Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells.

BACKGROUND: Primary resistance to anti-EGFR therapies affects 40% of metastatic colorectal cancer patients harbouring wild-type RAS/RAF. YAP1 activation is associated with this resistance, prompting an investigation into AURKA's role in mediating YAP1 phosphorylation at Ser397, as observed in breast cancer. METHODS: We used transcriptomic analysis along with in vitro and in vivo models of RAS/RAF wild-type CRC to study YAP1 Ser397 phosphorylation as a potential biomarker for cetuximab resistance. We assessed cetuximab efficacy using CCK8 proliferation assays and cell cycle analysis. Additionally, we examined the effects of AURKA inhibition with alisertib and created a dominant-negative YAP1 Ser397 mutant to assess its impact on cancer stem cell features. RESULTS: The RAS/RAF wild-type CRC models exhibiting primary resistance to cetuximab prominently displayed elevated YAP1 phosphorylation at Ser397 primarily mediated by AURKA. AURKA-induced YAP1 phosphorylation was identified as a key trigger for cancer stem cell reprogramming. Consequently, we found that AURKA inhibition had the capacity to effectively restore cetuximab sensitivity and concurrently suppress the cancer stem cell phenotype. CONCLUSIONS: AURKA inhibition holds promise as a therapeutic approach to overcome cetuximab resistance in RAS/RAF wild-type colorectal cancer, offering a potential means to counter the development of cancer stem cell phenotypes associated with cetuximab resistance.

Triple vasodilator therapy in pulmonary arterial hypertension associated with congenital heart disease.

OBJECTIVE: This study assessed the long-term effects of triple therapy with prostanoids on patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD), as there is limited information on the safety and efficacy of this treatment approach. METHODS: A retrospective cohort study was conducted on patients with PAH-CHD who were actively followed up at our centre. All patients were already receiving dual combination therapy at maximum doses. Clinical characteristics, including functional class (FC), 6-minute walking test distance (6MWTD) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, were documented before initiating triple therapy and annually for a 2-year follow-up period. RESULTS: A total of 60 patients were included in the study, with a median age of 41 years and 68% being women. Of these, 32 had Eisenmenger syndrome, 9 had coincidental shunts, 18 had postoperative PAH and 1 had a significant left-to-right shunt. After 1 year of triple combination initiation, a significant improvement in 6MWTD was observed (406 vs 450; p=0.0027), which was maintained at the 2-year follow-up. FC improved in 79% of patients at 1 year and remained stable in 76% at 2 years. NT-proBNP levels decreased significantly by 2 years, with an average reduction of 199 ng/L. Side effects were experienced by 33.3% of patients but were mostly mild and manageable. Subgroup analysis showed greater benefits in patients without Eisenmenger syndrome and those with pre-tricuspid defects. CONCLUSIONS: Triple therapy with prostanoids is safe and effective for patients with PAH-CHD, improving FC, 6MWTD and NT-proBNP levels over 2 years. The treatment is particularly beneficial for patients with pre-tricuspid defects and non-Eisenmenger PAH-CHD.

Takotsubo Syndrome, Stressful Triggers, and Risk of Recurrence.

The risk of recurrence in takotsubo syndrome (TTS) appears to be low, although previous studies have shown conflicting results and factors associated with recurrences are unclear. The aim of this study is to evaluate the incidence and predictors of TTS recurrences. Adult patients included in the Spanish Multicenter REgistry of TAKOtsubo syndrome (RETAKO) between January 2003 and September 2019 were identified. Patients were categorized based on recurrences during follow-up and a multivariate logistic regression model was used to identify factors associated with recurrences. A total of 1097 patients (mean age 71.0±11.9 years, 87% females) were included, repeated TTS events were documented in 44 patients (4.0%), including 13 patients with prior TTS and 31 patients with recurrent TTS during a median follow-up of 279 days. Two patients (0.02%) had two episodes of recurrence. Compared to patients who had no recurrence of TTS, those with recurrent TTS more frequently had no identifiable stressful trigger in the index admission (20 [64.5%] vs 352 [33.0%], p <0.001). Primary TTS, defined as TTS without physical trigger, was also more common in the recurrence group (93.5% vs 68.3%, p <0.001). The only factor independently associated with recurrences was the absence of an identifiable trigger (odds ratio 3.7 [95% confidence interval 1.8-7.8], p=0.001). In conclusion, our data indicate that for patients presenting with TTS, the rate of early recurrent TTS is approximately 4% per year. Among TTS patients, those who have no identifiable trigger events appear to have a higher rate of recurrence.

Novel Molecular Mechanisms Involved in the Medical Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a severe condition with a high mortality rate despite advances in diagnostic and therapeutic strategies. In recent years, significant scientific progress has been made in the understanding of the underlying pathobiological mechanisms. Since current available treatments mainly target pulmonary vasodilation, but lack an effect on the pathological changes that develop in the pulmonary vasculature, there is need to develop novel therapeutic compounds aimed at antagonizing the pulmonary vascular remodeling. This review presents the main molecular mechanisms involved in the pathobiology of PAH, discusses the new molecular compounds currently being developed for the medical treatment of PAH and assesses their potential future role in the therapeutic algorithms of PAH.

Prognostic implications of atrial fibrillation in adults with Ebstein anomaly.

OBJECTIVE: Supraventricular arrhythmias are common in adults with Ebstein anomaly (EA). However, there are limited data about prognostic implications of atrial fibrillation (AF) in this population. Accordingly, our aim was to assess the clinical profile and burden of AF in adults with EA, and the relationship between AF and outcomes. METHODS AND RESULTS: Six hundred eighty-two consecutive adults with a median age of 36 (24-49) years from Mayo Clinic, Minnesota, USA, between 2003 and 2020 were included. Sustained episodes of AF, clinical, echocardiographic, rhythm and surgical data were collected. Prevalence of AF at baseline was 18% (126 patients); the first episode occurred at a mean age of 43±17 years. Patients with AF were older, were more likely men, and had hypertension, renal dysfunction, cardiac devices, and more advanced right-sided and left-sided remodelling. During a median follow-up of 156 (81-240) months, 62 patients (11%) developed incident AF. At the last encounter, prevalence of AF was 28% (188 patients); of those, 63 (34%) had recurrent AF. Hospitalisation for heart failure (HF) occurred in 51 patients (7%). AF (HR 2.32, 95% CI 1.18 to 4.47; p=0.01) was independently associated with hospitalisation for HF. All-cause death occurred in 53 patients (8%); it was more frequent in those with AF in the univariable analysis, although it did not remain significant in the multivariable analysis. CONCLUSIONS: AF in EA develops at relatively young ages with one-third of the cohort exhibiting a recurrent pattern. Patients with AF had a higher prevalence of comorbidities and worse right-sided and left-sided cardiac remodelling. AF was independently associated with HF hospitalisation.

Haemodynamic and prognostic associations of liver fibrosis scores in Fontan-associated liver disease.

OBJECTIVES: Fontan-associated liver disease (FALD) is universal post-Fontan palliation; however, its impact on survival remains controversial and current diagnostic tools have limitations. We aimed to assess the prognostic role of liver fibrosis scores (aminotransferase to platelet ratio [APRI] and fibrosis-4 [FIB-4]) and their association with haemodynamics and other markers of liver disease. METHODS: 159 adults (age ≥18 years) post-Fontan undergoing catheterisation at Mayo Clinic, Minnesota, between 1999 and 2017 were included. Invasive haemodynamics and FALD-related laboratory, imaging and pathology data were documented. RESULTS: Mean age was 31.5±9.3 years, while median age at Fontan procedure was 7.5 years (4-14). Median APRI score (n=159) was 0.49 (0.33-0.61) and median FIB-4 score (n=94) was 1.12 (0.71-1.65). Correlations between APRI and FIB-4 scores and Fontan pressures (r=0.30, p=0.0002; r=0.34, p=0.0008, respectively) and pulmonary arterial wedge pressure (r=0.25, p=0.002; r=0.30, p=0.005, respectively) were weak. Median average hepatic stiffness by magnetic resonance elastography was 4.9 kPa (4.3-6.0; n=26) and 24 (77.4%) showed stage 3 or 4 liver fibrosis on biopsy; these variables were not associated with APRI/FIB-4 scores. On multivariable analyses, APRI and FIB-4 scores were independently associated with overall mortality (HR 1.31 [1.07-1.55] per unit increase, p=0.003; HR 2.15 [1.31-3.54] per unit increase, p=0.003, respectively). CONCLUSIONS: APRI and FIB-4 scores were associated with long-term all-cause mortality in Fontan patients independent of other prognostic markers. Correlations between haemodynamic status and liver scores were weak; furthermore, most markers of liver fibrosis failed to correlate with non-invasive indices, underscoring the complexity of FALD.

Surgical Repair of Truncus Arteriosus: A Long-Term Hemodynamic Assessment.

Background: Unrepaired truncus arteriosus (TA) carries poor prognosis due to complications of unrestricted pulmonary flow, truncal valve insufficiency, and pulmonary vascular disease. Currently, the hemodynamic profile of adults late after TA repair is unknown. We reviewed the hemodynamics, prevalence, and pathophysiology of pulmonary hypertension (PH) in this population. Methods: Eighteen adult patients with repaired TA who underwent cardiac catheterization at Mayo Clinic, MN, between 1997 and 2021 were identified. PH was defined as either precapillary (mean pulmonary artery pressure [mPAP] ≥25 mm Hg, pulmonary artery wedge pressure [PAWP] ≤15 mm Hg, and pulmonary vascular resistance [PVR] >3 Wood units), isolated postcapillary (mPAP ≥25, PAWP >15, PVR ≤3), or combined (mPAP ≥25, PAWP >15, and PVR >3). Diastolic pressure and transpulmonary gradients were used as ancillary data for classification. Results: Mean age at catheterization was 34 ± 10 years. Mean right ventricular (RV) systolic pressure was 82 ± 22.6 mm Hg, mean right and left mPAPs 28.1 ± 16.2 and 27.9 ± 11.9 mm Hg, respectively. Seven patients (41.2%) had PAWP >15 mm Hg and, among those undergoing arterial catheterization, 7 (53.8%) had a left ventricular (LV) end-diastolic pressure >15 mm Hg. PH was diagnosed in 13 patients (72.2%): 6 (33.3%) precapillary, 4 (22.2%) isolated postcapillary, and 3 (16.7%) combined. PAWP >15 mm Hg was associated with male sex (P = .049),

Antiplatelet therapy at discharge and long-term prognosis in Takotsubo syndrome: Insights from the Spanish National Registry (RETAKO).

INTRODUCTION: Endothelial dysfunction and platelet activation have been highlighted as possible mediators in Takotsubo syndrome (TTS). Nevertheless, to date, evidence on the usefulness of antiplatelet therapy in TTS remains controversial. The aim of our study is to evaluate long-term prognosis in TTS patients treated with antiplatelet therapy (APT) at hospitalization discharge. MATERIAL AND METHODS: An ambispective cohort study from the Spanish National Takotsubo Registry database was performed (June 2002 to March 2017). Patients were divided into two groups: those who received APT at hospital discharge (APT cohort) and those who did not (non-APT cohort). Primary endpoint was all-cause death. Secondary endpoints included the composite of recurrence or readmission and a composite of death, recurrence or readmission. RESULTS: From a total of 741 patients, 728 patients were alive at discharge. Follow-up was performed in 544 patients, who were included in the final analysis: 321 patients (59.0%) in the APT cohort and 223 patients (41.0%) in the non-APT cohort. The APT cohort had a better clinical presentation and received more heart failure and acute coronary syndrome-like therapies (angiotensin converting enzyme inhibitors/angiotensin receptor blockers: 75.1% vs. 51.1%; p<0.001, betablockers: 71.3% vs. 50.7%; p<0.001, statins: 67.9% vs. 33.2%; p<0.001). After adjusting for confounder factors, APT at discharge was a protective factor for all-cause death (adjusted hazard ratio (HR) 0.315, 95% confidence interval (CI): 0.106-0.943; p=0.039) and the composite endpoint of all-cause death, recurrence or readmission (adjusted HR 0.318, 95% CI: 0.164-0.619; p=0.001) at month 25 of follow-up. CONCLUSION: Patients with TTS receiving APT at discharge presented better prognosis up to two-years of follow-up compared with their counterparts not receiving APT.

Differences Between Takotsubo and the Working Diagnosis of Myocardial Infarction With Nonobstructive Coronary Arteries.

Aim: Whether Takotsubo syndrome (TTS) should be classified within myocardial infarction with non-obstructive coronary arteries (MINOCAs) is still controversial. The aim of this work was to evaluate the main differences between TTS and non-TTS MINOCAs. Methods and Results: A cohort study based on two prospective registries: TTS from the RETAKO registry (N:1,015) and patients with non-TTS MINOCAs from contemporary records of acute myocardial infarction from five 5 national centers (N:1,080). Definitions and management recommended by the ESC were used. Survival analysis was based on the Cox regression analysis; propensity score matching (PS) was created to adjust prognostic variables. Takotsubo syndrome were more often women (85.9 vs. 51.9%; p < 0.001) and older (69.4 ± 12.5 vs. 64.5 ± 14.1 years; p < 0.001). Atrial fibrillation (AF) was more frequent in non-TTS MINOCAs (10.4 vs. 14.4%; p = 0.007). Psychiatric disorders were more prevalent in TTS (15.5 vs. 10.2%, p < 0.001). In-hospital mortality and complications were higher in TTS: 3.4 vs. 1.8%, (p = 0.015), and 25.8 vs. 11.5%, (p < 0.001). Global mortality before PS matching was 16.1% in non-TTS MINOCAs and 8.1% in TTS. Median follow-up was 32.4 months; after PS matching, TTS had fewer major adverse cardiovascular events (MACEs): hazard ratio (HR) 0.59; 95% CI 0.42-0.83. There were no differences in global mortality (HR 0.87; CI: 0.64-1.19), but TTS had lower cardiovascular mortality (HR 0.58; CI: 0.35-0.98). Conclusion: Compared to the rest of MINOCAs, TTS presents a different patient profile and a more aggressive acute phase. However, its long-term cardiovascular prognosis is better. These results support that TTS should be considered a separate entity with unique characteristics and prognosis.

Electrocardiographic Characteristics and Associated Outcomes in Patients with Takotsubo Syndrome. Insights from the RETAKO Registry.

Electrocardiographic disturbances in Takotsubo syndrome have been previously partially described but their consequences remain mostly unknown. Our aim was to describe the prevalence and prognostic significance of different electrocardiographic features in patients with Takotsubo syndrome. Our data come from the Spanish multicenter REgistry of TAKOtsubo syndrome (RETAKO). All patients with an available 12-lead surface electrocardiogram at admission and 48 hours post-admission were included. A total of 246 patients were studied, mean age was 71.3 ± 11.5 and 215 (87.4%) were women. ST-segment elevation was seen in 143 patients (59.1%) and was present in ≥2 wall leads in 97 (39.8%). Exclusive elevation in inferior leads was infrequent (5% - 2.0%). After 48 hours, 198 patients (88.0%) developed negative T waves in a median of 8 leads with a mean amplitude of 0.7 ± 0.5 mV and 137 (60.9%) had pathological Q waves. The mean corrected QT interval was 520 ± 72 ms. Corrected QT interval was independently associated with the primary endpoint of all-cause death and nonfatal cardiovascular events (P = 0.002) and all-cause death (P = 0.008). A higher heart rate at admission was an independent predictor of the primary endpoint (P = 0.001) and of acute pulmonary edema (P = 0.04). ST-segment elevation with reciprocal depression was an independent predictor of all-cause death (P = 0.04). Absence of ST-segment deviation was a protective factor (P = 0.005) for the primary endpoint. Tachyarrhythmias were independently associated with cardiogenic shock (P< 0.001). Takotsubo syndrome patients present with distinct electrocardiographic features. Prolonged corrected QT interval, tachyarrhythmias, heart rate at admission, and more extensive repolarization alterations are associated with poor outcomes.

Atrial Fibrillation in Congenital Heart Disease.

The increasing prevalence of AF in a growing population of adults with congenital heart disease (CHD) poses new challenges to clinicians involved in the management of these patients. Distinctive underlying anatomies, unique physiological aspects, a high diversity of corrective surgeries and associated comorbidities can complicate clinical decision-making. In this review, the authors provide an overview of the current knowledge on epidemiology and pathophysiology, with a special focus on the differences to the non-CHD population and the clinical impact of AF in adults with CHD. Acute and long-term management strategies are summarised, including the use of antiarrhythmic drugs, catheter or surgical ablation and prophylaxis of thromboembolism. Finally, gaps of knowledge and potential areas of future research are highlighted.

Design and Synthesis of Novel Epigenetic Inhibitors Targeting Histone Deacetylases, DNA Methyltransferase 1, and Lysine Methyltransferase G9a with In Vivo Efficacy in Multiple Myeloma.

Concomitant inhibition of key epigenetic pathways involved in silencing tumor suppressor genes has been recognized as a promising strategy for cancer therapy. Herein, we report a first-in-class series of quinoline-based analogues that simultaneously inhibit histone deacetylases (from a low nanomolar range) and DNA methyltransferase-1 (from a mid-nanomolar range, IC50 < 200 nM). Additionally, lysine methyltransferase G9a inhibitory activity is achieved (from a low nanomolar range) by introduction of a key lysine mimic group at the 7-position of the quinoline ring. The corresponding epigenetic functional cellular responses are observed: histone-3 acetylation, DNA hypomethylation, and decreased histone-3 methylation at lysine-9. These chemical probes, multitarget epigenetic inhibitors, were validated against the multiple myeloma cell line MM1.S, demonstrating promising in vitro activity of 12a (CM-444) with GI50 of 32 nM, an adequate therapeutic window (>1 log unit), and a suitable pharmacokinetic profile. In vivo, 12a achieved significant antitumor efficacy in a xenograft mouse model of human multiple myeloma.

Implicaciones clínicas y pronósticas en síndrome de Takotsubo y cáncer: percepciones del registro RETAKO / Takotsubo syndrome and cancer, clinical and prognostic implications, insights of RETAKO

ANTECEDENTES Y OBJETIVO: Se ha postulado una relación entre neoplasias y síndrome de Takotsubo (STB). Nuestro objetivo fue determinar su prevalencia en enfermos con STB, comparar el perfil clínico de STB con cáncer o no y estudiar su evolución a largo plazo. MATERIALES Y MÉTODOS: Analizamos la situación oncológica de pacientes incluidos en el REgistro nacional sobre síndrome de TAKOtsubo (RETAKO), ingresados entre 2002 y 2019, aportados por 38 hospitales de todo el país. Se admitió cualquier antecedente de malignidad/tumor que, aun benigno, recibiera quimioterapia, radioterapia o cirugía específica, actual o pasado. RESULTADOS: Se describió cualquier tipo de neoplasia en 129 (11,8%) casos, dentro de una cohorte de 1.097 pacientes con STB. Los oncológicos, con menor porcentaje de mujeres (79,1 vs. 88,3%; p = 0,003), mostraron una tendencia no significativa a mayor edad, hiperuricemia, apnea del sueño, con un menor FEVI al ingreso, y un perfil de factores de riesgo cardiovascular similar, pero más anemia crónica e inmunosupresión. La neoplasia más frecuente fue el cáncer de mama. Durante su estancia hospitalaria, los oncológicos mostraron más complicaciones, destacando insuficiencia cardiaca/shock, insuficiencia renal aguda y una tendencia en el combinado de infecciones. En el seguimiento, presentaron mayor mortalidad y más sucesos combinados MACE, con una tendencia, no significativa, a la aparición de recurrencias o reingresos cardiovasculares. CONCLUSIONES: La prevalencia de neoplasias en pacientes con STB fue elevada. La presentación clínica fue diferente en relación con los pacientes que no las presentan y suponen probablemente un factor de riesgo de peor pronóstico, tanto hospitalario como a largo plazo

BACKGROUND AND OBJECTIVES: A relationship between neoplasms and Takotsubo syndrome (TS) has been postulated. Our goal was to determine its prevalence in patients with TS, compare the clinical profile of TS with or without cancer and study its long-term evolution. MATERIALS AND METHODS: The oncological situation of patients included in the National Registry on TAKOtsubo syndrome (RETAKO), admitted between 2002 and 2019, provided by 38 hospitals throughout the country is analysed. Any history of malignancy or tumour, even benign, that received chemotherapy, radiotherapy or specific surgery, current or past, was considered. RESULTS: Any type of neoplasm was described in 129 (11.8%), within a cohort of 1,097 patients with TS. The cohort of patients with neoplasm, with a lower percentage of women (79.1 vs. 88.3%; P=.003), showed a non-significant tendency at an older age, hyperuricaemia, sleep apnoea and lower LVEF on admission, with a similar cardiovascular risk factor profile, but more chronic anaemia and immunosuppression. The most common neoplasm was breast cancer. During their hospital stay, the cancer patients suffered more complications, highlighting heart failure/shock, acute renal failure and a trend towards combined infections. On follow-up, they presented higher mortality and more combined MACE events, with a non-significant trend in the occurrence of cardiovascular recurrences or readmissions. CONCLUSIONS: The prevalence of neoplasms in patients with TS is high. The clinical presentation is different in relation to patients who do not have neoplasms and they probably represent a risk factor for a worse hospital and long term prognosis

Takotsubo syndrome and cancer, clinical and prognostic implications, insights of RETAKO. / Implicaciones clínicas y pronósticas en síndrome de Takotsubo y cáncer: percepciones del registro RETAKO.

BACKGROUND AND OBJECTIVES: A relationship between neoplasms and Takotsubo syndrome (TS) has been postulated. Our goal was to determine its prevalence in patients with TS, compare the clinical profile of TS with or without cancer and study its long-term evolution. MATERIALS AND METHODS: The oncological situation of patients included in the National Registry on TAKOtsubo syndrome (RETAKO), admitted between 2002 and 2019, provided by 38 hospitals throughout the country is analysed. Any history of malignancy or tumour, even benign, that received chemotherapy, radiotherapy or specific surgery, current or past, was considered. RESULTS: Any type of neoplasm was described in 129 (11.8%), within a cohort of 1,097 patients with TS. The cohort of patients with neoplasm, with a lower percentage of women (79.1 vs. 88.3%; P=.003), showed a non-significant tendency at an older age, hyperuricaemia, sleep apnoea and lower LVEF on admission, with a similar cardiovascular risk factor profile, but more chronic anaemia and immunosuppression. The most common neoplasm was breast cancer. During their hospital stay, the cancer patients suffered more complications, highlighting heart failure/shock, acute renal failure and a trend towards combined infections. On follow-up, they presented higher mortality and more combined MACE events, with a non-significant trend in the occurrence of cardiovascular recurrences or readmissions. CONCLUSIONS: The prevalence of neoplasms in patients with TS is high. The clinical presentation is different in relation to patients who do not have neoplasms and they probably represent a risk factor for a worse hospital and long term prognosis.

Dysregulated lipid metabolism in hepatocellular carcinoma cancer stem cells.

According to the stem cell theory for cancer, hepatocellular carcinomas are sustained by a group of cancer stem cells (CSCs) which are responsible for resistance to chemotherapy. In the present study we aimed to examine lipid metabolism in cancer stem cells induced by long-term treatment with sorafenib and its relationship with acquisition of a CSC-like phenotype. Two cell lines (HepG2SF1 and Huh7SF1) were generated by incubation with a step-wise increase of sorafenib concentrations for 10 months. These cell lines displayed stem-like characteristics like increase in the expression of ABCB1A, Nanog and Oct4 as well as an E-cadherin/N-cadherin switch. HepG2SF1 and Huh7SF1 cells showed intracellular accumulation of neutral lipids, assessed by flow cytometry and confocal microscopy. The exam of lipid metabolism revealed that HepG2SF1 and Huh7SF1 cells increased the expression of the enzymes involved in de novo lipid synthesis ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) and that of the fatty acid transporter CD36. In addition, these CSC-like cells had enhanced expression of the lipogenic transcription factor SREBP1c. Analysis of the key metabolic sensor AMP-activated kinase (AMPK) demonstrated that both AMPK phosphorylation and levels were decreased in the CSC-like cells compared to their parental cells. Interestingly, transfection of HepG2SF1 and Huh7SF1 cells with AMPK, restored the levels of the lipogenic enzymes and SREBP1c and decreased the intracellular lipid accumulation. Furthermore, AMPK transfection decreased the stemness markers and inhibited the E-cadherin/N-cadherin switch. Targeting AMPK and lipid metabolism of hepatocellular cancer stem cells is a promising strategy to face stemness and chemotherapy resistance.

Multitarget Approach for the Treatment of Alzheimer's Disease: Inhibition of Phosphodiesterase 9 (PDE9) and Histone Deacetylases (HDACs) Covering Diverse Selectivity Profiles.

Here, we present a series of dual-target phosphodiesterase 9 (PDE9) and histone deacetylase (HDAC) inhibitors devised as pharmacological tool compounds for assessing the implications of these two targets in Alzheimer's disease (AD). These novel inhibitors were designed taking into account the key pharmacophoric features of known selective PDE9 inhibitors as well as privileged chemical structures, bearing zinc binding groups (hydroxamic acids and ortho-amino anilides) that hit HDAC targets. These substituents were selected according to rational criteria and previous knowledge from our group to explore diverse HDAC selectivity profiles (pan-HDAC, HDAC6 selective, and class I selective) that were confirmed in biochemical screens. Their functional response in inducing acetylation of histone and tubulin and phosphorylation of cAMP response element binding (CREB) was measured as a requisite for further progression into complete in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo brain penetration profiling. Compound 31b, a selective HDAC6 inhibitor with acceptable brain permeability, was chosen for assessing in vivo efficacy of these first-in-class inhibitors, as well as studying their mode of action (MoA).

Discovery of in Vivo Chemical Probes for Treating Alzheimer's Disease: Dual Phosphodiesterase 5 (PDE5) and Class I Histone Deacetylase Selective Inhibitors.

In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDE5) and pan-HDAC inhibitors on in vivo models of Alzheimer's disease (AD), we have designed, synthesized, and tested novel chemical probes with the desired target compound profile of PDE5 and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these molecules exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC50 values of these compounds and therefore on their corresponding selectivity profiles on the different HDAC isoforms. On the other hand, different chemical series have been explored and, as expected, some pairwise comparisons show a clear impact of the scaffold on biological responses (e.g., 35a vs 40a). The lead identification process led to compound 29a, which shows an adequate ADME-Tox profile and in vivo target engagement (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation) in the central nervous system (CNS), suggesting that this compound represents an optimized chemical probe; thus, 29a has been assayed in a mouse model of AD (Tg2576).