Comparison of Contemporary Risk Scores in All Groups of Pulmonary Hypertension: A Pulmonary Vascular Research Institute GoDeep Meta-Registry Analysis.

BACKGROUND: Pulmonary hypertension (PH) is a heterogeneous disease with a poor prognosis. Accurate risk stratification is essential for guiding treatment decisions in pulmonary arterial hypertension (PAH). Although various risk models have been developed for PAH, their comparative prognostic potential requires further exploration. Additionally, the applicability of risk scores in PH groups beyond group 1 remains to be investigated. RESEARCH QUESTION: Are risk scores originally developed for PAH predictive in PH groups 1 through 4? STUDY DESIGN AND METHODS: We conducted a comprehensive analysis of outcomes among patients with incident PH enrolled in the multicenter worldwide Pulmonary Vascular Research Institute GoDeep meta-registry. Analyses were performed across PH groups 1 through 4 and further subgroups to evaluate the predictive value of PAH risk scores, including REVEAL Lite 2, REVEAL 2.0, ESC/ERS 2022, COMPERA 3-strata, and COMPERA 4-strata. RESULTS: Eight thousand five hundred sixty-five patients were included in the study, of whom 3,537 patients were assigned to group 1 PH, whereas 1,807 patients, 1,635 patients, and 1,586 patients were assigned to group 2 PH, group 3 PH, and group 4 PH, respectively. Pulmonary hemodynamics were impaired with median mean pulmonary arterial pressure of 42 mm Hg (33-52 mm Hg) and pulmonary vascular resistance of 7 WU (4-11 WU). All risk scores were prognostic in the entire PH population and in each of the PH groups 1 through 4. The REVEAL scores, when used as continuous prediction models, demonstrated the highest statistical prognostic power and granularity; the COMPERA 4-strata risk score provided subdifferentiation of the intermediate-risk group. Similar results were obtained when separately analyzing various subgroups (PH subgroups 1.1, 1.4.1, and 1.4.4; PH subgroups 3.1 and 3.2; group 2 with isolated postcapillary PH vs combined precapillary and postcapillary PH; patients of all groups with concomitant cardiac comorbidities; and severe [> 5 WU] vs nonsevere PH). INTERPRETATION: This comprehensive study with real-world data from 15 PH centers showed that PAH-designed risk scores possess predictive power in a large PH cohort, whether considered as common to the group or calculated separately for each PH group (1-4) and various subgroups.

Mitral valve transcatheter edge-to-edge repair with PASCAL Vs MitraClip: A aystematic teview and meta-analysis.

BACKGROUND: Transcatheter edge-to-edge repair (TEER) using the MitraClip (Abbott Vascular) system has emerged as a standard treatment for patients with symptomatic severe secondary or inoperable primary mitral regurgitation (MR). The relatively recent approval of the PASCAL Transcatheter Valve Repair System (Edwards Lifesciences) has expanded the options of TEER devices. However, evidence comparing PASCAL with MitraClip systems is still limited. METHODS: We conducted a systematic literature research and meta-analysis in PubMed, Medline, and EMBASE databases for studies comparing PASCAL and MitraClip systems. RESULTS: Four observational studies and 1 randomized controlled trial, involving 1315 patients total, were eligible for inclusion. All patients exhibited symptomatic (NYHA II-IV) MR grades 3+ or 4+. Baseline characteristics were comparable across all included studies. The clinical outcomes were assessed according to the Mitral Valve Academic Research Consortium consensus. The procedural success rates for the 2 devices were comparable in terms of achieving post-procedural MR grades of less than or equal to 2+ and less than or equal to 1+. Furthermore, most patients improved their clinical status, with no significant differences between patients treated with PASCAL and those treated with MitraClip. In terms of safety, both procedures exhibited low overall mortality rates and occurrence of major adverse events (MAE), without significant difference between the 2 devices. These findings remained consistent in both short- and long-term follow-up assessments. CONCLUSIONS: Our study revealed similar effectiveness and safety profiles between the PASCAL and MitraClip devices in patients experiencing significant symptomatic MR.

Hypertrophic Cardiomyopathy and Atrial Fibrillation: A Systematic Review and Meta-analysis of Anticoagulation Strategy.

BACKGROUND: Atrial fibrillation (AF) frequently complicates hypertrophic cardiomyopathy (HCM), and anticoagulation significantly decreases the risk of stroke in this population. To date, no randomized controlled trials (RCTs) have compared direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs). The present study aimed to systematically compare the two anticoagulation strategies in terms of effectiveness and safety. METHOD: We performed a systematic literature search and meta-analysis in the PubMed, MEDLINE, and EMBASE databases for studies reporting all-cause mortality, major bleeding, or thromboembolic events (TEs). Since no RCTs were available, we included observational studies only. The overall hazard ratio (HR) and 95% confidence interval (CI) for each analyzed parameter were pooled using a random-effects model. RESULTS: Five observational studies including 6919 patients were eligible for inclusion. Compared with VKAs, DOACs were associated with statistically significant lower rates of all-cause mortality (HR 0.64, 95% CI 0.35-0.54; p < 0.00001), comparable major bleeding events (HR 0.64, 95% CI 0.40-1.03; p = 0.07), and TEs (HR 0.94, 95% CI 0.73-1.22; p = 0.65). CONCLUSIONS: Compared with VKAs, a DOAC-based strategy might represent an effective and safe strategy regarding all-cause mortality, major/life-threatening bleeding complications, and TEs in HCM patients with concomitant AF. However, further prospective studies are necessary to reinforce a DOAC-based anticoagulation strategy in this population.

SAR study on Novel truxillic acid monoester-Based inhibitors of fatty acid binding proteins as Next-Generation antinociceptive agents.

Fatty acid binding protein 5 (FABP5) is a highly promising target for the development of analgesics as its inhibition is devoid of CB1R-dependent side-effects. The design and discovery of highly potent and FABP5-selective truxillic acid (TA) monoesters (TAMEs) is the primary aim of the present study. On the basis of molecular docking analysis, ca. 2,000 TAMEs were designed and screened in silico, to funnel down to 55 new TAMEs, which were synthesized and assayed for their affinity (Ki) to FABP5, 3 and 7. The SAR study revealed that the introduction of H-bond acceptors to the far end of the 1,1'-biphenyl-3-yl and 1,1'-biphenyl-2-yl ester moieties improved the affinity of α-TAMEs to FABP5. Compound γ-3 is the first γ-TAME, demonstrating a high affinity to FABP5 and competing with α-TAMEs. We identified the best 20 TAMEs based on the FABP5/3 selectivity index. The clear front runner is α-16, bearing a 2­indanyl ester moiety. In sharp contrast, no ε-TAMEs made the top 20 in this list. However, α-19 and ε-202, have been identified as potent FABP3-selective inhibitors for applications related to their possible use in the protection of cardiac myocytes and the reduction of α-synuclein accumulation in Parkinson's disease. Among the best 20 TAMEs selected based on the affinity to FABP7, 13 out of 20 TAMEs were found to be FABP7-selective, with α-21 as the most selective. This study identified several TAMEs as FABP7-selective inhibitors, which would have potentially beneficial therapeutic effects in diseases such as Down's syndrome, schizophrenia, breast cancer, and astrocytoma. We successfully introduced the α-TA monosilyl ester (TAMSE)-mediated protocol to dramatically improve the overall yields of α-TAMEs. α-TAMSEs with TBDPS as the silyl group is isolated in good yields and unreacted α-TA/ α-MeO-TA, as well as disilyl esters (α-TADSEs) are fully recycled. Molecular docking analysis provided rational explanations for the observed binding affinity and selectivity of the FABP3, 5 and 7 inhibitors, including their α, γ and ε isomers, in this study.

Pulmonary Vascular Research Institute GoDeep: A meta-registry merging deep phenotyping datafrom international PH reference centers.

The Pulmonary Vascular Research Institute GoDeep meta-registry is a collaboration of pulmonary hypertension (PH) reference centers across the globe. Merging worldwide PH data in a central meta-registry to allow advanced analysis of the heterogeneity of PH and its groups/subgroups on a worldwide geographical, ethnical, and etiological landscape (ClinTrial. gov NCT05329714). Retrospective and prospective PH patient data (diagnosis based on catheterization; individuals with exclusion of PH are included as a comparator group) are mapped to a common clinical parameter set of more than 350 items, anonymized and electronically exported to a central server. Use and access is decided by the GoDeep steering board, where each center has one vote. As of April 2022, GoDeep comprised 15,742 individuals with 1.9 million data points from eight PH centers. Geographic distribution comprises 3990 enrollees (25%) from America and 11,752 (75%) from Europe. Eighty-nine perecent were diagnosed with PH and 11% were classified as not PH and provided a comparator group. The retrospective observation period is an average of 3.5 years (standard error of the mean 0.04), with 1159 PH patients followed for over 10 years. Pulmonary arterial hypertension represents the largest PH group (42.6%), followed by Group 2 (21.7%), Group 3 (17.3%), Group 4 (15.2%), and Group 5 (3.3%). The age distribution spans several decades, with patients 60 years or older comprising 60%. The majority of patients met an intermediate risk profile upon diagnosis. Data entry from a further six centers is ongoing, and negotiations with >10 centers worldwide have commenced. Using electronic interface-based automated retrospective and prospective data transfer, GoDeep aims to provide in-depth epidemiological and etiological understanding of PH and its various groups/subgroups on a global scale, offering insights for improved management.

Direct oral anticoagulants or vitamin K antagonists after TAVR: A systematic review and meta-analysis.

BACKGROUND: Several patients undergoing transcatheter aortic valve replacement (TAVR) also require oral anticoagulation (OAC) for atrial fibrillation (AF) or deep vein thromboembolism. However, the optimal type of OAC strategy (direct oral anticoagulants, DOACs, or vitamin K antagonists, VKA) is still unclear in this setting. METHOD: We performed systematic literature research and meta-analysis in PubMed, Medline, and EMBASE databases for studies reporting either all-cause mortality, major/life-threatening bleeding or stroke events. RESULTS: Ten observational studies and two randomized controlled trials (RCTs) including a total of 29,485 patients were eligible for inclusion. Compared to VKA, DOACs use after TAVR was associated with a modest but significantly lower rates of all-cause mortality (RR 0.90; 95% CI: 0.81-0.99, p-value 0.04) with results mainly driven by observational studies. Cardiovascular mortality (RR 1.03; 95% CI: 0.81-1.30; p-value 0.84), total stroke events (RR 0.97; 95% CI: 0.76-1.23, p-value 0.79), major/life-threatening bleeding (RR 0.93; 95% CI: 0.72-1.21, p-value 0.61) and minor bleeding (RR 0.96; 95% CI: 0.74-1.23; p-value 0.72) were similar between VKA and DOACs. CONCLUSION: Considering the totality of available evidence, in patients who underwent TAVR with a concomitant indication for OAC, DOACs-based strategy is an effective and safe anticoagulation strategy compared to VKA.

Statin and Postcardiac Surgery Atrial Fibrillation Prevention: A Systematic Review and Meta-Analysis.

ABSTRACT: Postoperative atrial fibrillation (POAF) is a frequently reported postcardiac surgery complication leading to increased in-hospital and long-term mortality rates. Many randomized controlled trials (RCTs) have recently suggested using statins to protect against POAF. Therefore, we performed a systematic literature search and meta-analysis in electronic databases for eligible studies published between January 2006 and January 2022. The principal inclusion criteria were as follows: RCTs' study design, statin-naive patients, total study participants ≥50 units, and statin pretreatment started no more than 21 days before cardiac surgery. In the primary analysis, statin pretreatment reduced the incidence of POAF compared with placebo. Analyzing different molecules, atorvastatin was associated with lower incidence of POAF but rosuvastatin was not. We therefore performed a sensitivity analysis excluding RCTs affected by important risk of biases. Thus, studies whose participants were ≥199 were those eligible for the secondary analysis. No statistically significant difference between statin pretreatment and placebo (OR 0.87; 95% CI: 0.71-1.07, P = 0.18) as well as for atorvastatin (OR 0.88; 95% CI: 0.61-1.28; P = 0.48; I 2 = 84%) and rosuvastatin (OR 0.87; 95% CI: 0.68-1.12, P = 0.29) was observed. To conclude, statin pretreatment before cardiac surgery is not associated with a significant reduction in POAF occurrence.

Conservation of Cdc14 phosphatase specificity in plant fungal pathogens: implications for antifungal development.

Cdc14 protein phosphatases play an important role in plant infection by several fungal pathogens. This and other properties of Cdc14 enzymes make them an intriguing target for development of new antifungal crop treatments. Active site architecture and substrate specificity of Cdc14 from the model fungus Saccharomyces cerevisiae (ScCdc14) are well-defined and unique among characterized phosphatases. Cdc14 appears absent from some model plants. However, the extent of conservation of Cdc14 sequence, structure, and specificity in fungal plant pathogens is unknown. We addressed this by performing a comprehensive phylogenetic analysis of the Cdc14 family and comparing the conservation of active site structure and specificity among a sampling of plant pathogen Cdc14 homologs. We show that Cdc14 was lost in the common ancestor of angiosperm plants but is ubiquitous in ascomycete and basidiomycete fungi. The unique substrate specificity of ScCdc14 was invariant in homologs from eight diverse species of dikarya, suggesting it is conserved across the lineage. A synthetic substrate mimetic inhibited diverse fungal Cdc14 homologs with similar low µM Ki values, but had little effect on related phosphatases. Our results justify future exploration of Cdc14 as a broad spectrum antifungal target for plant protection.

1,4-Substituted Triazoles as Nonsteroidal Anti-Androgens for Prostate Cancer Treatment.

Prostate cancer (PC) is the fifth leading cause of cancer death in men, and the androgen receptor (AR) represents the primary target for PC treatment, even though the disease frequently progresses toward androgen-independent forms. Most of the commercially available nonsteroidal antiandrogens show a common scaffold consisting of two aromatic rings connected by a linear or a cyclic spacer. By taking advantage of a facile, one-pot click chemistry reaction, we report herein the preparation of a small library of novel 1,4-substituted triazoles with AR antagonistic activity. Biological and theoretical evaluation demonstrated that the introduction of the triazole core in the scaffold of nonsteroidal antiandrogens allowed the development of small molecules with improved overall AR-antagonist activity. In fact, compound 14d displayed promising in vitro antitumor activity toward three different prostate cancer cell lines and was able to induce 60% tumor growth inhibition of the CW22Rv1 in vivo xenograft model. These results represent a step toward the development of novel and improved AR antagonists.

Identification of the first inhibitor of the GBP1:PIM1 interaction. Implications for the development of a new class of anticancer agents against paclitaxel resistant cancer cells.

Class III ß-tubulin plays a prominent role in the development of drug resistance to paclitaxel by allowing the incorporation of the GBP1 GTPase into microtubules. Once in the cytoskeleton, GBP1 binds to prosurvival kinases such as PIM1 and initiates a signaling pathway that induces resistance to paclitaxel. Therefore, the inhibition of the GBP1:PIM1 interaction could potentially revert resistance to paclitaxel. A panel of 44 4-azapodophyllotoxin derivatives was screened in the NCI-60 cell panel. The result is that 31 are active and the comparative analysis demonstrated specific activity in paclitaxel-resistant cells. Using surface plasmon resonance, we were able to prove that NSC756093 is a potent in vitro inhibitor of the GBP1:PIM1 interaction and that this property is maintained in vivo in ovarian cancer cells resistant to paclitaxel. Through bioinformatics, molecular modeling, and mutagenesis studies, we identified the putative NSC756093 binding site at the interface between the helical and the LG domain of GBP1. According to our results by binding to this site, the NSC756093 compound is able to stabilize a conformation of GBP1 not suitable for binding to PIM1.

Synthesis and structure-activity relationship studies of novel dihydropyridones as androgen receptor modulators.

A library of 3-hydroxy-2,3-dihydropyridones was synthesized, and their activities as antiandrogens were tested in the human prostate cancer cell line LNCaP. Structure-activity relationship (SAR) studies resulted in the identification of a potent compound whose activity is comparable to that of MDV3100. Homology modeling and molecular mechanics were used to build a structural model of the androgen receptor-ligand binding domain and to investigate the structural basis of the antagonism. The model is qualitatively consistent with the observed SAR. Moreover, the enrichment plot shows that screening with the model performs significantly better than random screening. Therefore, the model probably represents a realistic conformation of the antagonist form and can be utilized for structure-based design of novel antiandrogens.

Mechanism of the antiproliferative activity of some naphthalene diimide G-quadruplex ligands.

G-quadruplexes are higher-order nucleic acid structures that can form in G-rich telomeres and promoter regions of oncogenes. Telomeric quadruplex stabilization by small molecules can lead to telomere uncapping, followed by DNA damage response and senescence, as well as chromosomal fusions leading to deregulation of mitosis, followed by apoptosis and downregulation of oncogene expression. We report here on investigations into the mechanism of action of tetra-substituted naphthalene diimide ligands on the basis of cell biologic data together with a National Cancer Institute COMPARE study. We conclude that four principal mechanisms of action are implicated for these compounds: 1) telomere uncapping with subsequent DNA damage response and senescence; 2) inhibition of transcription/translation of oncogenes; 3) genomic instability through telomeric DNA end fusions, resulting in mitotic catastrophe and apoptosis; and 4) induction of chromosomal instability by telomere aggregate formation.

Synthesis of fused bicyclic systems with nitrogen atom at the bridgehead, including indolizidines and quinolizidines.

Monocyclic as well as fused bicyclic systems with a nitrogen 10 atom at the bridgehead, including indolizidines and quinolizidines, can be prepared in four steps from N-Boc ß-lactams. These easily prepared, highly robust, and flexible building blocks allow the incorporation of chirality and structural diversity, rendering the method feasible for diversity- as well as target-oriented synthesis.

Novel C-seco-taxoids possessing high potency against paclitaxel-resistant cancer cell lines overexpressing class III beta-tubulin.

Novel C-seco-taxoids were synthesized from 10-deacetylbaccatin III and their potencies evaluated against drug-sensitive and drug-resistant cancer cell lines. The drug-resistant cell lines include ovarian cancer cell lines resistant to cisplatin, topotecan, adriamycin and paclitaxel overexpressing class III beta-tubulin, A2780TC1 and A2780TC3. The last two cell lines were selected through chronic exposure of A2780wt to paclitaxel and Pgp blocker cyclosporine. All novel C-seco-taxoids exhibited remarkable potency against A2780TC1 and A2780TC3 cell lines, and no cross resistance to cisplatin- and topotecan-resistant cell lines, A2780CIS and A2780TOP. Four of those C-seco-taxoids exhibit much higher activities than IDN5390 against paclitaxel-resistant cell lines, A2780ADR, A2780TC1 and A2780TC3. SB-CST-10202 possesses the best all-round high potencies across different drug-resistant cell lines. Molecular modeling studies, including molecular dynamics simulations, on the drug-protein complexes of class I and III beta-tubulins were performed to identify possible cause of the remarkable potency of these C-seco-taxoids against paclitaxel-resistant cell lines overexpressing class III beta-tubulin.

Syntheses and Structure-Activity Relationships of Novel 3'-Difluoromethyl and 3'-Trifluoromethyl-Taxoids.

A series of novel 3'-difluoromethyl-taxoids and 3'-trifluoromethyl-taxoids with modifications at the C2 and C10 positions were synthesized and evaluated for their in vitro cytotoxicities against human breast carcinoma (MCF7-S, MCF7-R, LCC6-WT, LCC6-MDR), non-small cell lung carcinoma (H460) and colon adenocarcinoma (HT-29) cell lines. These second-generation fluoro-taxoids exhibited several times to more than 20 times better potency than paclitaxel against drug-sensitive cancer cell lines, MCF7-S, LCC6-WT, H460, and HT-29. These fluoro-taxoids also possess two orders of magnitude higher potency than paclitaxel against drug-resistant cancer cell lines, MCF7-R and LCC6-MDR. Structure-activity relationship study shows the importance of the C10 modification for increasing the activity against multidrug-resistant cancer cell lines. Effects of the C2-benzoate modifications on the potency in the 3-difluoromethyl-taxoid series are very clear (i.e., F < MeO < Cl < N(3)), while those in the 3-trifluoromethyl-taxoid series are less obvious. Also, different trends in the sensitivity to the C2-substitution are observed between drug-sensitive cell lines and drug-resistant cancer cell lines that overexpress efflux pumps.

Targeting FtsZ for antituberculosis drug discovery: noncytotoxic taxanes as novel antituberculosis agents.

Screening of 120 taxanes identified a number of compounds that exhibited significant antituberculosis activity. Rational optimization of selected compounds led to the discovery that the C-seco-taxane-multidrug-resistance (MDR) reversal agents (C-seco-TRAs) are noncytotoxic at the upper limit of solubility and detection (>80 microM), while maintaining MIC(99) values of 1.25-2.5 microM against drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis (MTB). Treatment of MTB cells with TRA 3aa and 10a at the MIC caused filamentation and prolongation of the cells, a phenotypic response to FtsZ inactivation.

Syntheses and evaluation of novel fatty acid-second-generation taxoid conjugates as promising anticancer agents.

Polyunsaturated fatty acids such as docosahexaenoic acid (DHA), linolenic acid, and linoleic acid were linked to the C-2' position of the second-generation taxoids that could overcome MDR caused by overexpressed ABC transporters. The new conjugates, tested in vivo, exhibited strong activity against drug-resistant colon cancer and drug-sensitive ovarian cancer xenografts in mice. Two of the new conjugates, DHA-SB-T-1214 and DHA-SB-T-1213, were found to achieve the total regression of drug-resistant and drug-sensitive tumors, respectively, in the animal models with substantially reduced systemic toxicity.

Transport and cytotoxicity of paclitaxel, docetaxel, and novel taxanes in human breast cancer cells.

The resistance of tumors to classic taxanes (paclitaxel and docetaxel) presents problems in chemotherapy. Thus, new taxanes with higher antitumor activity in resistant tumors are synthesized. This study compared cytotoxicity and transport of paclitaxel and docetaxel with novel taxanes SB-T-1103, SB-T-1214, and SB-T-1216 in adriamycin-sensitive (MDA-MB-435) and -resistant (NCI/ADR-RES) human breast cancer cells. The cell lines examined differ in adriamycin transport, suggesting different expression of ABC membrane transporters. Reverse transcription-polymerase chain reaction revealed that NCI/ADR-RES cells expressed high levels of P-glycoprotein mRNA, which was absent in MDA-MB-435 cells, while the opposite was true for MRP2 mRNA. Both cell lines shared or differently expressed eight other ABC transporters and LRP. NCI/ADR-RES cells were 1,000-fold more resistant to paclitaxel and 600-fold more resistant to docetaxel in MTT assay than MDA-MB-435 cells, but almost equally sensitive to SB-T-1103, SB-T-1214, and SB-T-1216. This complied with the fact that NCI/ADR-RES cells absorbed almost 20-fold less [14C]paclitaxel, about 7-fold less docetaxel, and almost equal amounts of SB-T-1103, SB-T-1214, and SB-T-1216 as the MDA-MB-435 cells. Verapamil increased uptake of [14C]paclitaxel by NCI/ADR-RES cells 7-fold and decreased its efflux 2.5-fold; in contrast, it weakly influenced uptake and increased the efflux in MDA-MB-435 cells. SB-T-1103 and SB-T-1216 did not influence transport of paclitaxel, but SB-T-1214 decreased [14C]paclitaxel uptake in both cell lines indicating inhibition of uptake. This suggests that the novel taxanes are not inhibitors of P-glycoprotein. However, novel taxanes exert much higher activity on resistant tumor cells than classic taxanes and seem to be potential drugs for therapy in taxane-resistant tumors.