Pathway Transcriptional Output and Causes Tumor Regression in Preclinical Mesothelioma Models.

The Hippo pathway and its downstream effectors, the YAP and TAZ transcriptional coactivators, are deregulated in multiple different types of human cancer and are required for cancer cell phenotypes in vitro and in vivo, while largely dispensable for tissue homeostasis in adult mice. YAP/TAZ and their main partner transcription factors, the TEAD1-4 factors, are therefore promising anticancer targets. Because of frequent YAP/TAZ hyperactivation caused by mutations in the Hippo pathway components NF2 and LATS2, mesothelioma is one of the prime cancer types predicted to be responsive to YAP/TAZ-TEAD inhibitor treatment. Mesothelioma is a devastating disease for which currently no effective treatment options exist. Here, we describe a novel covalent YAP/TAZ-TEAD inhibitor, SWTX-143, that binds to the palmitoylation pocket of all four TEAD isoforms. SWTX-143 caused irreversible and specific inhibition of the transcriptional activity of YAP/TAZ-TEAD in Hippo-mutant tumor cell lines. More importantly, YAP/TAZ-TEAD inhibitor treatment caused strong mesothelioma regression in subcutaneous xenograft models with human cells and in an orthotopic mesothelioma mouse model. Finally, SWTX-143 also selectively impaired the growth of NF2-mutant kidney cancer cell lines, suggesting that the sensitivity of mesothelioma models to these YAP/TAZ-TEAD inhibitors can be extended to other tumor types with aberrations in Hippo signaling. In brief, we describe a novel and specific YAP/TAZ-TEAD inhibitor that has potential to treat multiple Hippo-mutant solid tumor types.

Photoplethysmography wave morphology in patients with atrial fibrillation.

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.Approach.10 min 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 theR-Rintervals [SDNN]) were calculated.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 andp< 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.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.

The Path of a Cardiac Patient-From the First Symptoms to Diagnosis to Treatment: Experiences from the Tertiary Care Center in Poland.

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.

Regeneration Defects in Yap and Taz Mutant Mouse Livers Are Caused by Bile Duct Disruption and Cholestasis.

BACKGROUND AND AIMS: The Hippo pathway and its downstream effectors YAP and TAZ (YAP/TAZ) are heralded as important regulators of organ growth and regeneration. However, different studies provided contradictory conclusions about their role during regeneration of different organs, ranging from promoting proliferation to inhibiting it. Here we resolve the function of YAP/TAZ during regeneration of the liver, where Hippo's role in growth control has been studied most intensely. METHODS: We evaluated liver regeneration after carbon tetrachloride toxic liver injury in mice with conditional deletion of Yap/Taz in hepatocytes and/or biliary epithelial cells, and measured the behavior of different cell types during regeneration by histology, RNA sequencing, and flow cytometry. RESULTS: We found that YAP/TAZ were activated in hepatocytes in response to carbon tetrachloride toxic injury. However, their targeted deletion in adult hepatocytes did not noticeably impair liver regeneration. In contrast, Yap/Taz deletion in adult bile ducts caused severe defects and delay in liver regeneration. Mechanistically, we showed that Yap/Taz mutant bile ducts degenerated, causing cholestasis, which stalled the recruitment of phagocytic macrophages and the removal of cellular corpses from injury sites. Elevated bile acids activated pregnane X receptor, which was sufficient to recapitulate the phenotype observed in mutant mice. CONCLUSIONS: Our data show that YAP/TAZ are practically dispensable in hepatocytes for liver development and regeneration. Rather, YAP/TAZ play an indirect role in liver regeneration by preserving bile duct integrity and securing immune cell recruitment and function.

Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice.

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.

Modulation of the Hippo pathway and organ growth by RNA processing proteins.

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.