[Angioplasty with ductal stent: experience at Garrahan Hospital]. / Angioplastia con stent ductal: experiencia en el Hospital Garrahan.

Objective: To describe and evaluate the outcomes of ductal angioplasty with stent placement at a single high-complexity center during the period 2016-2022. Method: A retrospective descriptive cross-sectional study was conducted, including patients under 3 months of age who underwent ductal stent implantation as initial palliative treatment. Demographic, clinical, and anatomical data were collected before the intervention. Mortality, intra- and post-procedural complications, need for re-intervention, intensive care requirements, and hospital stay were recorded. The characteristics at the time of definitive surgery are described. Discrete variables are presented as percentages, and continuous variables are presented with their medians and respective interquartile ranges. Results: Twenty patients who underwent this treatment were reviewed, revealing a success rate of 80%. Complications due to stent dysfunction required surgical resolution. 95% of patients were dischargedfrom the institution after the procedure, and 17 patients reached a second definitive surgical stage. Three patients died afterthe procedure, but with no direct relation to it. Conclusions: Indications for ductal angioplasty with stent as an alternative treatment to systemic-pulmonary anastomosis by surgery are not yet fully defined; the strategy represents a valid alternative in appropriately selected patients. The presented experience shows results similar to international reference centers.

Objetivo: Describir y evaluar los resultados de la angioplastia con stent ductal en un único centro de alta complejidad durante el periodo 2016-2022. Método: Estudio descriptivo retrospectivo de corte transversal en el que se incluyeron pacientes menores de 3 meses a quienes se implantó un stent en el conducto arterioso como tratamiento paliativo inicial. Se recolectaron datos demográficos, clínicos y anatómicos previos a la intervención. Se registraron la mortalidad, las complicaciones intra- y posprocedimiento, la necesidad de reintervención, los requerimientos de cuidados intensivos y la estadía hospitalaria. Se describen las características al momento de la cirugía definitiva. Las variables discretas son presentadas con porcentajes, y las variables continuas con sus medianas y sus respectivos intervalos intercuartílicos. Resultados: Se revisaron 20 pacientes que habían recibido este tratamiento y se evidenció una tasa de éxito del 80%. Las complicaciones por disfunción del stent requirieron resolución quirúrgica. Egresaron de la institución el 95% de los pacientes luego del procedimiento y lograron arribar a un segundo estadio quirúrgico definitivo 17 pacientes. Fallecieron tres pacientes luego del procedimiento, pero sin relación directa con este. Conclusiones: Las indicaciones de angioplastia del conducto con stent como tratamiento alternativo a la realización de una anastomosis sistémico-pulmonar por cirugía todavía no están completamente definidas; la estrategia constituye una alternativa válida en pacientes adecuadamente seleccionados. La experiencia presentada muestra resultados similares a los de otros centros de referencia internacional.

Mesenteric artery smooth muscle cells from hypertensive rats have increased microtubule acetylation.

The dynamic nature of the microtubule network is dependent in part by post-translational modifications (PTMs) - particularly through acetylation, which stabilizes the microtubule network. Whether PTMs of the microtubule network in vascular smooth muscle cells (VSMCs) contribute to the pathophysiology of hypertension is unknown. The aim of this study was to determine the acetylated state of the microtubule network in the mesenteric arteries of spontaneously hypertensive rats (SHR). Experiments were performed on male normotensive rats and SHR mesenteric arteries. Western blotting and mass spectrometry determined changes in tubulin acetylation. Wire myography was used to investigate the effect of tubacin on isoprenaline-mediated vasorelaxations. Isolated cells from normotensive rats were used for scanning ion conductance microscopy (SICM). Mass spectrometry and Western blotting showed that tubulin acetylation is increased in the mesenteric arteries of the SHR compared with normotensive rats. Tubacin enhanced the ß-adrenoceptor-mediated vasodilatation by isoprenaline when the endothelium was intact, but attenuated relaxations when the endothelium was denuded or nitric oxide production was inhibited. By pre-treating vessels with colchicine to disrupt the microtubule network, we were able to confirm that the effects of tubacin were microtubule-dependent. Using SICM, we examined the cell surface Young's modulus of VSMCs, but found no difference in control, tubacin-treated, or taxol-treated cells. Acetylation of tubulin at Lys40 is elevated in mesenteric arteries from the SHR. Furthermore, this study shows that tubacin has an endothelial-dependent bimodal effect on isoprenaline-mediated vasorelaxation.

Microtubule-Mediated Regulation of ß2AR Translation and Function in Failing Hearts.

BACKGROUND: ß1AR (beta-1 adrenergic receptor) and ß2AR (beta-2 adrenergic receptor)-mediated cyclic adenosine monophosphate signaling has distinct effects on cardiac function and heart failure progression. However, the mechanism regulating spatial localization and functional compartmentation of cardiac ß-ARs remains elusive. Emerging evidence suggests that microtubule-dependent trafficking of mRNP (messenger ribonucleoprotein) and localized protein translation modulates protein compartmentation in cardiomyocytes. We hypothesized that ß-AR compartmentation in cardiomyocytes is accomplished by selective trafficking of its mRNAs and localized translation. METHODS: The localization pattern of ß-AR mRNA was investigated using single molecule fluorescence in situ hybridization and subcellular nanobiopsy in rat cardiomyocytes. The role of microtubule on ß-AR mRNA localization was studied using vinblastine, and its effect on receptor localization and function was evaluated with immunofluorescent and high-throughput Förster resonance energy transfer microscopy. An mRNA protein co-detection assay identified plausible ß-AR translation sites in cardiomyocytes. The mechanism by which ß-AR mRNA is redistributed post-heart failure was elucidated by single molecule fluorescence in situ hybridization, nanobiopsy, and high-throughput Förster resonance energy transfer microscopy on 16 weeks post-myocardial infarction and detubulated cardiomyocytes. RESULTS: ß1AR and ß2AR mRNAs show differential localization in cardiomyocytes, with ß1AR found in the perinuclear region and ß2AR showing diffuse distribution throughout the cell. Disruption of microtubules induces a shift of ß2AR transcripts toward the perinuclear region. The close proximity between ß2AR transcripts and translated proteins suggests that the translation process occurs in specialized, precisely defined cellular compartments. Redistribution of ß2AR transcripts is microtubule-dependent, as microtubule depolymerization markedly reduces the number of functional receptors on the membrane. In failing hearts, both ß1AR and ß2AR mRNAs are redistributed toward the cell periphery, similar to what is seen in cardiomyocytes undergoing drug-induced detubulation. This suggests that t-tubule remodeling contributes to ß-AR mRNA redistribution and impaired ß2AR function in failing hearts. CONCLUSIONS: Asymmetrical microtubule-dependent trafficking dictates differential ß1AR and ß2AR localization in healthy cardiomyocyte microtubules, underlying the distinctive compartmentation of the 2 ß-ARs on the plasma membrane. The localization pattern is altered post-myocardial infarction, resulting from transverse tubule remodeling, leading to distorted ß2AR-mediated cyclic adenosine monophosphate signaling.

Antioxidant Properties and Secondary Metabolites Profile of Hyptis colombiana at Various Phenological Stages.

Hyptis colombiana (Lamiaceae family), a species also treated as Cantinoa colombiana in a recently segregated genus from Hyptis, is a perennial herb or subshrub native to the Andes of northern South America. H. colombiana leaves are commonly used in traditional medicine to treat respiratory and digestive illnesses. In this study, H. colombiana plants at different phenological stages (vegetative, flowering, and post-flowering) were harvested to obtain essential oils (EOs) and extracts (from fresh plant materials or post-distillation waste) whose chemical compositions and antioxidant activities were determined. H. colombiana EOs distilled by microwave-assisted hydrodistillation were analyzed by GC/MS/FID, and hydroalcoholic extracts obtained from fresh plant materials or post-distillation waste were analyzed by UHPLC-ESI+/--Orbitrap-MS. The antioxidant activity was evaluated by the ABTS+• and ORAC assays. The principal compounds found in EOs were sesquiterpene hydrocarbons (65%); specifically, (E)-ß-caryophyllene and germacrene D. Pyranone, rosmarinic acid, rutin, and p-hydroxybenzoic acid were the main constituents in H. colombiana extracts. After analyzing the chemical composition and antioxidant activity (ORAC) of EOs and hydroethanolic extracts from flowering H. colombiana plants, minimal variations were found. It is advisable to harvest H. colombiana plants during their flowering stage to acquire EOs and extracts that can be utilized in the agro-industry of EOs and their natural derivatives.

Functional LTCC-ß2AR Complex Needs Caveolin-3 and Is Disrupted in Heart Failure.

BACKGROUND: Beta-2 adrenergic receptors (ß2ARs) but not beta-2 adrenergic receptors (ß1ARs) form a functional complex with L-type Ca2+ channels (LTCCs) on the cardiomyocyte membrane. However, how microdomain localization in the plasma membrane affects the function of these complexes is unknown. We aim to study the coupling between LTCC and ß adrenergic receptors in different cardiomyocyte microdomains, the distinct involvement of PKA and CAMKII (Ca2+/calmodulin-dependent protein kinase II) and explore how this functional complex is disrupted in heart failure. METHODS: Global signaling between LTCCs and ß adrenergic receptors was assessed with whole-cell current recordings and western blot analysis. Super-resolution scanning patch-clamp was used to explore the local coupling between single LTCCs and ß1AR or ß2AR in different membrane microdomains in control and failing cardiomyocytes. RESULTS: LTCC open probability (Po) showed an increase from 0.054±0.003 to 0.092±0.008 when ß2AR was locally stimulated in the proximity of the channel (<350 nm) in the transverse tubule microdomain. In failing cardiomyocytes, from both rodents and humans, this transverse tubule coupling between LTCC and ß2AR was lost. Interestingly, local stimulation of ß1AR did not elicit any change in the Po of LTCCs, indicating a lack of proximal functional interaction between the two, but we confirmed a general activation of LTCC via ß1AR. By using blockers of PKA and CaMKII and a Caveolin-3-knockout mouse model, we conclude that the ß2AR-LTCC regulation requires the presence of caveolin-3 and the activation of the CaMKII pathway. By contrast, at a cellular "global" level PKA plays a major role downstream ß1AR and results in an increase in LTCC current. CONCLUSIONS: Regulation of the LTCC activity by proximity coupling mechanisms occurs only via ß2AR, but not ß1AR. This may explain how ß2ARs tune the response of LTCCs to adrenergic stimulation in healthy conditions. This coupling is lost in heart failure; restoring it could improve the adrenergic response of failing cardiomyocytes.

Chemical Composition and In Vitro Antioxidant Activity of Salvia aratocensis (Lamiaceae) Essential Oils and Extracts.

Salvia aratocensis (Lamiaceae) is an endemic shrub from the Chicamocha River Canyon in Santander (Colombia). Its essential oil (EO) was distilled from the aerial parts of the plant via steam distillation and microwave-assisted hydrodistillation and analyzed using GC/MS and GC/FID. Hydroethanolic extracts were isolated from dry plants before distillation and from the residual plant material after distillation. The extracts were characterized via UHPLC-ESI(+/-)-Orbitrap-HRMS. The S. aratocensis essential oil was rich in oxygenated sesquiterpenes (60-69%) and presented τ-cadinol (44-48%) and 1,10-di-epi-cubenol (21-24%) as its major components. The in vitro antioxidant activity of the EOs, measured via an ABTS+• assay, was 32-49 µmol Trolox® g-1 and that measured using the ORAC assay was 1520-1610 µmol Trolox® g-1. Ursolic acid (28.9-39.8 mg g-1) and luteolin-7-O-glucuronide (1.16-25.3 mg g-1) were the major S. aratocensis extract constituents. The antioxidant activity of the S. aratocensis extract, obtained from undistilled plant material, was higher (82 ± 4 µmol Trolox® g-1, ABTS+•; 1300 ± 14 µmol Trolox® g-1, ORAC) than that of the extracts obtained from the residual plant material (51-73 µmol Trolox® g-1, ABTS+•; 752-1205 µmol Trolox® g-1, ORAC). S. aratocensis EO and extract had higher ORAC antioxidant capacity than the reference substances butyl hydroxy toluene (98 µmol Trolox® g-1) and α-tocopherol (450 µmol Trolox® g-1). S. aratocensis EOs and extracts have the potential to be used as natural antioxidants for cosmetics and pharmaceutical products.

Recent advances in the production of oligogalacturonides and their biological properties.

The human population is becoming old and ageing, which is related to a variety of health issues, such as Alzheimers disease, obesity, diabetes, hypercholesterolemia, and some types of cancers like colorectal cancer. Furthermore, diet is a determining factor in the appearance of some of these diseases due to its direct effect at the systemic level (for instance, increase in glucose and LDL-cholesterol levels in the serum) and its influence on the composition and activity of the gut microbiota. In this context, the use of functional ingredients can be a useful strategy to prevent or even treat (in combination with drugs) some of the above-mentioned pathologies. Among the variety of functional ingredients, prebiotics have received significant attention by the scientific community. Although the already commercialized FOS are the most studied prebiotics, some efforts have been devoted to the search and evaluation of new prebiotic candidates with additional properties. In particular, in the last decade, a variety of in vitro and in vivo assays have been carried out using well isolated and characterized oligogalacturonides, demonstrating that some of them have interesting biological properties, including anticancer, antioxidant, antilipidemic, anti-obesity and anti-inflammatory activities besides prebiotic effects. This work reviews the scientific literature published recently on the production of oligogalacturonides with a special focus on their biological properties.

A journey across dopamine Metabolism: A rotational study of DOPAC.

DOPAC, a relevant scaffold in dopamine metabolism, was probed in the gas phase and interrogated by high-resolution rotational spectroscopy. Herein, three distinct conformers were isolated in a supersonic jet and identified for the first time through an examination of the trend of the rotational constants and the dipole moment selection rules. Additionally, we examined the plausible relaxation pathways of the low-energy conformers of DOPAC, which helped us to claim the indirect detection of two additional conformers, providing conclusive experimental evidence of the flexible nature of this biomolecule. The current investigation sheds some light on the differences between jet-cooled rotational experiments and matrix-isolation infrared spectroscopy.

GPER limits adverse changes to Ca2+ signalling and arrhythmogenic activity in ovariectomised guinea pig cardiomyocytes.

Background: The increased risk of post-menopausal women developing abnormalities of heart function emphasises the requirement to understand the effect of declining oestrogen levels on cardiac electrophysiology and structure, and investigate possible therapeutic targets, namely the G protein-coupled oestrogen receptor 1 (GPER). Methods: Female guinea pigs underwent sham or ovariectomy (OVx) surgeries. Cardiomyocytes were isolated 150-days post-operatively. Membrane structure was assessed using di-8-ANEPPs staining and scanning ion conductance microscopy. Imunnohistochemistry (IHC) determined the localisation of oestrogen receptors. The effect of GPER activation on excitation-contraction coupling mechanisms were assessed using electrophysiological and fluorescence techniques. Downstream signalling proteins were investigated by western blot. Results: IHC staining confirmed the presence of nuclear oestrogen receptors and GPER, the latter prominently localised to the peri-nuclear region and having a clear striated pattern elsewhere in the cells. Following OVx, GPER expression increased and its activation reduced Ca2+ transient amplitude (by 40%) and sarcomere shortening (by 32%). In these cells, GPER activation reduced abnormal spontaneous Ca2+ activity, shortened action potential duration and limited drug-induced early after-depolarisation formation. Conclusion: In an animal species with comparable steroidogenesis and cardiac physiology to humans, we show the expression and localisation of all three oestrogen receptors in cardiac myocytes. We found that following oestrogen withdrawal, GPER expression increased and its activation limited arrhythmogenic behaviours in this low oestrogen state, indicating a potential cardioprotective role of this receptor in post-menopausal women.

The Nicotinic Agonist Cytisine: The Role of the NH···N Interaction.

We report a detailed structural study of cytisine, an alkaloid used to help with smoking cessation, looking forward to unveiling its role as a nicotinic agonist. High-resolution rotational spectroscopy has allowed us to characterize two different conformers exhibiting axial and equatorial arrangements of the piperidinic NH group. Unexpectedly, the axial form has been found as the predominant configuration, in contrast to that observed for related molecules, such as piperidine. This anomalous behavior has been justified in terms of an intramolecular NH···N hydrogen bond. Moreover, this interaction justifies the overstabilization of the axial conformer over the equatorial one and is crucial for the mechanism of action of cytisine over the nicotinic receptor, further rationalizing its behavior as a nicotinic agonist.

Unbiased disentanglement of conformational baths with the help of microwave spectroscopy, quantum chemistry, and artificial intelligence: The puzzling case of homocysteine.

An integrated experimental-computational strategy for the accurate characterization of the conformational landscape of flexible biomolecule building blocks is proposed. This is based on the combination of rotational spectroscopy with quantum-chemical computations guided by artificial intelligence tools. The first step of the strategy is the conformer search and relative stability evaluation performed by means of an evolutionary algorithm. In this step, last generation semiempirical methods are exploited together with hybrid and double-hybrid density functionals. Next, the barriers ruling the interconversion between the low-lying conformers are evaluated in order to unravel the possible fast relaxation paths. The relative stabilities and spectroscopic parameters of the "surviving" conformers are then refined using state-of-the-art composite schemes. The reliability of the computational procedure is further improved by the inclusion of vibrational and thermal effects. The final step of the strategy is the comparison between experiment and theory without any ad hoc adjustment, which allows an unbiased assignment of the spectroscopic features in terms of different conformers and their spectroscopic parameters. The proposed approach has been tested and validated for homocysteine, a highly flexible non-proteinogenic α-amino acid. The synergism of the integrated strategy allowed for the characterization of five conformers stabilized by bifurcated N-H2⋯O=C hydrogen bonds, together with an additional conformer involving a more conventional HN⋯H-O hydrogen bond. The stability order estimated from the experimental intensities as well as the number and type of conformers observed in the gas phase are in full agreement with the theoretical predictions. Analogously, a good match has been found for the spectroscopic parameters.

Rotational Spectrum and Conformational Analysis of Perillartine: Insights into the Structure-Sweetness Relationship.

We used high-resolution rotational spectroscopy coupled to a laser ablation source to study the conformational panorama of perillartine, a solid synthetic sweetener. Four conformers were identified under the isolation conditions of the supersonic expansion, showing that all of them present an E configuration of the C=N group with respect to the double bond of the ring. The observed structures were verified against Shallenberger-Acree-Kier's sweetness theory to shed light on the structure-sweetness relationship for this particular oxime, highlighting a deluge of possibilities to bind the receptor.

Shape-Shifting Molecules: Unveiling the Valence Tautomerism Phenomena in Bare Barbaralones.

We report a state-of-the-art spectroscopic study of an archetypical barbaralone, conclusively revealing the valence tautomerism phenomena for this bistable molecular system. The two distinct 1- and 5-substituted valence tautomers have been isolated in a supersonic expansion for the first time and successfully characterized by high-resolution rotational spectroscopy. This work provides irrefutable experimental evidence of the [3,3]-rearrangement in barbaralones and highlights the use of rotational spectroscopy to analyze shape-shifting mixtures. Moreover, this observation opens the window toward the characterization of new fluxional systems in the isolation conditions of the gas phase and should serve as a reference point in the general understanding of valence tautomerism.

Unleashing the shape of L-DOPA at last.

Herein, we report the first rotational study of neutral L-DOPA, an extensively used supramolecular synthon and an amino acid precursor of the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) using broadband and narrowband Fourier transform microwave spectroscopies coupled with a laser ablation vaporization system. The spectroscopic parameters derived from the analysis of the rotational spectrum conclusively identify the existence of four distinct conformers of L-DOPA in the supersonic jet, further rejecting the previously reported catechol ring-induced conformational restriction. The analysis of the 14N nuclear quadrupole coupling hyperfine structure further revealed the orientation of the N-bearing functional group, proving the existence of stabilizing N-H⋯π interactions for the observed structures.

Laboratory Detection of Cyanoacetic Acid: A Jet-Cooled Rotational Study.

Herein we present a laboratory rotational study of cyanoacetic acid (CH2(CN)C(O)OH), an organic acid as well as a -CN bearing molecule, that is a candidate molecular system to be detected in the interstellar medium (ISM). Our investigation aims to provide direct experimental frequencies of cyanoacetic acid to guide its eventual astronomical search in low-frequency surveys. Using different jet-cooled rotational spectroscopic techniques in the time domain, we have determined a precise set of the relevant rotational spectroscopic constants, including the 14N nuclear quadrupole coupling constants for the two distinct structures, cis- and gauche- cyanoacetic acid. We believe this work will potentially allow the detection of cyanoacetic acid in the interstellar medium, whose rotational features have remained unknown until now.

Use of hem-o-lok clips for laparoscopic appendectomy in children: retrospective analysis and comparison to ligature loop and endoscopic surgical stapler.

BACKGROUND: There are multiple techniques used for laparoscopic appendectomy (LA): ligature loop (LL), surgical stapler (SS) (Endopath Ets-Flex-Endoscopic Articulating Linear Cutter 33 mm Standard Ref Atb 35. Ethicon, Somerville, New Jersey, US), and hem-o-lok clips (HOL) (Weck Closure System. Triangle Park, NC, USA). The application of the LL usually demands dexterity and training, whilst using HOL may be more advantageous due to its simplicity in terms of application and its low cost in contrast with the SS. The objective of this study is to determine safety and efficacy of the different devices that can be used in the surgical procedure. METHODS: From June 2016 to December 2019, 253 consecutive children aged to 1 to 18 years were retrospectively reviewed. They were divided into three groups depending on the device used to secure the appendix: (I) in the first group, the base of the appendix was secured by double LL, (II) in the second group the base of the appendix was secured with SS, and (III) in the third group the base of the appendix was secured with two non-absorbable HOL. The data collected includes age, gender, operative time, device used to ligate the base of the appendix, previous tests (blood analysis, imaging), antibiotic prophylaxis administered, length of hospital stay, intraoperative and postoperative complications, shoulder pain and histological study of the specimen. RESULTS: There were 253 patients that underwent laparoscopic appendectomy during the study time, with a mean age of 10.3±4.1 in the LL group, 9.4±2.7 in the SS group and 10.4±3.3 in the HOL group, P=0.165. Distribution by gender was 77.8% for males in the LL group, 65.2% in the SS group and 61.3% in the HOL group, P=0.559. The mean surgical time with IQR in brackets was 60.0 (10.0) minutes (min), in the first group in which the base of the appendix was secured with LL, in the second group in which the base of the appendix was secured with SS 60.0 (15.0) min and finally in the third in which the base of the appendix was secured with HOL 40.0 (30.0) min, P<0.001. HOL clips have a significantly lower cost than their analogues. Specifically, 5 HOL clips have a cost of EUR 26.75, while three LL have a cost of EUR 53.70 and a single SS has a cost of EUR 276.58. Postoperative complications were found in 14.3% of the LL group, 9.8% in the SS group and 4.6% in the HOL group, P=0.137. Efficacy and safety in controlling the base of appendix were the same in all groups. CONCLUSIONS: The HOL are safe and reduce surgical costs during laparoscopic appendectomy in children.

Looking for the Elusive Imine Tautomer of Creatinine: Different States of Aggregation Studied by Quantum Chemistry and Molecular Spectroscopy.

New spectroscopic experiments and state-of-the-art quantum-chemical computations of creatinine in different aggregation states unequivocally unveiled a significant tuning of tautomeric equilibrium by the environment: from the exclusive presence of the amine tautomer in the solid state and aqueous solution to a mixture of amine and imine tautomers in the gas phase. Quantum-chemical calculations predict the amine species as the most stable tautomer by about 30 kJ mol-1 in condensed phases. On the contrary, moving to the isolated forms, both Z and E imine isomers become more stable by about 7 kJ mol-1 . Since the imine isomers and one amine tautomer are separated by significant energy barriers, all of them should be present in the gas phase. This prediction has indeed been confirmed by high-resolution rotational spectroscopy, which provides the first experimental characterization of the elusive imine tautomer. The interpretation of the complicated hyperfine structure of the rotational spectrum, originated by three 14 N nuclei, makes it possible to use the spectral signatures as a sort of fingerprint for each individual tautomer in the complex sample.

Shape of Testosterone.

We have successfully characterized the structure of testosterone, one of the essential steroids, through high-resolution rotational spectroscopy. A single conformer has been detected, and a total of 404 transitions have been fitted, allowing a precise determination of the rotational constants. It allowed us to unravel that the isolated structure of testosterone adopts an extended disposition. The results obtained in this work highlight how using laser ablation techniques in combination with Fourier transform microwave techniques allow the study of large biomolecules or common pharmaceuticals. It is an important step toward studying relevant biomolecules and developing new analytical techniques with unprecedented sensitivity and resolution.

Pembrolizumab plus eribulin in hormone-receptor-positive, HER2-negative, locally recurrent or metastatic breast cancer (KELLY): An open-label, multicentre, single-arm, phase â ¡ trial.

BACKGROUND: Pembrolizumab has modest activity if used in patients with hormone-receptor-positive (HR+), HER2-negative, previously treated metastatic breast cancer (BC). Our study investigated whether there would be any clinical benefit in combining chemotherapy with pembrolizumab in a similar patient population. METHODS: This single-arm, phase Ⅱ trial enrolled women aged ≥18 years with HR+, HER2-negative, inoperable, locally recurrent or metastatic BC. Patients were previously treated with hormonal therapy and 1-2 chemotherapy regimens for locally recurrent and/or metastatic BC. On each 21-day cycle, patients received intravenous pembrolizumab 200 mg on day 1 and eribulin 1∙23 mg/m2 on days 1 and 8. The primary endpoint was the clinical benefit rate. Analysis of safety and activity was carried out in all patients who met the screening criteria and received at least 1 dose of study treatment. The trial is registered at ClinicalTrials.gov, NCT03222856. RESULTS: Of the 44 patients enrolled between January 29 and October 17, 2018, clinical benefit was achieved in 25 (56∙8%, 95% confidence interval [CI]: 41∙0-71∙7), objective response in 18 (40∙9%, 95% CI: 26∙3-56∙8), median progression-free survival was 6∙0 months (95% CI: 3∙7-8∙4), and 1-year overall survival was 59∙1% (95% CI: 45∙8-76∙2). The most common treatment-emergent adverse events (AEs) of any grade were neutropenia (20 [45∙5%]), anaemia (17 [38∙6%]), alopecia (19 [43∙2%]), asthenia (19 [43∙2%]), diarrhoea (14 [31∙8%]), fatigue (14 [31∙8%]), and peripheral neuropathy (12 [27∙3%]). Serious AEs occurred in 14 (31∙8%) patients including febrile neutropenia (3 [6∙8%]), neutropenia (2 [4∙5%]), fever (2 [4∙5%]) and peripheral neuropathy (2 [4∙5%]). Immune-related AEs occurred in 11 (25∙0%) patients. One (2∙3%) patient died of cardiac arrest unrelated to study treatment. CONCLUSION: Pembrolizumab plus eribulin demonstrates encouraging antitumour activity in patients with heavily pre-treated, HR+, HER2-negative, locally recurrent or metastatic BC. The safety and tolerability of the combination is similar to eribulin or pembrolizumab monotherapy.

Exploring the Maze of Cycloserine Conformers in the Gas Phase Guided by Microwave Spectroscopy and Quantum Chemistry.

Cycloserine has in common with isoxazolidines the saturated five-membered ring, which is an important scaffold for drug design, exhibiting diverse biological activities. The most remarkable feature of these compounds is the presence of the N-O bond framed in a cyclic moiety. The lack of an accurate characterization of this structural feature in an isolated system calls for a state-of-the-art theoretical-experimental study. A quantum-chemical investigation of cycloserine unveiled the presence of 11 local energy minima, with only two of them being separated by significant barriers. This picture has been experimentally confirmed: two species have been unequivocally detected in the gas phase by means of laser ablation microwave spectroscopy, also disentangling the complicated hyperfine structure originating from the presence of two nitrogen atoms. A thorough characterization of cycloserine and isoxazolidine, benchmarked by the semiexperimental investigation of hydroxylamine, provided the first accurate determination of their structures and pointed out that the rev-DSD-PBEP86 functional is competitive with respect to explicitly correlated coupled-cluster computations. This outcome paves the way toward accurate studies of large flexible molecules.