International differences in treatment effect: do they really exist and why?

With the increasing globalization of clinical trials, the opportunity exists to explore potential geographic differences in treatment effect within any major trial. Such geographic differences may arise because of international differences in patient selection, medical practice, or evaluation of outcomes, and such international variations need better documentation in trial reports. Appropriate pre-defined statistical analyses, including statistical tests of interaction regarding geographic heterogeneity in treatment effect, are important. Geographic variations are a particularly tricky form of subgroup analysis: they lack statistical power, are at best hypothesis-generating and can generate more confusion than insight. Referring to key examples, e.g. the PLATO and MERIT-HF, we emphasize the need for caution in interpreting evidence of potential geographic inconsistencies in treatment effect. Although it is appropriate to explore any biological or practical reasons for apparent geographic anomalies in treatment effect, the play of chance is often the most plausible and wise interpretation

Radiopharmacokinetics and uptake of 99m Tc-cRGD in av B3 integrins for imaging angiogenesis in induced malignant tumors in athymic mice

The multistep process of angiogenesis offers several targets for therapeutic interventions. One molecular target structure is the alfa five beta three (av b3 ) integrin which is expressed on vascular endothelial cells and over-expressed in cancer tumor angiogenesis. To image neoangiogenesis in athymic mice with induced pancreatic, breast and prostate malignant tumors a new radiopharmaceutical was developed. The 99mTc-EDDA/HYNIC-cyclic-Arg-Gly- Asp-D-Phe-Lys (99mTc-cRGD) targets integrin receptors av b3 and was prepared with an average radiochemical purity > 95 %. 99mTc-cRGD shows high in vivo stability, fast blood clearance and rapid renal excretion in mice. There are statistical differences between tumor/muscle ratios for the 3 tumors studied. The highest tumor/non-target ratio was found in breast cancer (7.2 after 24 h) and a representative dorsal SPECT image was obtained where the tumor showed up very clearly over the background tissue. The high resolution of the image implies that 99mTc-cRGD will be of great value in nuclear medicine as a potential radiopharmaceutical for av b3 integrins receptor uptake and for imaging neoangiogenesis in neoplastic tissue and to follow up cancer tumor progression

Development of robust chiroptical systems through spirobifluorenes

Chiroptical responses are valuable for the structural determination of dissymmetric molecules. However, the development of everyday applications based on chiroptical systems is yet to come. We have been earlier using axially chiral allenes for the construction of linear, cyclic, and cage‐shaped molecules that present remarkable chiroptical responses. Additionally, we have developed chiral surfaces through upstanding chiral architectures. Since the goal is to obtain robust chiroptical materials, more recently we have been studying spirobifluorenes (SBFs), a well‐established building block in optoelectronic applications. After theoretical and experimental demonstration, the suitability of chiral SBFs for the development of robust chiroptical systems was certified by the construction all‐carbon double helices, flexible shape‐persistent macrocycles, chiral frameworks for surface functionalization, and structures featuring helical or spiroconjugated molecular orbitals. Here, we give an overview of our contribution to these matters.Ministerio de Ciencia e Innovacion | Ref. TED2021-131760B-100Ministerio de UniversidadesXunta de Galicia | Ref. ED431C 2017/51Universidade de Vigo/CISU

Optical and electrochemical properties of spirobifluorene iridanaphthalene complexes

Three new spirobifluorene iridaaromatic compounds bearing electron-withdrawing or electron-donor substituents or another iridanaphthalene moiety have been synthesized and structurally characterized. Thorough experimental and theoretical evaluation revealed that these novel systems present a high thermal, air and electrochemical stability as well as low optical and electronic energy gap values with a significant redshift of the absorption maximum in the UV-Vis spectra and predicted remarkably higher first hyperpolarizabilities compared to their organic counterparts. Therefore, the combination of a metallaaromatic system with a spirobifluorene moiety leads to the design and development of new spirobifluorene derivatives. These new systems have shown interesting optical and electronic properties making them of interest for future applications in optoelectronics.Xunta de Galicia | Ref. GRC2019/2

Study Protocol-Coping With the Pandemics: What Works Best to Reduce Anxiety and Depressive Symptoms

Background: The coronavirus disease 2019 (COVID-19) pandemic and lockdown might increase anxiety and depressive symptoms in most individuals. Health bodies recommend several coping behaviors to protect against such symptoms, but evidence on the relationship between these behaviors and symptoms mostly comes from cross-sectional studies in convenience samples. We will conduct a prospective longitudinal study of the associations between coping behaviors and subsequent anxiety and depressive symptoms during the COVID-19 pandemic in a representative sample of the Spanish general adult population. Methods: We will recruit 1,000 adult participants from all autonomous communities of Spain and with sex, age, and urbanicity distributions similar to those of their populations and assess anxiety and depressive symptoms and coping behaviors using fortnightly questionnaires and real-time methods (ecological momentary assessments) for 1 year. The fortnightly questionnaires will inquire about anxiety and depressive symptoms [General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9)] and the frequency of 10 potential coping behaviors (e.g., follow a routine) during the past 2 weeks. In addition, we will collect several variables that could confound or moderate these associations. These will include subjective well-being [International Positive and Negative Affect Schedule Short Form (I-PANAS-SF) and Satisfaction with Life Scale (SWLS)], obsessive-compulsive symptoms [Obsessive Compulsive Inventory-Revised (OCI-R)], personality and emotional intelligence [International Personality Item Pool (IPIP) and Trait Emotional Intelligence Questionnaire Short Form (TEIQue-SF)], sociodemographic factors (e.g., work status, housing-built environment), and COVID-19 pandemic-related variables (e.g., hospitalizations or limitations in social gatherings). Finally, to analyze the primary relationship between coping behaviors and subsequent anxiety and depressive symptoms, we will use autoregressive moving average (ARMA) models. Discussion: Based on the study results, we will develop evidence-based, clear, and specific recommendations on coping behaviors during the COVID-19 pandemic and lockdown. Such suggestions might eventually help health bodies or individuals to manage current or future pandemics

Metabolomic profile of neuroendocrine tumors (NETs) identifies methionine, porphyrin and tryptophan metabolism as key dysregulated pathways associated with patient survival

Objective: Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways.Design and Methods: Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P < .05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA).Results: Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P = .012); 5-year OS of 69.7%, 32.5%, and 27.7% (P = .003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs.Conclusions: We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients

Plasma miRNA profile at COVID-19 onset predicts severity status and mortality

BACKGROUND: MicroRNAs (miRNAs) have a crucial role in regulating immune response against infectious diseases, showing changes early in disease onset and before the detection of the pathogen. Thus, we aimed to analyze the plasma miRNA profile at COVID-19 onset to identify miRNAs as early prognostic biomarkers of severity and survival. METHODS AND RESULTS: Plasma miRNome of 96 COVID-19 patients that developed asymptomatic/mild, moderate and severe disease was sequenced together with a group of healthy controls. Plasma immune-related biomarkers were also assessed. COVID-19 patients showed 200 significant differentially expressed (SDE) miRNAs concerning healthy controls, with upregulated putative targets of SARS-CoV-2, and inflammatory miRNAs. Among COVID-19 patients, 75 SDE miRNAs were observed in asymptomatic/mild compared to symptomatic patients, which were involved in platelet aggregation and cytokine pathways, among others. Moreover, 137 SDE miRNAs were identified between severe and moderate patients, where miRNAs targeting the SARS CoV-2 genome were the most strongly disrupted. Finally, we constructed a mortality predictive risk score (miRNA-MRS) with ten miRNAs. Patients with higher values had a higher risk of 90-days mortality (hazard ratio = 4.60; p-value < 0.001). Besides, the discriminant power of miRNA-MRS was significantly higher than the observed for age and gender (AUROC = 0.970 vs. 0.881; p = 0.042). CONCLUSIONS: SARS-CoV-2 infection deeply disturbs the plasma miRNome from an early stage of COVID-19, making miRNAs highly valuable as early predictors of severity and mortality

Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis

CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage neurodegenerative disease highly prevalent in children. CLN7/MFSD8 gene encodes a lysosomal membrane glycoprotein, but the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments. Here, we found, in the Cln7∆ex2 mouse model of CLN7 disease, that failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria. In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis. Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFKFB3, normally unstable in healthy neurons. Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks. Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis and targeting PFKFB3 could alleviate this and other lysosomal storage diseases

Fernblock, a Nutriceutical with Photoprotective Properties and Potential Preventive Agent for Skin Photoaging and Photoinduced Skin Cancers

Many phytochemicals are endowed with photoprotective properties, i.e., the capability to prevent the harmful effects of excessive exposure to ultraviolet (UV) light. These effects include photoaging and skin cancer, and immunosuppression. Photoprotection is endowed through two major modes of action: UV absorption or reflection/scattering; and tissue repair post-exposure. We and others have uncovered the photoprotective properties of an extract of the fern Polypodium leucotomos (commercial name Fernblock). Fernblock is an all-natural antioxidant extract, administered both topically (on the skin) or orally. It inhibits generation of reactive oxygen species (ROS) production induced by UV including superoxide anion. It also prevents damage to the DNA, inhibits UV-induced AP1 and NF-κB, and protects endogenous skin natural antioxidant systems, i.e., CAT, GSH, and GSSR. Its photoprotective effects at a cellular level include a marked decrease of UV-mediated cellular apoptosis and necrosis and a profound inhibition of extracellular matrix remodeling. These molecular and cellular effects translate into long-term inhibition of photoaging and carcinogenesis that, together with its lack of toxicity, postulate its use as a novel-generation photoprotective nutriceutical of phytochemical origin