Search

Background: Triple negative breast cancer (TNBC) is well known for its more aggressive course and poorer prognosis compared to other BC subtypes. RegistEM study provides real world data to understand the distribution of BC subtypes in the advanced setting, being its primary objective. Biological samples collection is part of its procedures. This is a non-interventional cohort study and 1,907 patients (pts) have been enrolled up to now (females and males) with advanced BC (ABC), diagnosed from Jan-2016 to Dec-2019, either after recurrence or as first BC diagnosis, in 38 Spanish sites. These pts will be followed for at least 5 years. Methods: In the current analysis (cut-off date 08/April/2022, database ongoing), we describe characteristics, treatment patterns and outcomes, including comparison between recurrent and de novo disease, of 157 pts with advanced TNBC included in the RegistEM study. Those pts represent the 10% of pts available in the database at the cut-off date and with ABC diagnosis up to December 2018 (n=1559). The BC clinical subtypes were histologically confirmed on the most recent tumor lesion (metastatic [M] or primary BC) before starting with the 1st-line therapy. Results: At first ABC diagnosis, 73% pts had recurrent early BC (EBC), 26% de novo MBC and 1% unresectable locally ABC (ULABC). Median age was 57 years (range 30-88), all pts were women, 98% Caucasian and 65% postmenopausal. Family history of BC and/or ovarian cancer was reported in 37% pts, and a hereditary-risk genetic test was performed in 59 of 147 pts. Germline BRCA1/2 and TP53 were the most frequently mutated genes, 21% (6/28) and 47% (8/17) pts, respectively. Visceral involvement was present in 69% pts (similar between recurrent EBC and de novo ABC, although brain metastases were only present in the recurrent EBC group), and ≤ 2 metastatic locations in 59%. In 61% (70/115) pts with recurrent EBC, the subtype was assessed in metastatic lesions, and 39 pts of them also had TN subtype in primary BC. In terms of the most frequent therapies by line: 1) 1st-line: chemotherapy (CT) (60%) and CT/biological therapy (BT) (39%). Of the 87 pts with CT alone, monotherapy was the preferred option in 57% pts (capecitabine 25%, taxanes 16%, and eribulin or vinorelbine, 5% each). Bevacizumab was the most frequent BT (79%) combined with CT (single agent in 56% pts, mostly taxanes and capecitabine). Progressive disease (PD) was reported in 85% pts (similar in pts with both recurrent and de novo MBC or ULABC); 2) 2nd-line: CT (79%) (monotherapy capecitabine, eribulin, taxanes) and CT/BT (17%) (CT-containing bevacizumab 82%). Progression was reported in 92% pts; 3) 3rd-line: CT (90%) (eribulin 33%, platinum-based 25%) and CT/BT (9%) (CT-containing bevacizumab 67%). Progression was reported in 88% pts. At database cut-off date, death was reported in 133 (85%) pts, mainly because of PD. Overall survival (OS) was similar between both groups, recurrent and de novo MBC. Conclusion: In this population of Spanish TNBC pts with ABC, three quarters had recurrent disease. De novo ABC pts had a higher proportion of non-visceral metastases, with absence of brain involvement at the first diagnosis. Single-agent CT and CT plus bevacizumab were the most frequent therapies, and OS was similar between recurrent and de novo MBC pts, although numerically higher in the later group. Citation Format: Silvia Antolin Novoa, César A Rodríguez, Josefina Cruz, Sara López-Tarruella, Ariadna Tibau, Encarna Adrover, Ana Miguel, Mireia Margelí, Purificación Martínez, María Hernández, Antonio Antón, Álvaro Rodríguez-Lescure, Catalina Falo, Isabel Álvarez, Diego Malón, Raquel Andrés, José L Alonso-Romero, César Gómez, J. José Illaramendi, Ruth Campo, Juan José Miralles, Susana Bezares, Federico Rojo, Angel Guerrero-Zotano. Treatment strategies for advanced triple negative breast cancer patients as per routine clinical practice: analysis from the observational study GEICAM/2014-03 (RegistEM) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-45.

The human population is becoming old and ageing, which is related to a variety of health issues, such as Alzheimer's disease, obesity, diabetes, hypercholesterolemia, and some types of cancers like colorectal cancer.

The reaction force profile and the electronic reaction flux concepts were explored for the herbicide alloxydim and some of its derivatives at B3LYP/6-311G(d,p) level of theory. The exploration was achieved by rotating the oxime bond which is the most reactive region of the molecule. The main objective is to understand how the rotation of this bond influences the properties of the molecule and induces an electronic reorganization. The results show that the rotation of the dihedral angle triggers alloxydim to go through three transition states. The first step of the transformation begins by the rupture of the hydrogen bond and is characterized by a pronounced structural reorganization. In the last step of the process the electronic reorganization is more important.

Producción Científica, 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., Ministerio de Ciencia, Innovación y Universidades (project PID2019-111396GB-I00), Junta de Castilla y León (project VA244P20), European Research Council under the European Union’s Seventh Framework Programme (FP/2007- 2013)/ERC-2013-SyG (grant 610256 NANOCOSMOS)

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 14N nuclei, makes it possible to use the spectral signatures as a sort of fingerprint for each individual tautomer in the complex sample., A journey among the aggregation states of a key biomolecule, creatinine, is reported, guided by state‐of‐the‐art quantum‐chemical computations and spectroscopic techniques. The fine tuning of the creatinine tautomeric equilibrium by different environments is unveiled and fully understood by vis‐à‐vis comparison between simulated and experimental signatures.

Producción Científica, The unbiased, naked structures of tartaric acid, one of the most important organic compounds existing in nature and a candidate to be present in the interstellar medium, has been revealed in this work for the first time. Solid samples of its naturally occurring (R,R) enantiomer have been vaporized by laser ablation, expanded in a supersonic jet, and characterized by Fourier transform microwave spectroscopy. In the isolation conditions of the jet, we have discovered up to five different structures stabilized by intramolecular hydrogen-bond networks dominated by O−H⋅⋅⋅O=C and O−H⋅⋅⋅O motifs extended along the entire molecule. These five forms, two with an extended (trans) disposition of the carbon chain and three with a bent (gauche) disposition, can serve as a basis to represent the shape of tartaric acid. This work also reports the first set of spectroscopy data that can be used to detect tartaric acid in the interstellar medium., Ministerio de Ciencia e Innovación (CTQ2016- 76393-P y PID2019-111396GB-I00), Junta de Castilla y León (Subvenciones VA077U16 y VA244P20)

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 alpha-amino acid. The synergism of the integrated strategy allowed for the characterization of five conformers stabilized by bifurcated N-H-2 center dot center dot center dot O=C hydrogen bonds, together with an additional conformer involving a more conventional HN center dot center dot center dot 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.

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., This work has been supported by the Ministerio de Ciencia e Innovación (CTQ2016-76393-P and PID2019-111396GB-I00), Junta de Castilla y León (grants VA077U16 and VA244P20), and the European Research Council ERC-2013-SyG, no. 610256 NANOCOSMOS, MIUR ‘PRIN 2017’ (grant number 2017A4XRCA), and by the Italian Space Agency (ASI; ‘Life in Space’ project, no. 2019-3-U.0). E.R.A. acknowledges the Fundación Biofísica Bizkaia for a postdoctoral grant.

Background: HG is an on-target AE of PI3K inhibition, reported in 63.7% (36.6% G≥3) of HR[+]/HER2[-] ABC patients (pts) treated with ALP plus fulvestrant in SOLAR-1. HG was the most frequent adverse event (AE) leading to ALP discontinuation (6.3%). MET reduces systemic insulin resistance and suppress PI3K and Ras signaling. METALLICA is assessing the prophylactic use of MET for prevention of ALP-induced G3-4 HG in PIK3CA-mutated, HR[+]/HER2[-] ABC pts with normal fasting glycemia or prediabetic criteria. Methods: This is an open-label, single-arm, two-cohort, phase 2 trial. Pts aged ≥18 years, ECOG PS of 0–1, and PIK3CA-mutated, HR[+]/HER2[-] ABC, progressing to an aromatase inhibitor (AI)-containing regimen, ≤2 previous endocrine therapy (ET) and ≤1 prior chemotherapy regimens for ABC were eligible. Pts were enrolled into cohorts according to glycemia at baseline: (A) pts with normal fasting glycemia < 100 mg/dL and glycosylated hemoglobin (HbA1c) < 5.7%; (B) pts with prediabetic fasting glycaemia 100–140 mg/dL and/or HbA1c 5.7–6.4%. Pts received oral ALP 300 mg/day, starting from C1D8, in combination with ET; fulvestrant, letrozole, or exemestane as per standard of care; and oral MET 1000 mg/day on days 1-3 and 2000 mg/day thereafter. The primary endpoint was G3-4 HG incidence as per NCI-CTCAE v.4.03 at 2 first cycles of treatment. Assessment of glycemia was performed by rigorous self-monitoring blood glucose and local laboratory confirmation in fasting conditions. Secondary endpoints included objective response (ORR), clinical benefit rate (CBR), duration of response (DoR), progression-free survival (PFS), and safety. Sample size was based on a Simon’s two-stage design in cohorts A (H0: G3-4 HG ≥25%; H1: G3-4 HG ≤10%) and B (H0: G3-4 HG ≥40%; H1: G3-4 HG ≤15%). We planned to attain 80% power at the nominal one-sided α level of 0.05 for each cohort. Results: Between Aug 30, 2020, and Mar 10, 2022, 68 pts were enrolled at 18 sites (48 cohort A, 20 cohort B). Median age was 55 (range, 29–79) years and 58.8% pts had visceral disease and an ECOG PS 0. A total of 66 (97.1%) pts had been previously treated with a CDK4/6i and 13 (19.2%) pts had received chemotherapy for advanced disease. Sixty-three (92.6%) pts received fulvestrant as ET (45 cohort A, 18 cohort B). With a median follow-up of 8 (range, 1.6–14.9) months, 28 (41.2%) pts remain on study treatment. Disease progression was the main reason for discontinuation, reported in 32 (47.1%) pts. The primary endpoint of the study was reached, with 1 (2.1%) pts (95%CI, 0.8–9.5; p < 0.001) in cohort A and 3 (15%) pts (95%CI, 4.5–33; p = 0.012) in cohort B experiencing a G3-4 HG episode over the 2 first cycles of treatment. For patients on fulvestrant, G3-4 HG rates were 1 pts (2.2%) and 3 (16.7%) pts for cohorts A and B, respectively. No ALP discontinuation related to HG was reported during the first 2 treatment cycles. Median PFS in all patients was 7.4 months (95%CI, 6–NA). Among pts with measurable disease, ORR was 14 (36.8%) pts (95%CI, 21.8–54). At the time of this analysis, DoR and CBR were still immature. The most common AEs were diarrhea (67.6%; 13.2% G≥3), nausea (67.6%; 0% G≥3), and fatigue (45.6%; 2.9% G≥3). Serious AEs occurred in 15 (22.1%) pts. The main serious AEs were rash (2.9% G≥3) and vomiting (1.5% G≥3). No additional pts reported G≥3 HG after the first 2 cycles. The dose of ALP was reduced according to the protocol in 19 (27.9%) pts. Eight (11.8%) pts permanently discontinued ALP due to AEs, none of whom related to HG. No treatment-related deaths were reported. Conclusions: Prophylactic use of MET substantially reduced the incidence and severity of ALP-related HG with no additional toxicities and could be a new standard for PIK3CA-mutated, HR[+]/HER2[-] ABC pts receiving ALP plus fulvestrant or other ET. Citation Format: Manuel Ruiz Borrego, Pablo Tolosa, Salvador Blanch, Adela Fernández, Ander Urriticoechea, Isabel Blancas, Cristina Saura, Beatriz Rojas, Begoña Bermejo, Jose Ponce, Maria Gión, Elisenda Llabres, Elena Galve, Juan Fernando Cueva, Ana López, José L Alonso-Romero, Santiago González-Santiago, Eduardo Martínez De Dueñas, Fernando Gomez Peralta, Eva Ciruelos, José Manuel Pérez-García, Antonio Llombart-Cussac, Javier Cortés. Metformin (MET) for the prevention of Alpelisib (ALP)-related Hyperglycemia (HG) in PIK3CA-mutated, Hormone Receptor-Positive (HR[+]) HER2-Negative (HER2[-]) Advanced Breast Cancer (ABC): The METALLICA study. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD8-02.

Glycinamide is considered to be one of the possible precursors of the simplest amino acid glycine. Its only rotational spectrum reported so far has been in the cm-wave region. The aim of this work is to extend its laboratory spectrum into the mm wave region to support its searches in the ISM. Glycinamide was synthesised chemically and was studied with broadband rotational spectroscopy in the 90-329 GHz region. Tunneling across a low energy barrier between two symmetry equivalent configurations of the molecule resulted in splitting of each vibrational state and many perturbations in associated rotational energy levels, requiring careful coupled state fits for each vibrational doublet. We searched for emission of glycinamide in the imaging spectral line survey ReMoCA performed with ALMA toward Sgr B2(N). We report the first analysis of the mm-wave rotational spectrum of glycinamide, resulting in fitting to experimental measurement accuracy of over 1200 transition frequencies for the ground state tunneling doublet, of many lines for tunneling doublets for two singly excited vibrational states, and determination of precise vibrational separation in each doublet. We did not detect emission from glycinamide in the hot core Sgr B2(N1S). We found that glycinamide is at least seven times less abundant than aminoacetonitrile and 1.8 times less abundant than urea in this source. A comparison with results of astrochemical kinetics models for species related to glycinamide suggests that its abundance may be at least one order of magnitude below the upper limit obtained toward Sgr B2(N1S). This means that glycinamide emission in this source likely lies well below the spectral confusion limit in the frequency range covered by the ReMoCA survey. Targetting sources with a lower level of spectral confusion, such as the Galactic Center shocked region G+0.693-0.027, may be a promising avenue. [abridged], Accepted for publication in A&A

BACKGROUND: An earlier analysis of the PEARL phase III study showed that palbociclib plus endocrine therapy (ET) does not improve progression-free survival (PFS) over capecitabine in aromatase inhibitor-resistant, hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) patients. Here, we report the final overall survival (OS) analysis. METHODS: Postmenopausal patients (N = 601) were randomized 1:1 to capecitabine or palbociclib plus ET (exemestane, Cohort 1; fulvestrant, Cohort 2). OS was analysed in Cohort 2, the wild-type ESR1 population and the overall population. Additionally, we analysed subsequent systemic therapies and explored PFS2 (time from randomization to the end of the first subsequent therapy/death). RESULTS: OS was 31.1 months for palbociclib plus fulvestrant and 32.8 months for capecitabine (adjusted hazard ratio [aHR] 1.10, 95% confidence interval [CI] 0.81-1.50, P = 0.550). In the wild-type ESR1 population, OS was 37.2 months for palbociclib plus ET and 34.8 months for capecitabine (aHR 1.06, 95% CI 0.81-1.37, P = 0.683). In OS analyses, no subgroup showed superiority for palbociclib plus ET over capecitabine. OS in the overall population was 32.6 months for palbociclib plus ET and 30.9 months for capecitabine (P = 0.995). Subsequent systemic therapy was given to 79.8% and 82.9% of patients with palbociclib plus ET and capecitabine, respectively. Median PFS2 was similar between study arms (Cohort 2, P = 0.941; wild-type ESR1 population, P = 0.827). No new safety findings were observed. CONCLUSIONS: Palbociclib plus ET did not show a statistically superior OS compared to capecitabine in MBC patients progressing on aromatase inhibitors. TRIAL REGISTRATION: NCT02028507 (ClinTrials.gov), 2013-003170-27 (EudraCT).

Producción Científica, 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., Ministerio de Ciencia e Innovación y Agencia Estatal de Investigación (grants MCIN/A EI/10.13039/ 501100011 033, PID2019-111396GB-I00, PID2019-104815GB-I00, CEX2019-000925-S), Junta de Castilla y Leon (projects VA077U16 and VA244P20), Agencia de Gestión de Ayudas Universitarias y de Investigación y el Programa CERCA/Generalitat de Catalunya de apoyo financiero (2017 SGR 1257), Ministerio de Ciencia, Innovación y Universidades (grant FPU17/02987)

Four conformers of the non-proteinogenic α-amino acid isovaline, vaporized by laser ablation, are characterized by Fourier-transform microwave techniques in a supersonic expansion. The comparison between the experimental rotational and 14 N nuclear quadrupole coupling constants and the ab initio calculated ones provides conclusive evidence for the identification of the conformers. The most stable species is stabilized by an N-H⋅⋅⋅O =C intramolecular hydrogen bond and a cis-COOH interaction, whereas the higher-energy conformers exhibit an N⋅⋅⋅H-O intramolecular hydrogen bond and trans-COOH, as in other aliphatic amino acids. The spectroscopic data herein reported can be used for the astrophysical purpose in a possible detection of isovaline in space.

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

Producción Científica, 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., Ministerio de Ciencia e Innovación (grants CTQ2016-76393-P; PID2019-111396GBI00 and FJC2018-037320-I), Junta de Castilla y León (grants VA077U16 and VA244P2), Consejo Europeo de Investigación (grant 610256 NANOCOSMOS)

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., The authors thank the financial funding from Ministerio de Ciencia e Innovación (CTQ2016-76393-P and PID2019-111396GB-I00), Junta de Castilla y Leon (VA077U16 and VA244P20), and European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC-2013-SyG, grant agreement No. 610256 NANOCOSMOS. E.R.A. thanks Ministerio de Ciencia, Innovacion y Universidades for Juan de la Cierva grant (FJC2018-037320-I). M.S.N. acknowledges funding from the Spanish "Ministerio de Ciencia, Innovacion y Universidades" under predoctoral FPU Grant (FPU17/02987).

We present the first high-resolution rotational study of the artificial sweetener saccharin. By combining laser ablation (LA), narrow- and broadband Fourier transform microwave techniques (FTMW), and supersonic expansions, we have transferred the solid of saccharin (mp 229 °C) to a supersonic jet and captured its rotational spectrum. The rotational constants were accurately determined by fitting more than 60 rotational transitions for the parent and 34S isotopic species in the 6.4-10.4 GHz frequency range. Experiment and complementary quantum-chemical calculations provide accurate geometrical parameters for saccharin, the first artificial sweetener investigated by high-resolution microwave spectroscopy. The detailed structural information extracted from the rotational and 14N nuclear quadrupole coupling constants provided useful data in the context of the old theories of sweetness.

In the course of the investigation of the rotational spectrum of prebiotic hydantoic acid by Fourier transform microwave spectroscopy coupled to a laser ablation source in a supersonic expansion, rotational signatures of two cyclic molecules, hydantoin and 2,5-oxazolidinedione, have been unexpectedly observed along with the four most stable conformers of hydantoic acid. Interestingly, two of them presented folded geometric arrangements that might act as precursors in the cyclization reactions assisted by laser ablation. They could play the role of near-attack conformations (NACs) in the framework of the NAC theory for intramolecular reactions. A detailed analysis of the spectrum further revealed the simultaneous formation of other species in the jet, showing that the laser ablation of solid organic precursors constitutes an alternative tool in the generation of new chemical species.

Numerous studies have suggested that the n→π* interactions between carbonyls could contribute significantly to the stability of proteins. Nevertheless, their evaluation is challenging because of the solvent environment or crystal packing forces in solids. Here we study the rotational spectrum of HGlyProOH dipeptide, a very common sequence found in collagen, the most abundant protein in vertebrates, in isolated conditions. Three different structures are unequivocally characterized in the gas phase. Interestingly, the most abundant structure is stabilized by an n→π* interaction and adopts the same conformation as is found in crystalline collagen. This observation serves to support the importance of the n→π* interactions between carbonyl groups. The n→π* interaction between carbonyls in peptide bonds has been proposed to contribute to protein conformational stability. Here the authors report gas-phase rotational spectroscopy of the glycine-proline dipeptide, revealing that the n→π* interaction stabilizes the trans conformation of the dipeptide with energetics comparable to those of hydrogen bonds.

A gas-phase study on the artificial sweeteners sorbitol and dulcitol has been carried out for the first time by using a combination of chirped-pulse Fourier-transform microwave (CP-FTMW) spectroscopy and laser ablation (LA). The isolation conditions provided by the supersonic expansion reveal the intrinsic conformational structures of these sweeteners. The three and five observed conformers for sorbitol and dulcitol, respectively, are stabilized by networks of cooperative intramolecular hydrogen bonds between vicinal hydroxyl groups in clockwise or counterclockwise arrangements. Suitable places in the structure of seven out of eight conformers identified for both polyalcohols meet the requirements of the glucophore proposed by Shallenberger and Acree's molecular theory of sweet taste. Present results provide the first linkage between sweetness and structure in sugar alcohols.

Producción Científica, Context. Cyanoacetamide is a –CN bearing molecule that is also an amide derivative target molecule in the interstellar medium. Aims. The aim of our investigation is to analyze the feasibility of a plausible formation process of protonated cyanoacetamide under interstellar conditions and to provide direct experimental frequencies of the ground vibrational state of the neutral form in the microwave region in order to enable its eventual identification in the interstellar medium. Methods. We used high-level theoretical computations to study the formation process of protonated cyanoacetamide. Furthermore, we employed a high-resolution laser-ablation molecular beam Fourier transform spectroscopic technique to measure the frequencies of the neutral form. Results. We report the first rotational characterization of cyanoacetamide, and a precise set of the relevant rotational spectroscopic constants have been determined as a first step to identifying the molecule in the interstellar medium. We fully explored the potential energy surface to study a gas-phase reaction on the formation process of protonated cyanoacetamide. We found that an exothermic process with no net activation barrier is initiated by the high-energy isomer of protonated hydroxylamine, which leads to protonated cyanoacetamide., Ministerio de Ciencia, Innovación y Universidades (Project CTQ2016-76393-P), Ministerio de Economía, Industria y Competitividad (Grant AYA2017-87515-P), Junta de Castilla y León (Grants VA077U16 and Grant VA010G18), European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC-2013- SyG, Grant Agreement no. 610 256 NANOCOSMOS

The investigation of the structure of biomolecules and the intramolecular interactions responsible for the stabilization of their preferred conformations is of fundamental importance as the first step to understand their role in the mechanisms of molecular recognition and biochemical function. A thorough understanding of the forces affecting conformational preferences should be built up from the study of the isolated molecule to increasing levels of complexity. In general, large molecules, those of biological importance, have low vapor pressures and tend to undergo thermal reactions and degradation upon heating, making them out of reach for structural studies in the gas phase. Efficient spectroscopic techniques combining laser ablation with Fourier transform microwave spectroscopies in supersonic jets have been developed to overcome the problem. Amino acids, dipeptides, monosaccharides, and other relevant biomolecules have been studied using this experimental approach to extract important structural insights and unveiling the nature of the intramolecular interactions at play.

Arteritis de Takayasu; Tocilizumab; Teràpia biològica Arteritis de Takayasu; Tocilizumab; Terapia biológica Takayasu’s arteritis; Tocilizumab; Biological therapy Objective: To assess the efficacy and safety of tocilizumab (TCZ) in Caucasian patients with refractory Takayasu’s arteritis (TAK) in clinical practice. Methods: A multicenter study of Caucasian patients with refractory TAK who received TCZ. The outcome variables were remission, glucocorticoid-sparing effect, improvement in imaging techniques, and adverse events. A comparative study between patients who received TCZ as monotherapy (TCZMONO) and combined with conventional disease modifying anti-rheumatic drugs (cDMARDs) (TCZCOMBO) was performed. Results: The study comprised 54 patients (46 women/8 men) with a median [interquartile range (IQR)] age of 42.0 (32.5–50.5) years. TCZ was started after a median (IQR) of 12.0 (3.0–31.5) months since TAK diagnosis. Remission was achieved in 12/54 (22.2%), 19/49 (38.8%), 23/44 (52.3%), and 27/36 (75%) patients at 1, 3, 6, and 12 months, respectively. The prednisone dose was reduced from 30.0 mg/day (12.5–50.0) to 5.0 (0.0–5.6) mg/day at 12 months. An improvement in imaging findings was reported in 28 (73.7%) patients after a median (IQR) of 9.0 (6.0–14.0) months. Twenty-three (42.6%) patients were on TCZMONO and 31 (57.4%) on TCZCOMBO: MTX (n = 28), cyclosporine A (n = 2), azathioprine (n = 1). Patients on TCZCOMBO were younger [38.0 (27.0–46.0) versus 45.0 (38.0–57.0)] years; difference (diff) [95% confidence interval (CI) = -7.0 (-17.9, -0.56] with a trend to longer TAK duration [21.0 (6.0–38.0) versus 6.0 (1.0–23.0)] months; diff 95% CI = 15 (-8.9, 35.5), and higher c-reactive protein [2.4 (0.7–5.6) versus 1.3 (0.3–3.3)] mg/dl; diff 95% CI = 1.1 (-0.26, 2.99). Despite these differences, similar outcomes were observed in both groups (log rank p = 0.862). Relevant adverse events were reported in six (11.1%) patients, but only three developed severe events that required TCZ withdrawal. Conclusion: TCZ in monotherapy, or combined with cDMARDs, is effective and safe in patients with refractory TAK of Caucasian origin. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was partially supported by RETICS Programs, RD08/0075 (RIER), RD12/0009/0013 and RD16/0012 from “Instituto de Salud Carlos III” (ISCIII) (Spain). However, this research did not receive any specific grant from funding agencies in the commercial or not-for-profit sectors.

Molecular or condensed matter systems are often well approximated by hybrid quantum-classical models: the electrons retain their quantum character, whereas the ions are considered to be classical particles. We discuss various alternative approaches for the computation of equilibrium (canonical) ensemble averages for observables of these hybrid quantum-classical systems through the use of molecular dynamics (MD), i.e. by performing dynamics in the presence of a thermostat and computing time averages over the trajectories. Often, in classical or ab initio MD, the temperature of the electrons is ignored and they are assumed to remain at the instantaneous ground state given by each ionic configuration during the evolution. Here, however, we discuss the general case that considers both classical and quantum subsystems at finite temperature canonical equilibrium. Inspired by a recent formal derivation for the canonical ensemble for quantum classical hybrids, we discuss previous approaches found in the literature, and provide some new formulas., This is the version of the article before peer review or editing, as submitted by an author to New Journal of Physics. IOP Publishing Ltd is not responsible for any errors or omissions in this version of the manuscript or any version derived from it. The Version of Record is available online at https://doi.org/10.1088/1367-2630/abf9b3

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.

11 pags., 5 figs., 3 tabs., A dual microwave and optical spectroscopic study of a capped cysteine amino acid isolated in a supersonic expansion, combined with quantum chemistry modelling, enabled us to characterize the conformational preferences of Cys embedded in a protein chain. IR/UV double resonance spectroscopy provided evidence for the coexistence of two conformers, assigned to folded and extended backbones (with classical C7 and C5 backbone H-bonding respectively), each of them additionally stabilized by specific main-chain/side-chain H-bonding, where the sulfur atom essentially plays the role of H-bond acceptor. The folded structure was confirmed by microwave spectroscopy, which demonstrated the validity of the DFT-D methods currently used in the field. These structural and spectroscopic results, complemented by a theoretical Natural Bond Orbital analysis, enabled us to document the capacity of the weakly polar-CH2-SH side chain of Cys to adapt itself to the intrinsic local preferences of the peptide backbone, i.e., a γ-turn or a β-sheet extended secondary structure. The corresponding local H-bonding bridges the side chain acceptor S atom to the backbone NH donor site of the same or the next residue along the chain, through a 5-or a 6-membered ring respectively., Support from the French National Research Agency (ANR; Grant ANR-17-CE29-0008 ‘‘TUNIFOLD-S’’) and from the ‘‘Investissements d’Avenir’’ Funding program (LabEx PALM; grant ANR-10-LABX-0039-PALM; DIRCOS) are acknowledged. This work was granted access to the HPC facility of [TGCC/CINES/ IDRIS] under the Grant 2019-A0050807540 awarded by GENCI (Grand Equipement National de Calcul Intensif) and to the CCRT High Performance Computing (HPC) facility at CEA under the Grant CCRT2019-p606bren. We also acknowledge the use of the computing facility cluster Me´soLUM of the LUMAT federation (FR LUMAT 2764). The financial fundings from Ministerio de Ciencia e Innovacion (CTQ2016-76393-P), Junta de Castilla y Leon (Grant VA077U16) and the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC-2013-SyG, Grant Agreement no. 610256 NANOCOSMOS, are gratefully acknowledged.

High- and low-acetylated galactoglucomannooligosaccharides (GGMOS_Ac and GGMOS, respectively) were assayed as substrates in the TIM-2

Herein, we present the first rotational study of the AlaAla dipeptide, brought into the gas phase by laser ablation. Two different structures have been unveiled in the isolated environment of a supersonic expansion by Fourier transform microwave spectroscopy. These structures have been identified through their rotational and 14N quadrupole coupling constants. The flexibility of the -NH2 and -COOH ends allows the formation of strong intramolecular interactions giving rise to five- and seven-membered ring configurations.

Glycolamide is a glycine isomer and also one of the simplest derivatives of acetamide (e.g., one hydrogen atom is replaced with a hydroxyl group), which is a known interstellar molecule. Using a battery of state of the art rotational spectroscopic techniques in the frequency and time domain, around 1500 transitions have been newly assigned. Based on the reliable frequency predictions, we report a radioastronomical search for glycolamide in the well known high-mass star forming region Sgr B2(N) using the ALMA imaging spectral line survey ReMoCA. We also searched for glycolamide toward Sgr B2(N) with the Effelsberg radio telescope. We report the nondetection of glycolamide toward this source with an abundance at least six and five times lower than that of acetamide and glycolaldehyde, respectively. Our astrochemical model suggests that glycolamide may be present in this source at a level just below the upper limit, which was derived from the EMoCA survey. We could also not detect the molecule in the region's extended molecular envelope, which was probed with the Effelsberg telescope. We find an upper limit to its column density that is similar to the column densities obtained earlier for acetamide and glycolaldehyde with the Green Bank Telescope., Comment: The article will be published as a regular paper in Astronomy and Astrophysics (Forthcoming article since 19 May 2020)

The benefits of vaporization by laser ablation and the high resolution and sensitivity attained by the chirped pulse Fourier transform microwave spectroscopy CP-FTMW have provided the first conformational map of the simplest phenolic acids of trans-cinnamic and p-coumaric. Two conformers of trans-cinnamic acid and four conformers of trans-p-coumaric acid have been characterized under the isolation conditions of a supersonic expansion. The spectroscopic constants derived from the analysis of the rotational spectra compared with those predicted theoretically provide an unmatched means to achieve an unambiguous identification of the observed species.

The non-proteinogenic amino acid N-methyl-l-alanine has been brought into the gas phase using laser ablation techniques and studied by high resolution chirped pulse and molecular-beam Fourier transform microwave spectroscopies coupled to supersonic expansion. Four conformers showing the three types of hydrogen bond interactions I (NHO[double bond, length as m-dash]C), II (OHN) and III (N-HO-H) have been unambiguously identified, based on the comparison of the experimental rotational and 14N nuclear quadrupole constants with the calculated ab initio values. The observation of a type III conformer evidences the role of methyl groups in both sides to impose the steric hindrance, precluding the relaxation from type III to type I conformers and explains the responsibility for the unique conformational landscape observed in the case of NMA.

The pure rotational spectrum of N-methylhydroxylamine (CH3NHOH), a potential candidate in the interstellar medium, has been studied in the millimeter-wave region up to 360 GHz. The molecule was liberated from its hydrochloride salt and the ground and six lowest excited vibrational states of the most stable trans conformation as well as the 13C isotopologue in natural abundance have been measured and analyzed. From the observed ground state A–E splittings, a barrier hindering the methyl internal rotation V3 = 1245.8 (46) cm−1 has been derived. The sub-Doppler Lamb-dip technique has been employed to resolve the 14N hyperfine structure of strong transitions. The spectroscopic constants reported in the present study should constitute a solid set of laboratory data to support future searches of N-methylhydroxylamine in the interstellar medium.

The steric effects imposed by the isopropyl group of valine in the conformational stabilization of the capped dipeptide N-acetyl-l-valinamide (Ac-Val-NH2) have been studied by laser ablation molecular beam Fourier transform microwave (LA-MB-FTMW) spectroscopy. The rotational and quadrupole coupling constants of the two 14N nuclei determined in this work show that this dipeptide exists as a mixture of C7 and C5 conformers in the supersonic expansion. The conformers are stabilized by a C[double bond, length as m-dash]OH-N intramolecular hydrogen bond closing a seven- or a five-membered ring, respectively. The observation of both conformers is in good agreement with previous results on the related dipeptides containing different residues, confirming that the polarity/non-polarity of the side chains of the amino acid is responsible for the conformational locking/unlocking. The voluminous isopropyl group is not able to prevent the less stable C5 conformer from forming but it destabilizes the C[double bond, length as m-dash]OH-N interaction.