Identification of new multi-substituted 1H-pyrazolo[3,4-c]pyridin-7(6H)-ones as soluble guanylyl cyclase (sGC) stimulators with vasoprotective and anti-inflammatory activities.

Herein, we describe the rational design, synthesis and in vitro functional characterization of new heme-dependent, direct soluble guanylyl cyclase (sGC) agonists. These new compounds bear a 1H-pyrazolo[3,4-c]pyridin-7(6H)-one skeleton, modified to enable efficient sGC binding and stimulation. To gain insights into structure-activity relationships, the N6-alkylation of the skeleton was explored, while a pyrimidine ring, substituted with various C5'-polar groups, was installed at position C3. Among the newly synthesized 1H-pyrazolo[3,4-c]pyridin-7(6H)-ones, derivatives 14b, 15b and 16a display characteristic features of sGC "stimulators" in A7r5 vascular smooth muscle cells in vitro. They strongly synergize with the NO donor, sodium nitroprusside (SNP) in inducing cGMP generation in a manner that requires the presence of a reduced heme moiety associated with sGC, and elevate the cGMP-responsive phosphorylation of the protein VASP at Ser239. In line with their sGC stimulating capacity, docking calculations of derivatives 16a, 15(a-c) on a cryo-EM structure of human sGC (hsGC) in an ΝΟ-activated state indicated the implication of 1H-pyrazolo[3,4-c]pyridin-7(6H)-one skeleton in efficient bonding interactions with the recently identified region that binds known sGC stimulators, while the presence of either a N6-H or N6-methyl group pointed to enhanced binding affinity. Moreover, the in vitro functional effects of our newly identified sGC stimulators were compatible with a beneficial role in vascular homeostasis. Specifically, derivative 14b reduced A7r5 cell proliferation, while 16a dampened the expression of adhesion molecules ICAM-1 and P/E-Selectin in Human Umbilical Vein Endothelial Cells (HUVECs), as well as the subsequent adhesion of U937 leukocytes to the HUVECs, triggered by tumor necrosis factor alpha (TNF-α) or interleukin-1 beta (IL-1ß). The fact that these compounds elevate cGMP only in the presence of NO may indicate a novel way of interaction with the enzyme and may make them less prone than other direct sGC agonists to induce characteristic hypotension in vivo.

Targeting androgen receptor for prostate cancer therapy: From small molecules to PROTACs.

Prostate cancer (PCa) remains a serious type of cancer for men worldwide. The majority of new PCa cases are associated with androgen receptor (AR) hyperactivity. Various AR-targeting molecules that suppress its activity have been discovered. In this review, we present the already marketed antiandrogens and a selection of structurally and chemically interesting AR-targeting compounds, from a pharmacochemical perspective. Focus has been placed on the applied design approaches, structural evolution and structure-activity relationships of the most prominent compound classes. Passing from the traditional steroidal AR antagonists to the modern AR-targeting proteolysis targeting chimeras (PROTACs), we intend to provide a comprehensive overview on AR-targeting molecules for PCa treatment.

Excessive daytime sleepiness, morning tiredness and major adverse cardiovascular events in patients with chronic coronary syndrome.

BACKGROUND: Sleep-related breathing disorders (SRBDs), particularly obstructive sleep apnoea, are associated with increased cardiovascular (CV) risk. However, it is not known whether individual questions used for SRBD screening are associated with major adverse CV events (MACE) and death specifically in patients with chronic coronary syndrome (CCS). METHODS: Symptoms associated with SRBD were assessed by a baseline questionnaire in 15,640 patients with CCS on optimal secondary preventive therapy in the STABILITY trial. The patients reported the frequency (never/rarely, sometimes, often and always) of: 1) loud snoring; 2) more than one awakening/night; 3) morning tiredness (MT); 4) excessive daytime sleepiness (EDS); or 5) gasping, choking or apnoea when asleep. In adjusted Cox regression models, associations between the frequency of SRBD symptoms and CV outcomes were assessed with never/rarely as reference. RESULTS: During a median follow-up time of 3.7 years, 1,588 MACE events (541 CV deaths, 749 nonfatal myocardial infarctions [MI] and 298 nonfatal strokes) occurred. EDS was associated (hazard ratio [HR], 95% confidence interval [CI]) with increased risk of MACE (sometimes 1.14 [1.01-1.29], often 1.19 [1.01-1.40] and always 1.43 [1.15-1.78]), MI (always 1.61 [1.17-2.20]) and all-cause death (often 1.26 [1.05-1.52] and always 1.71 [1.35-2.15]). MT was associated with higher risk of MACE (often 1.23 [1.04-1.45] and always 1.46 [1.18-1.81]), MI (always 1.61 [1.22-2.14]) and all-cause death (always 1.54 [1.20-1.98]). The other SRBD-related questions were not consistently associated with worse outcomes. CONCLUSIONS: In patients with CCS, gradually higher levels of EDS and MT were independently associated with increased risk of MACE, including mortality.

Ultra-sensitive refractive index sensor using CMOS plasmonic transducers on silicon photonic interferometric platform.

Optical refractive-index sensors exploiting selective co-integration of plasmonics with silicon photonics has emerged as an attractive technology for biosensing applications that can unleash unprecedented performance breakthroughs that reaps the benefits of both technologies. However, towards this direction, a major challenge remains their integration using exclusively CMOS-compatible materials. In this context, herein, we demonstrate, for the first time to our knowledge, a CMOS-compatible plasmo-photonic Mach-Zehnder-interferometer (MZI) based on aluminum and Si3N4 waveguides, exhibiting record-high bulk sensitivity of 4764 nm/RIU with clear potential to scale up the bulk sensitivity values by properly engineering the design parameters of the MZI. The proposed sensor is composed of Si3N4 waveguides butt-coupled with an aluminum stripe in one branch to realize the sensing transducer. The reference arm is built by Si3N4 waveguides, incorporating a thermo-optic phase shifter followed by an MZI-based variable optical attenuation stage to maximize extinction ratio up to 38 dB, hence optimizing the overall sensing performance. The proposed sensor exhibits the highest bulk sensitivity among all plasmo-photonic counterparts, while complying with CMOS manufacturing standards, enabling volume manufacturing.

Plasmonics co-integrated with silicon nitride photonics for high-sensitivity interferometric biosensing.

We demonstrate a photonic integrated Mach-Zehnder interferometric sensor, utilizing a plasmonic stripe waveguide in the sensing branch and a photonic variable optical attenuator and a phase shifter in the reference arm to optimize the interferometer operation. The plasmonic sensor is used to detect changes in the refractive index of the surrounding medium exploiting the accumulated phase change of the propagating Surface-Plasmon-Polariton (SPP) mode that is fully exposed in an aqueous buffer solution. The variable optical attenuation stage is incorporated in the reference Si3N4 branch, as the means to counter-balance the optical losses introduced by the plasmonic branch and optimize interference at the sensor output. Bulk sensitivity values of 1930 nm/RIU were experimentally measured for a Mach Zehnder Interferometer (MZI) with a Free Spectral Range of 24.8 nm, along with extinction ratio of more than 35 dB, demonstrating the functional benefits of the co-integration of plasmonic and photonic waveguides.

Ivabradine and metoprolol in fixed dose combination: When, why and how to use it.

Heart rate is an important factor in coronary artery disease and its manifestations, and as such has been considered as a possible target for therapy. Although in epidemiological, and in less degree, in clinical studies derived indications of a possible pathogenetic role of heart rate in major cardiac diseases, clinical trials did not provided any strong evidence. However, even as a simple risk marker, remains important in the treatment of coronary artery disease and heart failure. Beta-blockers are the drugs most frequently used for heart rate control. However, recent studies constantly find insufficient effectiveness of beta-blockers in heart rate control and go further to question their efficacy on outcomes, making clear the need for an additional therapy. Ivabradine, a pure heart rate inhibitor, added to classic beta-blocker treatment represent the new therapeutic option in stable coronary disease and heart failure.

CMOS plasmonics in WDM data transmission: 200 Gb/s (8 × 25Gb/s) transmission over aluminum plasmonic waveguides.

We demonstrate wavelength-division-multiplexed (WDM) 200 Gb/s (8 × 25 Gb/s) data transmission over 100 µm long aluminum (Al) surface-plasmon-polariton (SPP) waveguides on a Si3N4 waveguide platform at telecom wavelengths. The Al SPP waveguide was evaluated in terms of signal integrity by performing bit-error-rate (BER) measurements that revealed error-free operation for all eight 25 Gb/s non-return-to-zero (NRZ) modulated data channels with power penalties not exceeding 0.2 dB at 10-9. To the best of our knowledge, this is the first demonstration of WDM enabled data transmission over complementary-metal-oxide-semiconductor (CMOS) SPP waveguides fueling future development of CMOS compatible plasmo-photonic devices for on-chip optical interconnections.

Atrial fibrillation and arterial hypertension.

Atrial fibrillation (AF) and arterial hypertension frequently coexist, not only because arterial hypertension increases the incidence of new onset of atrial fibrillation, but also because those two entities share common risk factors and conditions that increase the incidence of both. Thus, in our daily clinical practice we will often have to manage and treat those patients. In order to assess and treat these patients, proper blood pressure (BP) measurement as well as detection of atrial fibrillation is mandatory. The use of oscillometric devices for home and ambulatory blood pressure measurements may accurately measure systolic but not diastolic blood pressure levels. Current guidelines suggest to palpate the pulse and perform an electrocardiogram (ECG) as well as a long-term ECG monitoring in order to detect AF. However there is evidence that: the use of oscillometric BP device with a specific algorithm for the detection of AF as well as the interrogation of a permanent pacemaker may further help physicians to reveal periods of AF. Finnaly, although guidelines suggests the use of specific drugs in order to treat arterial hypertension in AF patients, the main goal is BP control per se. In this review, we are going to summarize the diagnostic work up of these patients namely the proper arterial blood pressure measurement, the detection of atrial fibrillation as well as the treatment of these patients based on the latest data of the literature.

Synthesis and cytotoxic activity of new artemisinin hybrid molecules against human leukemia cells.

A series of new artemisinin-derived hybrids which incorporate cholic acid moieties have been synthesized and evaluated for their antileukemic activity against sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 cells. The new hybrids 20-28 showed IC50 values in the range of 0.019µM-0.192µM against CCRF-CEM cells and between 0.345µM and 7.159µM against CEM/ADR5000 cells. Amide hybrid 25 proved the most active compound against both CCRF-CEM and CEM/ADR5000 cells with IC50 value of 0.019±0.001µM and 0.345±0.031µM, respectively. A relatively low cross resistance to hybrids 20-28 in the range of 5.7-fold to 46.1-fold was measured. CEM/ADR5000 cells showed higher resistance than CCRF-CEM to all the tested compounds. Interestingly, the lowest cross resistance to 23 was observed (5.7-fold), whereas hybrid 25 showed 18.2-fold cross-resistant to CEM/ADR5000 cells. Hybrid 25 which proved even more potent than clinically used doxorubicin against CEM/ADR5000 cells may serve as a promising antileukemic agent against both sensitive and multidrug-resistant cells.

Corrigendum to: 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases.

Corrigendum to: 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases [Eur Heart Journal (2014) 35, 2873­2926,doi:10.1093/eurheartj/ehu281]. In Table 3, the radiation for MRI is "0" and not "-". The corrected table is shown below.

The diagnostic approach and management of hypertension in the emergency department.

Hypertension urgency and emergency represents a challenging condition in which clinicians should determine the assessment and/or treatment of these patients. Whether the elevation of blood pressure (BP) levels is temporary, in need of treatment, or reflects a chronic hypertensive state is not always easy to unravel. Unfortunately, current guidelines provide few recommendations concerning the diagnostic approach and treatment of emergency department patients presenting with severe hypertension. Target organ damage determines: the timeframe in which BP should be lowered, target BP levels as well as the drug of choice to use. It's important to distinguish hypertensive emergency from hypertensive urgency, usually a benign condition that requires more likely an outpatient visit and treatment.

New Esters of Ferrediol and Sideritriol in Sideritis clandestina subsp. peloponnesiaca: Characterization and Antiproliferative Activity.

17-Isovalerate esters of ferrediol and sideritriol (compounds 1 and 5) and 17-(2-methylbutyrate) ferrediol (compound 2), which have not been earlier described, were isolated along with five known ent-15-kaurene diterpenes (siderol, sideridiol, sideroxol, eubotriol, and epi-candicandiol), one ent-beyerene (flavovirol), and one phytosterol (ß-sitosterol) from the aerial parts of Sideritis clandestina subsp. peloponnesiaca (Boiss. & Heldr.) Baden that is a mountain tea species endemic to Northern Peloponnese in Greece. Compounds 1-5 exhibited weak antiproliferative activity against triple-negative MDA-MB-231 and Hs578T breast cancer cells. In MCF-7 breast cancer cells, compounds 1, 2, siderol, and sideridiol were equipotent to 5-fluorouracil (moderate antiproliferative activity).

Steroidal esters of the aromatic nitrogen mustard 2-[4-N,N-bis(2-chloroethyl)amino-phenyl]butanoic acid (2-PHE-BU): synthesis and in-vivo biological evaluation.

On the basis of the results of in-silico predictions and in an effort to extend our structure-activity relationship studies, the aromatic nitrogen mustard 2-[4-N,N-bis(2-chloroethyl) amino-phenyl]butanoic acid (2-PHE-BU) was synthesized and conjugated with various steroidal alcohols. The resulting steroidal esters were evaluated for their in-vivo toxicity and antileukemic activity in P388-leukemia-bearing mice. The new derivatives showed significantly reduced toxicity and marginally improved antileukemic activity compared with free 2-PHE-BU. Nevertheless, they did not prove to be superior either to the template steroidal ester used for in-silico predictions or to previously synthesized steroidal esters of aromatic nitrogen mustards. The results obtained indicate that in-silico design predictions may guide the design and synthesis of new bioactive steroidal esters, but further parameters should be considered aiming at the discovery of compounds with optimum activity.

How low should blood pressure be in patients with chronic coronary and cerebrovascular diseases.

Over the last three decades, there are an increasing number of investigators and meta-analyses focusing on the fact that lowering blood pressure levels below a critical point is no longer beneficial and possibly even deleterious. In recent years, several trials and meta-analyses assessing intensive blood pressure (BP) lowering found that intensive treatment and lower blood pressure levels are associated with a reduction in CV events and mortality. However, a careful examination of the results shows that current data are not easily applicable to the general hypertensive population. In addition, recommendations of different guidelines since 2017 so far suggest different BP levels regarding the systolic and diastolic thresholds to be achieved and maintained, particularly in specific clinical situations such as patients with coronary artery disease and stroke. The challenge is to better define the limits of intervention and to define phenotypes of patients who are particularly vulnerable to over-aggressive lowering of blood pressure. This article reviews the evidence, controversies and current state of knowledge regarding intensive BP lowering and the lower thresholds of BP to be achieved in patients with chronic coronary or cerebrovascular diseases.

The Metastatic Risk of Renal Cell Carcinoma by Primary Tumor Size and Subtype.

Background: Current data on the association between tumor size, subtype, and metastases, and thresholds for intervention, for renal cell carcinoma (RCC), are largely based on single-center nephrectomy registries that may under-represent those presenting with metastatic disease. Objective: We sought to assess tumor size and histologic subtype in relation to metastatic status at presentation for patients with RCC. Design setting and participants: Using Surveillance, Epidemiology and End Results cancer registry data, we identified patients with a diagnosis of RCC made between 2004 and 2019, and a known size of primary tumor. We used nodal and metastatic TNM staging to assess metastatic disease at presentation. Outcome measurements and statistical analysis: We report the proportion of metastatic disease across varying tumor sizes for clear cell (ccRCC), papillary (pRCC), and chromophobe (chRCC) RCC. We also examine sarcomatoid RCC and RCC with sarcomatoid features (sarcRCC). Logistic regression models were used to model the likelihood of metastatic disease for each histologic subtype. Results and limitations: Of 181 096 RCC patients included, 23 829 had metastatic disease. For any RCC, metastatic rates of 3.6%, 13.1%, 30.3%, and 45.1% were observed for tumors ≤4, 4-≤7, 7-≤10, and >10 cm, respectively. Metastatic rates of chRCC were low at even large sizes, 11.0% at >10 cm. In contrast, sarcRCC had high metastatic rates at all sizes, 27.1% at ≤4 cm. Metastatic rates for ccRCC and pRCC increased steadily above 3 cm. For any RCC and each evaluated subtype, tumor size was found to be associated with metastatic disease on logistic regression (p < 0.001). Conclusions: The likelihood of a renal mass being metastatic varies greatly with both its subtype and size. We report higher likelihoods of metastatic disease across tumor sizes compared with what has been reported previously. These results may help clinicians pick appropriate thresholds for intervention and candidates for active surveillance. Patient summary: We find that the metastatic probability of renal cell carcinoma varies greatly with subtype and increases with tumor size.

Design, synthesis and biological evaluation of new 3,4-dihydroquinoxalin-2(1H)-one derivatives as soluble guanylyl cyclase (sGC) activators.

Herein, we present the structure-based design, synthesis and biological evaluation of novel mono- and di-carboxylic 3,4-dihydroquinoxalin-2(1H)-one derivatives as potential heme-independent activators of soluble guanylate cyclase (sGC). Docking calculations of several known sGC agonists by utilizing both a homology model of human sGC ß1 Η-ΝΟΧ domain and a recent cryo-EM structure of the same domain guided the structural optimization of various designed compounds. Among these, mono- and di-carboxylic 3,4-dihydroquinoxalin-2(1H)-one derivatives arose as promising candidate sGC activators. A series of such compounds was synthesized and assessed for their effect on sGC activity. None of them was able to trigger any detectable activation of native sGC in prostate cancer (LnCaP) or rat aortic smooth muscle (A7r5) cells, even after loss of heme by treatment with the heme oxidant ODQ. Furthermore, selected derivatives did not exhibit any antagonistic effect against the known heme-independent sGC activator BAY 60-2770 nor any additive or synergistic effect with the heme-dependent NO donor sodium nitroprusside (SNP) on heme-associated sGC in A7r5 cells. However, when tested in vitro using purified recombinant sGC enzyme, the dicarboxylic 3,4-dihydroquinoxalin-2(1H)-one derivative 30d was able to increase the enzymatic activity of both the wild-type α1/ß1 sGC dimer (by 4.4-fold, EC50 = 0.77 µΜ) as well as the heme-free α1/ß1 His105Ala mutant sGC (by 4.8-fold, EC50 = 1.8 µΜ). Notably, the activity of compound 30d towards the mutant α1/ß1 Η105A enzyme was comparable with that previously reported by us for the bona fide activator BAY 60-2770, using the functionally equivalent wild-type sGC preparation treated with ODQ. These results indicate that compound 30d can indeed act as a promising sGC activator and may serve as a basic structure in the design of novel, optimized analogues with enhanced sGC agonistic activity and improved efficiency in cell-based and in vivo systems.

State of the art approach to managing angina and ischemia: tailoring treatment to the evidence.

Stable angina represents a chronic and often debilitating condition that affects daily activities and quality of life in patients with chronic coronary syndromes (CCS). Current European Society of Cardiology guidelines recommend a four-step approach for the medical treatment of patients taking into consideration hemodynamic variables (heart rate and blood pressure) and the presence or absence of left ventricular dysfunction. However, CCS patients often have several comorbidities and risk factors. Thus, a tailored approach that takes into consideration patient risk factors and comorbidities may have additional benefits beyond angina relief. This is a state of the art review of stable angina treatment based on the currently available evidence.

20-Aminosteroids as a novel class of selective and complete androgen receptor antagonists and inhibitors of prostate cancer cell growth.

Here, the synthesis and the evaluation of novel 20-aminosteroids on androgen receptor (AR) activity is reported. Compounds 11 and 18 of the series inhibit both the wild type and the T877A mutant AR-mediated transactivation indicating AR antagonistic function. Interestingly, minor structural changes such as stereoisomers of the amino lactame moiety exhibit preferences for antagonism among wild type and mutant AR. Other tested nuclear receptors are only weakly or not affected. In line with this, the prostate cancer cell growth of androgen-dependent but not of cancer cells lacking expression of the AR is inhibited. Further, the expression of the prostate specific antigen used as a diagnostic marker is also repressed. Finally steroid 18 enhances cellular senescence that might explain in part the growth inhibition mediated by this derivative. Steroids 11 and 18 are the first steroids that act as complete AR antagonists and exhibit AR specificity.

Should we measure routinely oxidised and atherogenic dense low-density lipoproteins in subjects with type 2 diabetes?

Beyond low-density lipoprotein (LDL)-cholesterol concentrations, in recent years, several clinical studies have shown that both oxidised and small, dense LDL have a strong predictive role for the presence of vascular atherosclerosis. These two lipid parameters seem to have a synergistic impact on cardiovascular risk, with a greater importance in patients at higher-risk, such as those with type-2 diabetes. Increased levels of oxidised and small, dense LDL levels are a feature of diabetic dyslipidaemia, and small, dense LDL have been shown to be a good predictor of future cardiovascular events, at both univariate and multivariate analyses. On the other hand, although the association of oxidised LDL with surrogate markers of atherosclerosis is consistent, the correlation with hard clinical end points seems to be smaller. Yet, measurement of these two lipid parameters has not been widely used in daily practice because of the limited availability of clinical data and methodological problems: lack of availability of easy, cheap and reproducible essays for measurement of oxidised and, particularly, small, dense LDL has reduced their assessment in large clinical end-points trials. However, on the basis of available data, the therapeutic modulation of small, dense LDL is significantly associated with reduced cardiovascular risk, even after adjustment for confounding factors. In conclusion, the routine measurement of oxidised and small, dense LDL in patients with type-2 diabetes cannot be recommended in daily clinical practice so far; yet, their measurement is strongly encouraged to better understand their role on the cardiovascular risk of patients with type-2 diabetes.

The ESC 2019 CCS guidelines: Have we left our patients and scientific evidence behind?

The ESC CCS 2019 guidelines recognize that successful management of anginal symptoms relies on effective therapy tailored to individual patient characteristics but do not provide any specific advice or clarity on how to utilize pharmacotherapy in order to achieve these goals. In this review, we are going to summarize and discuss the main points of disagreement.