Early (Ti, Zr)-late (Rh, Ir) heteronuclear complexes with bridging sulphido ligands

[EN]: We report in this account on the controlled synthesis of novel d0-d8 early-late heteropolynuclear diolefin and carbonyl clusters. The synthetic approach was based on additive-deprotonation reactions involving the titanium and zirconium bis-hydrosulphido complexes of formula [Cp2Ti(SH)2] and [Cptt 2Zr(SH)2] and appropriate rhodium and iridium diolefin and carbonyl compounds. The significant differences between the resulting early-late complexes and their structures coming from the titanium or zirconium metalloligand precursors are highlighted. The catalytic activity of some representative titanium-rhodium and zirconium-rhodium compounds towards alkene hydroformylation was explored. Interestingly, the heterotetranuclear 'CpTi(μ3-S)3Rh3' structure was maintained as such under mild conditions.[FR]: Nous rapportons dans cet article la préparation contrôlée de nouveaux clusters hétéropolynucléaires early-late d0–d8 portant les ligands oléfine et carbonyle. La réaction de déprotonation–addition a été la méthode de synthèse utilisée et implique la condensation de complexes bis-hydrogénosulfure du titane et du zirconium, de formule [Cp2Ti(SH)2] et [Cptt2Zr(SH)2], sur les composés adéquats du rhodium et de l’iridium portant les ligands oléfine et carbonyle. Les différences significatives de structure entre les complexes early-late ainsi préparés, dues à la nature du métalloligand précurseur du titane ou du zirconium employé, sont mises en évidence. L’activité catalytique de quelques composés représentatifs titane–rhodium et zirconium–rhodium dans l’hydroformylation d’alcènes a été mesurée. Il convient de noter que la structure hétérotétranucléaire « CpTi(μ3-S)3Rh3 » est maintenue comme telle sous des conditions douces de réaction.Peer Reviewe

A Bayesian network approach to study host and viral genetic correlates of HIV-1 disease progression

HIV disease progression is very variable among infected patients. Using classical statistical methods based on a selected number of markers, Casado et al [1] identified a number of host and viral genetic correlates for the clinical definitions of HIV-1 disease progression: elite controllers, long term non progressors including viremic controllers and clinical non progressors, regular progressors and rapid progressors.S

T-cell epitopes of the major peach allergen, Pru p 3: Identification and differential T-cell response of peach-allergic and non-allergic subjects

Lipid transfer proteins (LTPs), particularly peach Pru p 3, are the most relevant plant food allergens in the South of Europe, and, therefore, their allergic properties have been extensively studied. However, neither T-cell epitopes nor their effect on the patients’ T-cell response has been investigated in any member of the LTP panallergen family. The objective of the present study was to map the major T-cell epitopes of Pru p 3, as well as to evaluate their induced T-cell response in peach-allergic versus control subjects. Thus, peripheral blood mononuclear cells (PBMCs) from 18 peach-allergic patients and Pru p 3-specific T-cell lines (TCLs) from 9 of them were cultured with Pru p 3 and with a panel of 17 derived peptides (10-mer overlapping in 5 amino acids representing the full sequence of Pru p 3). Proliferation in 5-day assays was carried out via tritiated-thymidine incorporation, while IL4 and IFNγ production was assessed via sandwich enzyme-linked immunosorbent tests (ELISA) of TCL culture supernatants. The results were compared to those obtained from 10 non-peach allergic control volunteers. Two consecutive peptides showed the highest activation capacity. About 74% of PBMCs and TCLs recognized them, forming a single T-epitope: Pru p 365–80. Additionally, other specific T-cell epitopes were observed. Pru p 325–35 was detected by more than 60% of TCLs from peach-allergic patients, and Pru p 345–55 only activated PBMCs from control subjects. Interestingly, TCLs from patients were associated with a Th2-type, whereas control TCLs presented a Th1-type cytokine response. The major immunogenic T-cell epitope identified in Pru p 3, Pru p 365–80, is a good candidate to develop new vaccines for hypersensitivity reactions associated with LTP allergens from Rosaceae fruits

Release of hypoacetylated and trimethylated histone H4 is an epigenetic marker of early apoptosis

Nuclear events such as chromatin condensation, DNA cleavage at internucleosomal sites, and histone release from chromatin are recognized as hallmarks of apoptosis. However, there is no complete understanding of the molecular events underlying these changes. It is likely that epigenetic changes such as DNA methylation and histone modifications that are involved in chromatin dynamics and structure are also involved in the nuclear events described. In this report we have shown that apoptosis is associated with global DNA hypomethylation and histone deacetylation events in leukemia cells. Most importantly, we have observed a particular epigenetic signature for early apoptosis defined by a release of hypoacetylated and trimethylated histone H4 and internucleosomal fragmented DNA that is hypermethylated and originates from perinuclear heterochromatin. These findings provide one of the first links between apoptotic nuclear events and epigenetic markers

Persistent HIV-controllers are more prone to spontaneously clear HCV: a retrospective cohort study.

HIV-controllers have the ability to spontaneously maintain viraemia at low or undetectable levels in the absence of antiretroviral treatment. Furthermore, HIV-controllers seem to have a superior capacity to spontaneously clear hepatitis C virus (HCV) compared to non HIV-controllers. Some of these subjects eventually lose HIV-controller status (transient controllers), whereas some HIV-controllers show a persistent natural HIV control (persistent controllers). We aimed to analyse whether persistent controllers have superior capacity to spontaneously clear HCV compared to transient controllers. We recruited HIV-controllers from January 1981 up to October 2016 with available antibodies to HCV (anti-HCV) data (n = 744). Factors associated with HIV spontaneous control in relation to HCV status were analysed in persistent and transient HIV-controllers with anti-HCV positive (n = 202 and n = 138 respectively) in comparison with 1700 HCV positive non HIV-controllers recruited from January 1981 up to March 2018, bivariate and multivariate analyses, following a logistic regression model, were applied. In addition, the factors related to the loss and time to lose HIV-controller status were explored (n = 744) using Log rank test and Kaplan-Meier curves, in this case the multivariate analysis consisted in a Cox regression model. A higher frequency of HCV spontaneous clearance was found in persistent HIV-controllers (25.5%) compared to non-controllers (10.2%). After adjusting for potential confounders, as sex, age, HIV transmission risk, CD4+ T-cell nadir and time of follow-up, HCV clearance was independently associated with persistent HIV spontaneous control (p = 0.002; OR (95% CI) = 2.573 (1.428 to 4.633)), but not with transient spontaneous control (p = 0.119; 1.589 (0.888 to 2.845)). Furthermore, persistent HIV-controllers were more likely to spontaneously clear the HCV in comparison with transient controllers (p = 0.027; 0.377 (0.159 to 0.893). Finally, not to lose or lengthen the time of losing this control was independently associated with HCV spontaneous clearance (p = 0.010; 0.503 (0.297 to 0.850). This study shows an association between spontaneous persistent HIV-control and HCV spontaneous clearance. The study findings support the idea of preserved immune mechanisms in persistent HIV control implicated in HCV spontaneous clearance. These results highlight persistent HIV-controllers but not transient controllers as a good model of functional HIV cure.This work was supported by the Instituto de Salud Carlos III (research contracts CPII014/00025 to E.R.‐M., and FI14/00431 to L.T.‐D. and research projects PI12/02283, PI16/00684, PI19/01127 to E.R.‐M.) and Red Temática de Investigación Cooperativa en SIDA (Projects RD12/0017/0029, RD12/0017/0031, and RD16/0025/0020 and RD16/0025/0013), which is included in the Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008 to 2011 and 2013 to 2016, Instituto de Salud Carlos III, Fondos FEDER. E.R.‐M. was supported by Consejería de Salud y Bienestar Social of Junta de Andalucía through the Nicolás Monardes program (C‐0032/17), N Rallón is a Miguel Servet investigator from the Spanish Carlos III Institute of Health (ISCIII), grant CP14/00198, Madrid, Spain and B.D.M. received a grant from The Spanish Ministry of Education (FPU13/02451). Work in CL‐G’s laboratory was supported by grants SAF (2010 to 17226) and (2016‐77894‐R) from MINECO (Spain) and FIS (PI 13/02269, ISCIII) and in part by the RIS‐RETIC grants RD06/006/0036 and RD12/0017/0028 funded by the ISC III‐FEDER. MP has a contract of RIS‐RETIC RD12/0017/0036.S

Validation of Calprotectin As a Novel Biomarker For The Diagnosis of Pleural Effusion: a Multicentre Trial

Discriminating between malignant pleural effusion (MPE) and benign pleural effusion (BPE) remains difficult. Thus, novel and efficient biomarkers are required for the diagnosis of pleural effusion (PE). The aim of this study was to validate calprotectin as a diagnostic biomarker of PE in clinical settings. A total of 425 patients were recruited, and the pleural fluid samples collected had BPE in 223 cases (53.7%) or MPE in 137 patients (33%). The samples were all analysed following the same previously validated clinical laboratory protocols and methodology. Calprotectin levels ranged from 772.48 to 3,163.8 ng/mL (median: 1,939 ng/mL) in MPE, and 3,216-24,000 ng/mL in BPE (median: 9,209 ng/mL; p < 0.01), with an area under the curve of 0.848 [95% CI: 0.810-0.886]. For a cut-off value of </= 6,233.2 ng/mL, we found 96% sensitivity and 60% specificity, with a negative and positive predictive value, and negative and positive likelihood ratios of 96%, 57%, 0.06, and 2.4, respectively. Multivariate analysis showed that low calprotectin levels was a better discriminator of PE than any other variable [OR 28.76 (p < 0.0001)]. Our results confirm that calprotectin is a new and useful diagnostic biomarker in patients with PE of uncertain aetiology which has potential applications in clinical practice because it may be a good complement to cytological methods

A multiple stakeholder multicriteria decision analysis in diabetic macular edema management: the MULTIDEX‑EMD study

Background The clinical and economic management of retinal diseases has become more complex following the introduction of new intravitreal treatments. Multicriteria decision analysis (MCDA) ofers the potential to overcome the challenges associated with traditional decision-making tools. Objectives A MCDA to determine the most relevant criteria to decision-making in the management of diabetic macular edema (DME) based on the perspectives of multiple stakeholders in Spain was developed. This MCDA was termed the MULTIDEX-EMD study. Methods Nineteen stakeholders (7 physicians, 4 pharmacists, 5 health authorities and health management experts, 1 psychologist, and 2 patient representatives) participated in this three-phase project. In phase A, an advisory board defned all of the criteria that could infuence DME treatment decision-making. These criteria were then screened using a discrete choice experiment (DCE) (phase B). Next, a multinomial logit model was ftted by applying the backward elimination algorithm (relevant criteria: p value<0.05). Finally, the results were discussed in a deliberative process (phase C). Results Thirty-one criteria were initially defned (phase A) and grouped into 5 categories: efcacy/efectiveness, safety, organizational and economic impact, patient-reported outcomes, and other therapeutic features. The DCE results (phase B) showed that 10 criteria were relevant to the decision-making process for a 50- to 65-year-old DME patient: mean change in best corrected visual acuity (p value<0.001), percentage of patients with an improvement of ≥15 letters (p value<0.001), efect duration per administration (p value=0.008), retinal detachment (p value<0.001), endophthalmitis (p value=0.012), myocardial infarction (p value<0.001), intravitreal hemorrhage (p value=0.021), annual treatment cost per patient (p value=0.001), health-related quality of life (HRQoL) (p value=0.004), and disability level (p value=0.021). Conclusions From a multi-stakeholder perspective, the selection of an appropriate treatment for DME patients should guarantee patient safety and maximize the visual acuity improvement and treatment efect duration. It should also contribute to system sustainability by being afordable, it should have a positive impact on HRQoL, and it should prevent disability

Molecular basis of allergen cross-reactivity: Non-specific lipid transfer proteins from wheat flour and peach fruit as models

Peach non-specific lipid transfer protein (Pru p 3; nsLTP) has been characterized as the major food allergen in the adult Mediterranean population. Its wheat homologous protein, Tri a 14 has a relevant inhalant allergen in occupational baker's asthma. Different sensitization patterns to these allergens have been found in patients with this latter disorder. The objective of the present study was to characterize IgE epitopes of Tri a 14 and to compare them with those of Pru p 3 using three complementary strategies: the analysis of IgE-binding capacity of decapeptides bound to membrane, the identification of mimotopes using a phage display random peptide library, and the analysis of the surface electrostatic potential of both allergens. Thus, synthetic overlapping decapeptides, covering the Pru p 3 and Tri a 14 amino acid sequences, were used to identify sequential regions involved in recognition of IgE from baker's asthma patients sensitized to both nsLTPs. A phage display library was screened with total IgE from the same patients, and positive clones sequentially selected using the purified allergens, allowed to identify mimotopes (conformational epitopes) of Tri a 14 and Pru p 3. Both sequential regions and mimotopes were localized in the corresponding 3D molecular surface and their electrostatic properties were analyzed. Common sequential regions with strong IgE-binding capacity (residues 31–40 and 71–80) were identified in Tri a 14 and Pru p 3, whereas regions Tri a 1451–60 and Pru p 311–20 were found specific of each allergen. A major conformational epitope (mimotope), L34H35N36R39S40S42D43G74V75L77P78Y79T80, which comprised the two common sequential epitopes, was located in Tri a 14, and a very similar one in Pru p 3. However, differences were detected on the surface electrostatic potential of both mimotopes: a first part (around residues 31–45) showed similar positive features in both allergens, whereas a second part (around residues 74–80) was markedly negative in Tri a 14 but neutral-positive in Pru p 3. Tri a 14 and Pru p 3 have a similar conformational region involved in IgE-binding, although their electrostatic features are different. Additionally, common and specific sequential IgE-binding regions were mapped in both allergens. These findings could be instrumental in understanding the cross-reactivity and specificity of sensitization to both homologous allergens

Prognostic Value of Serum Paraprotein Response Kinetics in Patients With Newly Diagnosed Multiple Myeloma

Response kinetics is not well-established as a prognostic marker in multiple myeloma (MM). We developed a mathematical model to assess the prognostic value of serum monoclonal component (MC) response kinetics during 6 induction cycles in 373 newly diagnosed MM patients. The model calculated a resistance parameter that reflects the stagnation in the response after an initial descent, dividing the patients into two kinetics categories with significantly different progression-free survival (PFS). Introduction: Response kinetics is a well-established prognostic marker in acute lymphoblastic leukemia. The situation is not clear in multiple myeloma (MM) despite having a biomarker for response monitoring (monoclonal component [MC]). Materials and Methods: We developed a mathematical model to assess the prognostic value of serum MC response kinetics during 6 induction cycles, in 373 NDMM transplanted patients treated in the GEM2012Menos65 clinical trial. The model calculated a resistance parameter that reflects the stagnation in the response after an initial descent. Results: Two patient subgroups were defined based on low and high resistance, that respectively captured sensitive and refractory kinetics, with progression-free survival (PFS) at 5 years of 72% and 59% (HR 0.64, 95% CI 0.44-0.93; P =.02). Resistance significantly correlated with depth of response measured after consolidation (80.9% CR and 68.4% minimal residual disease negativity in patients with sensitive vs. 31% and 20% in those with refractory kinetics). Furthermore, it modulated the impact of reaching CR after consolidation; thus, within CR patients those with refractory kinetics had significantly shorter PFS than those with sensitive kinetics (median 54 months vs. NR; P =.02). Minimal residual disease negativity abrogated this effect. Our study also questions the benefit of rapid responders compared to late responders (5-year PFS 59.7% vs. 76.5%, respectively [P <.002]). Of note, 85% of patients considered as late responders were classified as having sensitive kinetics. Conclusion: This semi-mechanistic modeling of M-component kinetics could be of great value to identify patients at risk of early treatment failure, who may benefit from early rescue intervention strategies. (C) 2022 The Authors. Published by Elsevier Inc