Preventing alpelisib-related hyperglycaemia in HR+/HER2-/PIK3CA-mutated advanced breast cancer using metformin (METALLICA): a multicentre, open-label, single-arm, phase 2 trial.

Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/PIK3CA-mutated advanced breast cancer (ABC). Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL [<5.6 mmol/L] and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100-140 mg/dL [5.6-7.8 mmol/L] and/or haemoglobin A1C [HbA1c] 5.7-6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0-1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3-4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3-4 hyperglycaemia over the first 8 weeks, respectively. Findings: 233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n = 48) and B (n = 20). Median follow-up was 7.8 months (IQR 1.4-19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5-11.1; P < 0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6-37.8; P = 0.016) had grade 3-4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two [2.9%]), vomiting (two [2.9%]), and diarrhoea (two [2.9%]). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9-not reached), ORR was 20.6% (95% CI: 11.7-32.1%), and CBR was 52.9% (95% CI: 40.4-65.2). Interpretation: In HR+/HER2-/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia. Funding: Novartis Pharmaceuticals.

Transplantation of dorsal root ganglia overexpressing the NaChBac sodium channel improves locomotion after complete SCI.

Spinal cord injury (SCI) is a debilitating condition currently lacking treatment. Severe SCI causes the loss of most supraspinal inputs and neuronal activity caudal to the injury, which, coupled with the limited endogenous capacity for spontaneous regeneration, can lead to complete functional loss even in anatomically incomplete lesions. We hypothesized that transplantation of mature dorsal root ganglia (DRGs) genetically modified to express the NaChBac sodium channel could serve as a therapeutic option for functionally complete SCI. We found that NaChBac expression increased the intrinsic excitability of DRG neurons and promoted cell survival and neurotrophic factor secretion in vitro. Transplantation of NaChBac-expressing dissociated DRGs improved voluntary locomotion 7 weeks after injury compared to control groups. Animals transplanted with NaChBac-expressing DRGs also possessed higher tubulin-positive neuronal fiber and myelin preservation, although serotonergic descending fibers remained unaffected. We observed early preservation of the corticospinal tract 14 days after injury and transplantation, which was lost 7 weeks after injury. Nevertheless, transplantation of NaChBac-expressing DRGs increased the neuronal excitatory input by an increased number of VGLUT2 contacts immediately caudal to the injury. Our work suggests that the transplantation of NaChBac-expressing dissociated DRGs can rescue significant motor function, retaining an excitatory neuronal relay activity immediately caudal to injury.

First-Line Ipatasertib, Atezolizumab, and Taxane Triplet for Metastatic Triple-Negative Breast Cancer: Clinical and Biomarker Results.

PURPOSE: To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer (mTNBC). PATIENTS AND METHODS: The single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1-21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance. RESULTS: Among 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months. The safety profile was consistent with the known toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels. CONCLUSIONS: In patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts.

Physical dependence in older adults and job burnout in their informal caregivers in the COVID-19 context, a correlational study / Dependencia física en personas adultas mayores y sobrecarga en sus cuidadores informales en el contexto de la pandemia por COVID-19, un estudio correlacional / Dependência física em idosos e sobrecarga em seus cuidadores informais no contexto da pandemia de COVID-19, um estudo correlacional

Introduction: The functional status of older adults (OA) is usually used as an indicator of their health. Increased dependence raises the need for an informal caregiver (IC), leading to a state of work overload, which was frequently observed during the COVID-19 confinement. Objective: To assess the relationship between physical dependence of OA, job burnout of their IC, and the confinement conditions in the context of the COVID-19 pandemic. Materials and methods: The participants included 77 OA together with their respective IC. The OA filled out a sociodemographic data sheet and a Confinement Conditions Questionnaire. In addition to these two forms, the IC filled out the Zarit Caregiver Burnout Scale and the ABVD Barthel Scale. Results: Statistically significant correlations were found between: physical dependence and job burnout (rho=0.475, p<0.01); physical dependence and confinement degree (rho=0.441, p<0.01); and job burden and confinement degree (rho=0.344, p<0.01). Conclusion: Caregivers develop a greater job burnout as a consequence of the OA's dependence. Furthermore, it seems that this burnout is more related to the confinement conditions experienced by older adults than to the caregiver's own conditions.

Introducción: El estado funcional de las personas adultas mayores (PAM) suele tomarse como indicador de salud; la presencia de dependencia incrementa la necesidad de un cuidador informal (CI) que puede desarrollar sobrecarga, lo cual se agudizó durante el confinamiento por COVID-19. Objetivo: Evaluar la relación de la dependencia física de las PAM, la sobrecarga de su CI y las condiciones de confinamiento en el contexto de la pandemia por COVID-19. Materiales y métodos: Participaron 77 diadas conformadas por una PAM y su CI. Las PAM contestaron una ficha de datos sociodemográficos y Cuestionario de Condiciones de Confinamiento. Los CI, diligenciaron una ficha de datos sociodemográficos, Cuestionario de Condiciones de Confinamiento, Escala de Carga del Cuidador de Zarit y Escala de Barthel de ABVD. Resultados: Se encontró correlaciones estadísticamente significativas entre la dependencia física y la sobrecarga (rho=0,475, p<0,01); la dependencia física y el grado de confinamiento (rho=0,441, p<0,01); y la sobrecarga y el grado de confinamiento (rho=0,344, p<0,01). Conclusión: Los cuidadores de PAM desarrollan mayor sobrecarga frente a su dependencia física; además parece ser que la sobrecarga del cuidador está más relacionada con las condiciones de confinamiento de las personas adultas mayores, que con las propias condiciones de confinamiento del cuidador.

Introdução: O estado funcional do idoso (PAM) é geralmente tomado como um indicador de saúde; A presença de dependência aumenta a necessidade de um cuidador informal (CI) que pode desenvolver sobrecarga, que se agravou durante o confinamento da COVID-19. Objetivo: Avaliar a relação entre a dependência física dos PAM, a sobrecarga do seu CI e as condições de confinamento no contexto da pandemia de COVID-19. Materiais e métodos: Participaram 77 díades compostas por uma PAM e seu CI. O PAM respondeu a uma ficha de dados sociodemográficos e a um Questionário de Condições de Confinamento. Os CI preencheram ficha de dados sociodemográficos, Questionário de Condições de Confinamento, Escala de Sobrecarga do Cuidador de Zarit e Escala Barthel (ABVD). Resultados: Foram encontradas correlações estatisticamente significativas entre dependência física e sobrecarga (rho=0,475, p<0,01); dependência física e grau de confinamento (rho=0,441, p<0,01); e sobrecarga e grau de confinamento (rho=0,344, p<0,01). Conclusão: Os cuidadores do PAM desenvolvem maior sobrecarga diante da dependência física; além disso, parece que a sobrecarga do cuidador está mais relacionada com as condições de confinamento dos idosos do que com as próprias condições de confinamento do cuidador.

Monocyte Activation and Ageing Biomarkers in the Development of Cardiovascular Ischaemic Events or Diabetes in People with HIV.

We investigated whether blood telomere length (TL), epigenetic age acceleration (EAA), and soluble inflammatory monocyte cytokines are associated with cardiovascular events or diabetes (DM) in people living with HIV (PLHIV). This was a case-control study nested in the Spanish HIV/AIDS Cohort (CoRIS). Cases with myocardial infarction, stroke, sudden death, or diabetes after starting antiretroviral therapy were included with the available samples and controls matched for sex, age, tobacco use, pre-ART CD4 cell count, viral load, and sample time-point. TL (T/S ratio) was analysed by quantitative PCR and EAA with DNA methylation changes by next-generation sequencing using the Weidner formula. Conditional logistic regression was used to explore the association with cardiometabolic events. In total, 180 participants (94 cases (22 myocardial infarction/sudden death, 12 strokes, and 60 DM) and 94 controls) were included. Of these, 84% were male, median (IQR) age 46 years (40-56), 53% were current smokers, and 22% had CD4 count ≤ 200 cells/mm3 and a median (IQR) log viral load of 4.52 (3.77-5.09). TL and EAA were similar in the cases and controls. There were no significant associations between TL, EAA, and monocyte cytokines with cardiometabolic events. TL and EAA were mildly negatively correlated with sCD14 (rho = -0.23; p = 0.01) and CCL2/MCP-1 (rho = -0.17; p = 0.02). We found no associations between TL, EAA, and monocyte cytokines with cardiovascular events or diabetes. Further studies are needed to elucidate the clinical value of epigenetic biomarkers and TL in PLHIV.

Impact of the 21-Gene Assay in Patients with High-Clinical Risk ER-Positive and HER2-Negative Early Breast Cancer: Results of the KARMA Dx Study.

BACKGROUND: The 21-gene Oncotype DX Breast Recurrence Score® assay is prognostic and predictive of chemotherapy benefit for patients with estrogen receptor-positive, HER2- early breast cancer (EBC). The KARMA Dx study evaluated the impact of the Recurrence Score® results (RS) on the treatment decision for patients with EBC and high-risk clinicopathological characteristics for whom chemotherapy (CT) was considered. METHODS: Eligible patients with EBC were candidates for the study if CT was considered standard recommendation by local guidelines. Three high-risk EBC cohorts were predefined: (A) pT1-2, pN0/N1mi, and grade 3; (B) pT1-2, pN1, and grades 1-2; and (C) neoadjuvant cT2-3, cN0, and Ki67 ≤ 30%. Treatment recommendations before and after 21-gene testing were registered, as well as treatment received and physicians' confidence levels in their final recommendations. RESULTS: A total of 219 consecutive patients were included from eight Spanish centers: 30 in cohort A, 158 in cohort B, and 31 in cohort C. Ten patients were excluded from the final analysis as CT was not initially recommended. After 21-gene testing, treatment decisions changed from CT + endocrine therapy (ET) to ET alone for 67% of the whole group. In total, 30% (95% confidence interval [CI] 15% to 49%), 73% (95% CI 65% to 80%), and 76% (95% CI 56% to 90%) of patients ultimately received ET alone in cohorts A, B, and C, respectively. Physicians' confidence in their final recommendations increased in 34% of cases. CONCLUSIONS: Use of the 21-gene test resulted in an overall 67% reduction in CT recommendation in patients considered candidates for CT. Our findings indicate the substantial potential of the 21-gene test to guide CT recommendations in patients with EBC considered to be at high risk of recurrence based on clinicopathological parameters, regardless of nodal status or treatment setting.

A Strategy for Magnetic and Electric Stimulation to Enhance Proliferation and Differentiation of NPCs Seeded over PLA Electrospun Membranes.

Neural progenitor cells (NPCs) have been shown to serve as an efficient therapeutic strategy in different cell therapy approaches, including spinal cord injury treatment. Despite the reported beneficial effects of NPC transplantation, the low survival and differentiation rates constrain important limitations. Herein, a new methodology has been developed to overcome both limitations by applying a combination of wireless electrical and magnetic stimulation to NPCs seeded on aligned poly(lactic acid) nanofibrous scaffolds for in vitro cell conditioning prior transplantation. Two stimulation patterns were tested and compared, continuous (long stimulus applied once a day) and intermittent (short stimulus applied three times a day). The results show that applied continuous stimulation promotes NPC proliferation and preferential differentiation into oligodendrocytic and neuronal lineages. A neural-like phenotypic induction was observed when compared to unstimulated NPCs. In contrast, intermittent stimulation patterns did not affect NPC proliferation and differentiation to oligodendrocytes or astrocytes morphology with a detrimental effect on neuronal differentiation. This study provides a new approach of using a combination of electric and magnetic stimulation to induce proliferation and further neuronal differentiation, which would improve therapy outcomes in disorders such as spinal cord injury.

Primary Chemoradiotherapy Treatment (PCRT) for HER2+ and Triple Negative Breast Cancer Patients: A Feasible Combination.

Primary systemic treatment (PST) downsizes the tumor and improves pathological response. The aim of this study is to analyze the feasibility and tolerance of primary concurrent radio−chemotherapy (PCRT) in breast cancer patients. Patients with localized TN/HER2+ tumors were enrolled in this prospective study. Radiation was delivered concomitantly during the first 3 weeks of chemotherapy, and it was based on a 15 fractions scheme, 40.5 Gy/2.7 Gy per fraction to whole breast and nodal levels I-IV. Chemotherapy (CT) was based on Pertuzumab−Trastuzumab−Paclitaxel followed by anthracyclines in HER2+ and CBDCA-Paclitaxel followed by anthracyclines in TN breast cancers patients. A total of 58 patients were enrolled; 25 patients (43%) were TN and 33 patients HER2+ (57%). With a median follow-up of 24.2 months, 56 patients completed PCRT and surgery. A total of 35 patients (87.5%) achieved >90% loss of invasive carcinoma cells in the surgical specimen. The 70.8% and the 53.1% of patients with TN and HER-2+ subtype, respectively, achieved complete pathological response (pCR). This is the first study of concurrent neoadjuvant treatment in breast cancer in which three strategies were applied simultaneously: fractionation of RT (radiotherapy) in 15 sessions, adjustment of CT to tumor phenotype and local planning by PET. The pCR rates are encouraging.

NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation.

Neural progenitor cell (NPC) transplantation represents a promising treatment strategy for spinal cord injury (SCI); however, the underlying therapeutic mechanisms remain incompletely understood. We demonstrate that severe spinal contusion in adult rats causes transcriptional dysregulation, which persists from early subacute to chronic stages of SCI and affects nearly 20,000 genes in total tissue extracts. Functional analysis of this dysregulated transcriptome reveals the significant downregulation of cAMP signalling components immediately after SCI, involving genes such as EPAC2 (exchange protein directly activated by cAMP), PKA, BDNF, and CAMKK2. The ectopic transplantation of spinal cord-derived NPCs at acute or subacute stages of SCI induces a significant transcriptional impact in spinal tissue, as evidenced by the normalized expression of a large proportion of SCI-affected genes. The transcriptional modulation pattern driven by NPC transplantation includes the rescued expression of cAMP signalling genes, including EPAC2. We also explore how the sustained in vivo inhibition of EPAC2 downstream signalling via the intrathecal administration of ESI-05 for 1 week impacts therapeutic mechanisms involved in the NPC-mediated treatment of SCI. NPC transplantation in SCI rats in the presence and absence of ESI-05 administration prompts increased rostral cAMP levels; however, NPC and ESI-05 treated animals exhibit a significant reduction in EPAC2 mRNA levels compared to animals receiving only NPCs treatment. Compared with transplanted animals, NPCs + ESI-05 treatment increases the scar area (as shown by GFAP staining), polarizes microglia into an inflammatory phenotype, and increases the magnitude of the gap between NeuN + cells across the lesion. Overall, our results indicate that the NPC-associated therapeutic mechanisms in the context of SCI involve the cAMP pathway, which reduces inflammation and provides a more neuropermissive environment through an EPAC2-dependent mechanism.

SARS-CoV2 hospital surveillance and control system with contact tracing for patients and health care workers at a large reference hospital in Spain during the first wave: An observational descriptive study.

BACKGROUND AND AIMS: During the first peak of the COVID-19 pandemic, the Preventive Medicine Department and the Occupational Health Department at Hospital Clinic de Barcelona (HCB), a large Spanish referral hospital, developed an innovative comprehensive SARS-CoV2 Surveillance and Control System (CoSy-19) in order to preserve patients' and health care workers' (HCWs) safety. We aim to describe the CoSy-19 and to assess the impact in the number of contacts that new cases generated along this time. METHODS: Observational descriptive study of the findings of the activity of contact tracing of all cases received at the HCB during the first peak of COVID-19 in Spain (February 25th-May 3rd, 2020). RESULTS: A team of 204 professionals and volunteers performed 384 in-hospital contact-tracing studies which generated contacts, detecting 298 transmission chains which suggested preventive measures, generated around 22 000 follow-ups and more than 30 000 days of work leave. The number of contacts that new cases generated decreased during the study period. CONCLUSION: Coordination between Preventive Medicine and Occupational Health departments and agile information systems were necessary to preserve non-COVID activity and workers safety.

Optogenetic Stimulation Array for Confocal Microscopy Fast Transient Monitoring.

Optogenetics is an emerging discipline with multiple applications in neuroscience, allowing to study neuronal pathways or serving for therapeutic applications such as in the treatment of anxiety disorder, autism spectrum disorders (ASDs), or Parkinson's disease. More recently optogenetics is opening its way also to stem cell-based therapeutic applications for neuronal regeneration after stroke or spinal cord injury. The results of optogenetic stimulation are usually evaluated by immunofluorescence or flow cytometry, and the observation of transient responses after stimulation, as in cardiac electrophysiology studies, by optical microscopy. However, certain phenomena, such as the ultra-fast calcium waves acquisition upon simultaneous optogenetics, are beyond the scope of current instrumentation, since they require higher image resolution in real-time, employing for instance time-lapse confocal microscopy. Therefore, in this work, an optogenetic stimulation matrix controllable from a graphical user interface has been developed for its use with a standard 24-well plate for an inverted confocal microscope use and validated by using a photoactivable adenyl cyclase (bPAC) overexpressed in rat fetal cortical neurons and the consequent calcium waves propagation upon 100 ms pulsed blue light stimulation.

Antibacterial Activity of Copper Nanoparticles (CuNPs) against a Resistant Calcium Hydroxide Multispecies Endodontic Biofilm.

Endodontic treatment reduces the amount of bacteria by using antimicrobial agents to favor healing. However, disinfecting all of the canal system is difficult due to its anatomical complexity and may result in endodontic failure. Copper nanoparticles have antimicrobial activity against diverse microorganisms, especially to resistant strains, and offer a potential alternative for disinfection during endodontic therapy. This study evaluated the antibacterial action of copper nanoparticles (CuNPs) on an ex vivo multispecies biofilm using plaque count compared to the antibacterial activity of calcium hydroxide Ca(OH)2. There were significant differences between the Ca(OH)2 and CuNPs groups as an intracanal dressing compared with the CuNPs groups as an irrigation solution (p < 0.0001). An increase in the count of the group exposed to 7 days of Ca(OH)2 was observed compared to the group exposed to Ca(OH)2 for 1 day. These findings differ from what was observed with CuNPs in the same period of time. Antibacterial activity of CuNPs was observed on a multispecies biofilm, detecting an immediate action and over-time effect, gradually reaching their highest efficacy on day 7 after application. The latter raises the possibility of the emergence of Ca(OH)2-resistant strains and supports the use of CuNPs as alternative intracanal medication.

Genomic and Transcriptomic Analyses of Breast Cancer Primaries and Matched Metastases in AURORA, the Breast International Group (BIG) Molecular Screening Initiative.

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA, and RB1 mutations; MDM4 and MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes such as ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR+/HER2- cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC. SIGNIFICANCE: The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.This article is highlighted in the In This Issue feature, p. 2659.

Characterization and Processing of Table Olives: A Special Issue.

Table olives are recognized as an essential component of the Mediterranean diet, having been explicitly included in the second level of its nutritional pyramid as an aperitif or culinary ingredient, with a recommended daily consumption of one to two portions (15-30 g). Producers demand innovative techniques improving the performance and industrial sustainability, as well as the development of new products that respond efficiently to increasingly demanding consumers. The purpose of this special issue was to publish high-quality papers with the aim to cover the state-of-the-art, recent progress and perspectives related to characterization and processing of table olives. Two reviews offer an overview about the processing and storage effects on the nutritional and sensory properties of table olives, as well as the main technologies used for olive fermentation, and the role of lactic acid bacteria and yeasts characterizing this niche during the fermentation. A total of 10 research papers cover a broad range of aspects such as characterization of their chemical composition, bioavailability, advances in the processing technology, chemical and microbiological changes, optimized use of starter cultures for the improvement of the different fermentative processes, and new strategies to reduce sodium and additives to stabilize the organoleptic properties and avoid defects.

Comparative transcriptome analysis identifies CARM1 and DNMT3A as genes associated with osteoporosis.

To identify new candidate genes in osteoporosis, mainly involved in epigenetic mechanisms, we compared whole gene-expression in osteoblasts (OBs) obtained from women undergoing hip replacement surgery due to fragility fracture and severe osteoarthritis. Then, we analyzed the association of several SNPs with BMD in 1028 women. Microarray analysis yielded 2542 differentially expressed transcripts belonging to 1798 annotated genes, of which 45.6% (819) were overexpressed, and 54.4% (979) underexpressed (fold-change between - 7.45 and 4.0). Among the most represented pathways indicated by transcriptome analysis were chondrocyte development, positive regulation of bone mineralization, BMP signaling pathway, skeletal system development and Wnt signaling pathway. In the translational stage we genotyped 4 SNPs in DOT1L, HEY2, CARM1 and DNMT3A genes. Raw data analyzed against inheritance patterns showed a statistically significant association between a SNP of DNMT3A and femoral neck-(FN) sBMD and primarily a SNP of CARM1 was correlated with both FN and lumbar spine-(LS) sBMD. Most of these associations remained statistically significant after adjusting for confounders. In analysis with anthropometric and clinical variables, the SNP of CARM1 unexpectedly revealed a close association with BMI (p = 0.000082), insulin (p = 0.000085), and HOMA-IR (p = 0.000078). In conclusion, SNPs of the DNMT3A and CARM1 genes are associated with BMD, in the latter case probably owing to a strong correlation with obesity and fasting insulin levels.

[Diabetic patient control in Primary Care: Influence of service portfolio and other factors]. / Control del paciente diabético en Atención Primaria: influencia de cartera de servicios y otros factores.

OBJECTIVE: To study the effect of the type of follow-up according to Service Portfolio and other associated factors, in the reduction of HbA1c levels in people with a new diagnosis of type 2 diabetes and poor initial control. DESIGN: Analytical observational study of a cohort under routine clinical practice conditions. LOCATION: 262 Primary Health Care Centres in Madrid. PARTICIPANTS: 1,838 individuals older than 18 years with a new diagnosis of type 2 DM and initial HbA1c levels ≥ 7%, or ≥ 8.5% if older than 75 years. INTERVENTIONS: The exposure variable was the type of follow-up according to Portfolio, categorised as minimum, medium, and optimal, according to the number of interventions performed and periodicity of type of therapeutic-pharmacological plan. MAIN MEASUREMENTS: A study was made of the comorbidity, therapeutic-pharmacological plan, diet - exercise advice and deprivation index. The main outcome was the difference between the final and initial HbA1c. RESULTS: After 2 years of follow-up there was a mean decrease in HbA1c by -1.7 percentage points (95% CI: -1.6;-1.8), which was 0.36 points higher in patients with optimal follow-up: -2.1 (95% CI: -1.7;-2.4). The factors associated with a decrease in HbA1c were the optimal follow-up -0.29 (95% CI: -0.5;-0.1), the medium follow-up -0.26 (95% CI: -0.5; -0.0), and the initial HbA1c value -0.9 (95% CI: -0.9; -0.9. The factors associated with the increase were insulin treatment and living in socially disadvantaged areas. CONCLUSIONS: Glycaemic control was improved in patients with a new diagnosis of diabetes in which optimal follow-up is performed as proposed in the Service Portfolio.

Influence of Alkaline Treatment on Structural Modifications of Chlorophyll Pigments in NaOH-Treated Table Olives Preserved without Fermentation.

Alkaline treatment is a key stage in the production of green table olives and its main aim is rapid debittering of the fruit. Its action is complex, with structural changes in both the skin and the pulp, and loss of bioactive components in addition to the bitter glycoside oleuropein. One of the components seriously affected are chlorophylls, which are located mainly in the skin of the fresh fruit. Chlorophyll pigments are responsible for the highly-valued green color typical of table olive specialties not preserved by fermentation. Subsequently, the effect on chlorophylls of nine processes, differentiated by NaOH concentration and/or treatment time, after one year of fruit preservation under refrigeration conditions, was investigated. A direct relationship was found between the intensity of the alkali treatment and the degree of chlorophyll degradation, with losses of more than 60% being recorded when NaOH concentration of 4% or greater were used. Oxidation with opening of the isocyclic ring was the main structural change, followed by pheophytinization and degradation to colorless products. To a lesser extent, decarbomethoxylation and dephytylation reactions were detected. An increase in NaOH from 2% to 5% reduced the treatment time from 7 to 4 h, but fostered greater formation of allomerized derivatives, and caused a significant decrease in the chlorophyll content of the olives. However, NaOH concentrations between 6% and 10% did not lead to further time reductions, which remained at 3 h, nor to a significant increase in oxidized compounds, though the proportion of isochlorin e4-type derivatives was modified. Chlorophyll compounds of series b were more prone to oxidation and degradation reactions to colorless products than those of series a. However, the latter showed a higher degree of pheophytinization, and, exclusively, decarbomethoxylation and dephytylation reactions.

Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: In hormone receptor-positive, HER2-negative early stage breast cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition in combination with endocrine therapy could represent an alternative to multiagent chemotherapy. We aimed to evaluate the biological and clinical activity of neoadjuvant ribociclib plus letrozole in the luminal B subtype of early stage breast cancer. METHODS: CORALLEEN is a parallel-arm, multicentre, randomised, open-label, phase 2 trial completed across 21 hospitals in Spain. We recruited postmenopausal women (≥18 years) with stage I-IIIA hormone receptor-positive, Eastern Cooperative Oncology Group Performance Status 0-1, HER2-negative breast cancer and luminal B by PAM50 with histologically confirmed, operable primary tumour size of at least 2 cm in diameter as measured by MRI. Patients were randomly assigned (1:1) using a web-based system and permuted blocks of 25 to receive either six 28-days cycles of ribociclib (oral 600 mg once daily for 3 weeks on, 1 week off) plus daily letrozole (oral 2·5 mg/day) or four cycles of doxorubicin (intravenous 60 mg/m2) and cyclophosphamide (intravenous 600 mg/m2) every 21 days followed by weekly paclitaxel (intravenous 80 mg/m2) for 12 weeks. The total duration of the neoadjuvant therapy was 24 weeks. Randomisation was stratified by tumour size and nodal involvement. Samples were prospectively collected at baseline (day 0), day 15, and surgery. The primary endpoint was to evaluate the proportion of patients with PAM50 low-risk-of-relapse (ROR) disease at surgery in the modified intention-to-treat population including all randomly assigned patients who received study drug and had a baseline and at least one post-baseline measurement of ROR score. The PAM50 ROR risk class integrated gene expression data, tumour size, and nodal status to define prognosis. This trial was registered at ClinicalTrials.gov, NCT03248427. FINDINGS: Between July 27, 2017 to Dec 7, 2018, 106 patients were enrolled. At baseline, of the 106 patients, 92 (87%) patients had high ROR disease (44 [85%] of 52 in the ribociclib and letrozole group and 48 [89%] of 54 in the chemotherapy group) and 14 (13%) patients had intermediate-ROR disease (eight [15%] and six [11%]). Median follow-up was 200·0 days (IQR 191·2-206·0). At surgery, 23 (46·9%; 95% CI 32·5-61·7) of 49 patients in the ribociclib plus letrozole group and 24 (46·1%; 32·9-61·5) of 52 patients in the chemotherapy group were low-ROR. The most common grade 3-4 adverse events in the ribociclib plus letrozole group were neutropenia (22 [43%] of 51 patients) and elevated alanine aminotransferase concentrations (ten [20%]). The most common grade 3-4 adverse events in the chemotherapy group were neutropenia (31 [60%] of 52 patients) and febrile neutropenia (seven [13%]). No deaths were observed during the study in either group. INTERPRETATION: Our results suggest that some patients with high-risk, early stage, hormone receptor-positive, HER2-negative breast cancer could achieve molecular downstaging of their disease with CDK4/6 inhibitor and endocrine therapy. FUNDING: Novartis, Nanostring, Breast Cancer Research Foundation-AACR Career Development Award.

Optogenetic Modulation of Neural Progenitor Cells Improves Neuroregenerative Potential.

Neural progenitor cell (NPC) transplantation possesses enormous potential for the treatment of disorders and injuries of the central nervous system, including the replacement of lost cells or the repair of host neural circuity after spinal cord injury (SCI). Importantly, cell-based therapies in this context still require improvements such as increased cell survival and host circuit integration, and we propose the implementation of optogenetics as a solution. Blue-light stimulation of NPCs engineered to ectopically express the excitatory light-sensitive protein channelrhodopsin-2 (ChR2-NPCs) prompted an influx of cations and a subsequent increase in proliferation and differentiation into oligodendrocytes and neurons and the polarization of astrocytes from a pro-inflammatory phenotype to a pro-regenerative/anti-inflammatory phenotype. Moreover, neurons derived from blue-light-stimulated ChR2-NPCs exhibited both increased branching and axon length and improved axon growth in the presence of axonal inhibitory drugs such as lysophosphatidic acid or chondroitin sulfate proteoglycan. Our results highlight the enormous potential of optogenetically stimulated NPCs as a means to increase neuroregeneration and improve cell therapy outcomes for enhancing better engraftments and cell identity upon transplantation in conditions such as SCI.

Effect of roasting conditions on pigment composition and some quality parameters of pistachio oil.

Pistachio roasting before oil extraction increases consumer preference but may cause changes in the oil composition. In this work, the effect of different roasting conditions on the physical parameters, oxidative stability, and pigment composition of pistachio oil extracted by pressure was studied. Density value of pistachio oil was reduced with severe roasting conditions (125 °C), while viscosity increased slightly. This adverse effect was compensated by a significant increase in both oxidative stability and, especially, in the content of chlorophyll and carotenoid pigments. Pistachio roasting temperature had a clear impact on the color of the pistachio oils, changing from yellow in oils from raw or minimally roasted pistachios (50-75 °C) to brilliant green in oils from pistachios subjected to higher temperature treatments (100-125 °C). An increase in temperature favored the pigment transfer to the oil. The green oils had a total pigment content between 2.3 and 4 times higher than the yellow oils.