Randomized phase 2 study of valproic acid combined with simvastatin and gemcitabine/nab-paclitaxel-based regimens in untreated metastatic pancreatic adenocarcinoma patients: the VESPA trial study protocol.

BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (mPDAC) patients have very poor prognosis highlighting the urgent need of novel treatments. In this regard, repurposing non-oncology already-approved drugs might be an attractive strategy to offer more-effective treatment easily tested in clinical trials. Accumulating evidence suggests that epigenetic deregulation is a hallmark of cancer contributing to treatment resistance in several solid tumors, including PDAC. Histone deacetylase inhibitors (HDACi) are epigenetic drugs we have investigated preclinically and clinically as anticancer agents. Valproic acid (VPA) is a generic low-cost anticonvulsant and mood stabilizer with HDAC inhibitory activity, and anticancer properties also demonstrated in PDAC models. Statins use was reported to be associated with lower mortality risk in patients with pancreatic cancer and statins have been shown to have a direct antitumor effect when used alone or in combination therapy. We recently showed capability of VPA/Simvastatin (SIM) combination to potentiate the antitumor activity of gemcitabine/nab-paclitaxel in vitro and in vivo PDAC preclinical models. METHODS/DESIGN: VESPA is a patient-centric open label randomized multicenter phase-II investigator-initiated trial, evaluating the feasibility, safety, and efficacy of VPA/SIM plus first line gemcitabine/nab-paclitaxel-based regimens (AG or PAXG) (experimental arm) versus chemotherapy alone (standard arm) in mPDAC patients. The study involves Italian and Spanish oncology centers and includes an initial 6-patients safety run-in-phase. A sample size of 240 patients (120 for each arm) was calculated under the hypothesis that the addition of VPA/SIM to gemcitabine and nab-paclitaxel-based regimens may extend progression free survival from 6 to 9 months in the experimental arm. Secondary endpoints are overall survival, response rate, disease control rate, duration of response, CA 19.9 reduction, toxicity, and quality of life. The study includes a patient engagement plan and complementary biomarkers studies on tumor and blood samples. CONCLUSIONS: VESPA is the first trial evaluating efficacy and safety of two repurposed drugs in oncology such as VPA and SIM, in combination with standard chemotherapy, with the aim of improving mPDAC survival. The study is ongoing. Enrollment started in June 2023 and a total of 63 patients have been enrolled as of June 2024. TRIAL REGISTRATION: EudraCT number: 2022-004154-63; ClinicalTrials.gov identifier NCT05821556, posted 2023/04/20.

Pediatric Plexiform Fibromyxoma: A Case Report.

The plexiform fibromyxoma is a rare mesenchymal tumor in adults that generally originates in the antrum of stomach, being its occurrence in pediatric patients exceptional. It was classified as a distinct entity by World Health Organization in 2010. No recurrences and metastases have been documented in many of the reported patients to date, being the surgical treatment curative. We report the case of a 3-month-old infant who presented to the emergency department with an episode of intestinal subocclusion requiring an emergent surgery. During the surgical intervention, a mass was identified in the jejunum, causing partial occlusion of its lumen. The surgical pathology report revealed an infiltrative tumor composed of spindle-shaped cells disposed in a stroma with a plexiform pattern alternating myxoid areas. These findings and the immunohistochemical characteristics of the neoplastic cells led to classify the tumor as a plexiform fibromyxoma. A description of the immunophenotype of this tumor is made and differential diagnosis with other gastrointestinal tumors is also discussed.

Cow's Milk-related Symptom Score (CoMiSS) values in presumed healthy European infants aged 6-12 months: a cross-sectional study.

The Cow's Milk-related Symptom Score (CoMiSS) is an awareness tool for evaluating cow's milk-related symptoms. Previous studies have focused on providing CoMiSS values for healthy and symptomatic infants aged 0-6 months. However, there is a notable gap in the literature concerning CoMiSS values for infants older than 6 months. This cross-sectional study aimed to determine CoMiSS values in presumed healthy infants who have completed 6 months and are up to 12 months old, hereafter referred to as 6 to 12 months old. Physicians from six European countries prospectively determined CoMiSS values in infants attending well-child clinics. Exclusion criteria included preterm delivery, acute or chronic disease, and the consumption of a therapeutic formula, dietary supplements (except vitamins), or medication. The following information was collected: gestational age, gender, age, type of feed (breast milk or infant formula), and complementary feeding. Descriptive statistics were summarized with mean and standard deviation for normally distributed continuous variables, median and IQR for non-normally distributed variables, and differences in CoMiSS values were analyzed with appropriate tests. Data from 609 infants were obtained. The overall median (Q1-Q3) CoMiSS values were 3 (1-5). Significant differences were found across age groups (p < 0.001), but not across groups based on gender (p = 0.551) or feeding type (p = 0.880).   Conclusions: This study provided CoMiSS values in presumed healthy infants aged 6-12 months. Additional studies should be conducted to establish the use of CoMiSS to assess cow's milk-related symptoms in infants 6 months and older. What is Known: • The Cow's Milk-related Symptom Score (CoMiSS) is an awareness tool for evaluating symptoms related to cow's milk. • CoMiSS values for presumed healthy infants aged 0-6 months infants are already available. What is New: • CoMiSS values in European infants aged 6-12 months are provided. • These CoMiSS values differed across various age groups but not across groups based on gender or feeding type.

Gender-related stress factors and emotional perception in migraine: a structured online questionnaire in migraine patients and controls.

BACKGROUND: While migraine is markedly prevalent in women, gender-related phenotype differences were rarely assessed. For this reason, we investigated, through a multicenter observational cross-sectional study, based on an online questionnaire, gender-related differences in stress factors, emotions, and pain perception in migraine patients and controls and their impact on migraine severity. METHODS: The study was designed as an online questionnaire. The link was emailed to healthy subjects (C) and migraine patients (MIG) (age 18-75, education ≥ 13 years) recruited during the first visit in 8 Italian Headache Centers adhering to Italian Society for Headache Study (SISC). The questionnaire included personal/social/work information, the Perceived Stress Scale, the Romance Quality Scale, the Emotion Regulation Questionnaire, the Beck Anxiety Inventory, the Body Perception Questionnaire, the pain perception, and a self-assessment of migraine severity in the last 3 months. RESULTS: 202 MIG and 202 C completed the survey. Independently from gender, migraine was characterized by higher pain sensitivity and more severe partner relationships. The female gender, in MIG, exhibited higher anxiety scores, body awareness, and reduced emotional suppression. Body awareness and emotional suppression were discriminating factors between genders in control and migraine groups without relevant influence on disease features. Perceived perception of migraine severity was similar between genders. CONCLUSION: Gender-related emotional and stress factors did not contribute to delineate a distinct phenotype in migraine men and women. The possible impact of emotional and stress factors characterizing genders could be considered for a single case-tailored therapeutic approach.

Exploring histological remission in pediatric patients with celiac disease.

In response to the article presented by Laura Rodríguez-Martínez et al., which discusses mucosal healing rates in celiac disease and the risk factors for persistent damage despite a gluten-free diet in adults, we present a review of biopsies from pediatric patients with celiac disease performed at our center between 2001 and 2020. Notably, there is a higher rate of mucosal healing compared to adults (83%), and factors such as age at diagnosis, histological involvement, and anti-tissue transglutaminase antibody levels at diagnosis do not appear to be significant risk factors, unlike in adults.

Clinical leadership and coping strategies in times of COVID-19: observational study with health managers in Mendoza.

BACKGROUND: The outbreak of the COVID-19 pandemic required an immediate response to the healthcare challenges it posed. This study was conducted to identify actions that helped healthcare professionals to overcome the initial impact in Mendoza (Argentina). METHODS: A cross-sectional study was carried out in a non-random sample of managers and staff of the public health system of Mendoza (Argentina) (n = 134). An ad-hoc and voluntary survey was carried out with 5 multi-response questions that combined questions referring to the management of the pandemic at the organizational level with others referring to coping at the individual level. The survey questions were formulated based on the results of six focus groups that were conducted previously. Descriptive frequency analysis was performed. RESULTS: 60 people agreed to participate and 45 answered the full questionnaire. At both the organizational and individual level, there was consensus with at least 50% of votes. The most outstanding at the organizational level was "Prioritize the need according to risk" and at the individual level it was "Support from family or friends", being also the most voted option in the whole questionnaire. CONCLUSIONS: The responses that emerged for coping with COVID-19 must be seen as an opportunity to identify strategies that could be effective in addressing future crisis situations that jeopardize the system's response capacity. Moreover, it is essential to retain both changes at the organizational level (e.g., new protocols, multidisciplinary work, shift restructuring, etc.) and coping strategies at the individual level (e.g., social support, leisure activities, etc.) that have proven positive outcomes.

Intestinal anti-tissue transglutaminase IgA deposits as a complementary method for the diagnostic evaluation of celiac disease in patients with low-grade histological lesions.

Evaluating the usefulness of intestinal anti-transglutaminase IgA (anti-TG2 IgA) deposits detection as a complementary or decision-supporting tool in the diagnosis of celiac disease (CD) in patients with low degree of enteropathy. Small intestinal biopsies (SIB) were performed from 2008 to 2017 in patients on suspicion of CD (positive CD serology and/or symptoms) referred to our Pediatric Gastroenterology Unit. We determined anti-TG2 IgA deposits by using double immunofluorescence in all the patients in whom Marsh 0 or Marsh 1 was detected in the conventional histological study and in a random selection of patients with clearly positive serology and histological Marsh 2-3 lesion. Seventy-five pediatric patients were split into three groups according to the final diagnosis: (i) 13 children with a Marsh 0 or 1, negative CD serology and final non-CD diagnosis; none presented intestinal anti-TG2 IgA deposits; (ii) 15 potential CD cases (Marsh 0 or 1 and CD-associated antibodies), detecting anti-TG2 IgA deposits in 12; on follow-up, another biopsy performed in 11/15 showed villi atrophy in seven and a Marsh 2 lesion in two of them, patients being finally diagnosed as CD cases; and (iii) 47 children with Marsh 2-3 histological lesion and final CD diagnosis; all of them had intestinal anti-TG2 IgA deposits. Anti-TG2 deposits are a useful complementary tool for CD diagnosis in pediatric population with digestive pathologies suggestive of CD. It is especially helpful in those with low-grade lesion, in which anti-TG2 deposits are predictive of the development of more severe lesions on follow-up.

Inhibition of autophagy by chloroquine prevents resistance to PI3K/AKT inhibitors and potentiates their antitumor effect in combination with paclitaxel in triple negative breast cancer models.

BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive disease characterized by high risk of relapse and development of resistance to different chemotherapy agents. Several targeted therapies have been investigated in TNBC with modest results in clinical trials. Among these, PI3K/AKT inhibitors have been evaluated in addition to standard therapies, yielding conflicting results and making attempts on elucidating inherent mechanisms of resistance of great interest. Increasing evidences suggest that PI3K/AKT inhibitors can induce autophagy in different cancers. Autophagy represents a supposed mechanism of drug-resistance in aggressive tumors, like TNBC. We, therefore, investigated if two PI3K/AKT inhibitors, ipatasertib and taselisib, could induce autophagy in breast cancer models, and whether chloroquine (CQ), a well known autophagy inhibitor, could potentiate ipatasertib and taselisib anti-cancer effect in combination with conventional chemotherapy. METHODS: The induction of autophagy after ipatasertib and taselisib treatment was evaluated in MDAMB231, MDAM468, MCF7, SKBR3 and MDAB361 breast cancer cell lines by assaying LC3-I conversion to LC3-II through immunoblotting and immunofluorescence. Other autophagy-markers as p62/SQSTM1 and ATG5 were evaluated by immunoblotting. Synergistic antiproliferative effect of double and triple combinations of ipatasertib/taselisib plus CQ and/or paclitaxel were evaluated by SRB assay and clonogenic assay. Anti-apoptotic effect of double combination of ipatasertib/taselisib plus CQ was evaluated by increased cleaved-PARP by immunoblot and by Annexin V- flow cytometric analysis. In vivo experiments were performed on xenograft model of MDAMB231 in NOD/SCID mice. RESULTS: Our results suggested that ipatasertib and taselisib induce increased autophagy signaling in different breast cancer models. This effect was particularly evident in PI3K/AKT resistant TNBC cells, where the inhibition of autophagy by CQ potentiates the therapeutic effect of PI3K/AKT inhibitors in vitro and in vivo TNBC models, synergizing with taxane-based chemotherapy. CONCLUSION: These data suggest that inhibition of authophagy with CQ could overcome mechanism of drug resistance to PI3K/AKT inhibitors plus paclitaxel in TNBC making the evaluation of such combinations in clinical trials warranted.

ESPGHAN Position Paper on Management and Follow-up of Children and Adolescents With Celiac Disease.

OBJECTIVES: To gather the current evidence and to offer recommendations for follow-up and management. METHODS: The Special Interest Group on Celiac Diseases of the European Society of Paediatric Gastroenterology Hepatology and Nutrition formulated ten questions considered to be essential for follow-up care. A literature search (January 2010-March 2020) was performed in PubMed or Medline. Relevant publications were identified and potentially eligible studies were assessed. Statements and recommendations were developed and discussed by all coauthors. Recommendations were voted upon: joint agreement was set as at least 85%. RESULTS: Publications (n = 2775) were identified and 164 were included. Using evidence or expert opinion, 37 recommendations were formulated on: The need to perform follow-up, its frequency and what should be assessed, how to assess adherence to the gluten-free diet, when to expect catch-up growth, how to treat anemia, how to approach persistent high serum levels of antibodies against tissue-transglutaminase, the indication to perform biopsies, assessment of quality of life, management of children with unclear diagnosis for which a gluten-challenge is indicated, children with associated type 1 diabetes or IgA deficiency, cases of potential celiac disease, which professionals should perform follow-up, how to improve the communication to patients and their parents/caregivers and transition from pediatric to adult health care. CONCLUSIONS: We offer recommendations to improve follow-up of children and adolescents with celiac disease and highlight gaps that should be investigated to further improve management.

Correlation of Anti-Tissue Transglutaminase Antibodies With the Mucosal Changes and IgA Status of Children With Celiac Disease.

OBJECTIVES: The objective of this study was to assess the association between serological markers and changes of the intestinal mucosa in children with celiac disease (CD). METHODS: Clinical data from CD patients under 15 years old were collected from the participating centers in an on-line multicenter nationwide observational Spanish registry called REPAC-2 (2011-2017). Correlation between anti-tissue transglutaminase antibodies (t-TGA) levels and other variables, including mucosal damage and clinical findings (symptoms, age, and gender), was assessed. RESULTS: A total of 2955 of 4838 patients had t-TGA and a small bowel biopsy (SBB) performed for CD diagnosis. A total of 1931 (66.2%) patients with normal IgA values had a Marsh 3b-c lesion and 1892 (64.9%) had t-TGA Immunoglobulin A (IgA) ≥ 10 times upper limit of normal (ULN). There is a statistically significant association between t-TGA IgA levels and the degree of mucosal damage ( P < 0.001), the higher the t-TGA IgA levels the more severe the mucosal damage. Those patients who reported symptoms had more severe mucosal damage ( P = 0.001). On the contrary, there was a negative association between age and changes of the intestinal mucosa ( P < 0.001). No association was found with gender. Regarding the IgA-deficient patients, 47.4% (18 cases) had t-TGA Immunoglobulin A (IgA) ≥ 10 times ULN and a Marsh 3b-c lesion was observed in 68.4% (26 patients). No statistical relation was found between t-TGA IgG levels and the changes of the intestinal mucosa, neither a relation with age, gender, or symptoms. CONCLUSIONS: There is a positive correlation between t-TGA IgA levels and the severity of changes of the intestinal mucosa. Such correlation was not found in IgA-deficient patients who had positive t-TGA IgG serology. The results in this group of patients support the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition recommendations about the need of performing a SBB in IgA-deficient individuals despite high t-TGA IgG levels.

Follow-up practices for children and adolescents with celiac disease: results of an international survey.

Adequate follow-up in celiac disease is important to improve dietary compliance and treat disease-related symptoms and possible complications. However, data on the follow-up of celiac children is scarce. We aimed to assess current pediatric celiac follow-up practices across Europe. Pediatricians and pediatric gastroenterologists from 35 countries in Europe, Israel, Turkey, and Russia completed an anonymous survey which comprised a 52-item questionnaire developed by the ESPGHAN Special Interest Group on Celiac Disease. A total of 911 physicians, the majority of whom exclusively worked in pediatric care (83%) and academic institutions (60%), completed the questionnaire. Mean age and mean experience with celiac care were 48.7 years (± 10.6) and 15.7 years (± 9.9), respectively. The vast majority (≥ 92%) always assessed anthropometry, dietary adherence, and tissue-transglutaminase IgA-antibodies at every visit, with the first visit being between 3 and 6 months after diagnosis. Other parameters (% always tested) were as follows: complete blood count (60%), iron status (48%), liver enzymes (42%), thyroid function (38%), and vitamin D (26%). Quality of life was never assessed by 35% of the responding physicians. Transition to adult care was mostly completed via a written transition report (37%) or no formal transition at all (27%).Conclusions: Follow-up of celiac children and adolescents in Europe may be improved, especially regarding a more rational use of (laboratory) tests, dietary and QoL assessment, and transition to adult care. Evidence-based advice from international scientific societies is needed. What is Known: • Follow-up in celiac disease is important to treat disease-related symptoms, improve dietary compliance, and prevent possible complications. • There is a lack of consensus about the appropriate follow-up. What is New: • Almost all European physicians assess anthropometry, tissue-transglutaminase IgA-antibodies, and dietary adherence at every visit, but there are large variations in other follow-up aspects. • Follow-up could be improved by a more rational use of (laboratory) tests, increased intention to dietary compliance, and quality of life together with transition programs to adult care.

Work Patterns and Support Needs of People with Serious Mental Illness.

People with serious mental illness (SMI) are frequently unemployed, despite their willingness to work. Several employment interventions approaches have proven efficacy; however, work integration rates for people with SMI continue to be low. In total, 145 participants with a SMI completed a survey, answering questions regarding their personal information, work history, whether they received supports towards work integration, and their functional level. In addition, clinical records were accessed to verify and complete clinical history. A quantitative descriptive approach was used to analyze the data. No significant differences were found between those who were working and who were not, based on age, gender, educational level, living situation, and suicide risk. Those who were working presented higher levels of functional capacity than those who were not working. Factors associated with employment outcomes continue to remain unclear, adding value to the role that the different supports towards work integration may have.

HPLC-MS2 Analysis of Chlorophylls in Green Teas Establishes Differences among Varieties.

Green teas are nonfermented teas, the quality of which is measured by the green color. However, this category encompasses a high number of tea varieties that differ in cultivation and processing. For example, leaf or stem/bubble tea, plants cultivated under a light or shadow regime, powdered or unpowdered tea, etc. These variables determine the different qualities among green teas (Matcha, Sencha, Gyokuro, etc.) and consequently their different values on the market. Our purpose is to determine if these variables can exert an influence on the chlorophyll profile and to establish a characteristic profile for specific green teas. With such an aim, we analyzed the chlorophyll profiles of 6 different green tea varieties via HPLC-hr ESI/APCI-MS2 and identified up to 17 different chlorophyll compounds. For the first time, 132-hydroxy-chlorophylls, 132-hydroxy-pheophytins, and 151-hydroxy-lactone-pheophytins have been identified in green teas. Shadow teas (Matcha and Sencha) and light-regimen green teas can be statistically differentiated by the total chlorophyll content and the a/b ratio. However, only Matcha tea contains a higher proportion of chlorophylls a and b among the green tea varieties analyzed, justifying the higher quality and price of this variety. Other chlorophyll metabolites (pheophytins, pyropheophytins, and oxidized chlorophylls) are indicative of the various processing and storage conditions.

Association between faecal pH and fat absorption in children with cystic fibrosis on a controlled diet and enzyme supplements dose.

BACKGROUND: Despite treatment with pancreatic enzyme replacement therapy (PERT), patients with cystic fibrosis (CF) can still suffer from fat malabsorption. A cause could be low intestinal pH disabling PERT. The aim of this study was to assess the association between faecal pH (as intestinal pH surrogate) and coefficient of fat absorption (CFA). Additionally, faecal free fatty acids (FFAs) were quantified to determine the amount of digested, but unabsorbed fat. METHODS: In a 24-h pilot study, CF patients followed a standardised diet with fixed PERT doses, corresponding to theoretical optimal doses determined by an in vitro digestion model. Study variables were faecal pH, fat and FFA excretion, CFA and transit time. Linear mixed regression models were applied to explore associations. RESULTS: In 43 patients, median (1st, 3rd quartile) faecal pH and CFA were 6.1% (5.8, 6.4) and 90% (84, 94), and they were positively associated (p < 0.001). An inverse relationship was found between faecal pH and total fat excretion (p < 0.01), as well as total FFA (p = 0.048). Higher faecal pH was associated with longer intestinal transit time (p = 0.049) and the use of proton pump inhibitors (p = 0.009). CONCLUSIONS: Although the clinical significance of faecal pH is not fully defined, its usefulness as a surrogate biomarker for intestinal pH should be further explored. IMPACT: Faecal pH is a physiological parameter that may be related to intestinal pH and may provide important physiopathological information on CF-related pancreatic insufficiency. Faecal pH is correlated with fat absorption, and this may explain why pancreatic enzyme replacement therapy is not effective in all patients with malabsorption related to CF. Use of proton pump inhibitors is associated to higher values of faecal pH. Faecal pH could be used as a surrogate biomarker to routinely monitor the efficacy of pancreatic enzyme replacement therapy in clinical practice. Strategies to increase intestinal pH in children with cystic fibrosis should be targeted.

Analysis of gluten immunogenic peptides in feces to assess adherence to the gluten-free diet in pediatric celiac patients.

PURPOSE: In celiac disease (CD) there is a need for precise and non-invasive tools to assess dietary compliance to the gluten-free diet (GFD). Our aim is to evaluate the efficacy of the detection of gluten immunogenic peptides (GIP) in feces, to monitor in real life, the adherence to GFD in pediatric patients with CD. METHODS: A cross-sectional, prospective study was conducted. Fecal samples from CD children were analyzed by a rapid immunochromatographic (IC) test and by an ELISA method, both based on the antigliadin 33-mer monoclonal antibody. RESULTS: Group 1 comprises 43 children on a GFD. According to the food records (FR), 39/43 patients were compliant with the GFD and gluten consumption was recorded in 4. GIP were detected in 15/43 individuals by the ELISA method and also in 7 by IC strips. Group 2: comprise 18 children at CD diagnosis; GIP levels decreased over time (p < 0.001) in a non-linear way (p = 0.028) after starting a GFD and were below the detection limit on the third day in most individuals. CONCLUSION: GIP were detected, both by ELISA and by IC strips, in CD patients on a GFD, in which no consumption of gluten had been registered on the FR, confirming GIP detection to be superior to FR discovering involuntary transgressions. Despite a positive correlation between the amount of gluten intake and the concentration of GIP in feces, the interindividual variations observed suggest gastrointestinal factors influencing GIP recovery need to be further investigated.

The role of pro-, pre- and symbiotics in cancer: A systematic review.

WHAT IS KNOWN AND OBJECTIVE: Cancer is one of the most important causes of morbidity and mortality worldwide. Pro-, pre- and symbiotics can modulate host metabolism and gut microbiota and potentially help prevent cancer and modulate the adverse effects (AEs) of treatments. Numerous studies on this role for pro-, pre- and symbiotics have reported inconsistent results. The purpose of this review was to examine current scientific evidence from randomized controlled trials (RCTs) on the effects of pro-, pre- and symbiotics on the incidence of complications and AEs, especially diarrhoea, in cancer management. METHODS: A systematic literature search was implemented in MEDLINE using the MeSH terms "probiotics", "prebiotics", "symbiotics" and "neoplasms", according to PRISMA guidelines. Reference lists were also handsearched to identify additional eligible RCTs. Three reviewers independently assessed the eligibility of each RCT. Of 714 retrieved abstracts, 22 articles with 2287 participants were included in the analysis. RESULTS AND DISCUSSION: The most studied bacteriotherapies were probiotics and symbiotics, in 10 and 7 studies, respectively. Both Lactobacillus and Bifidobacterium strains were used in 18 studies, while Lactobacillus and Bifidobacterium strains were individually used in 9 and 2 studies, respectively. Diarrhoea incidence rates were 3.2%-39.1% in intervention groups and 6.7%-60.9% in control groups, while infection incidence rates were 11.1%-22.7% in intervention groups and 17.3%-28.7% in control groups. WHAT IS NEW AND CONCLUSIONS: Pro-, pre- and symbiotics may potentially be efficacious in reducing complications associated with chemotherapy, radiotherapy and surgery in patients with cancer.

Evaluating the reliability of neurocognitive biomarkers of neurodegenerative diseases across countries: A machine learning approach.

Accurate early diagnosis of neurodegenerative diseases represents a growing challenge for current clinical practice. Promisingly, current tools can be complemented by computational decision-support methods to objectively analyze multidimensional measures and increase diagnostic confidence. Yet, widespread application of these tools cannot be recommended unless they are proven to perform consistently and reproducibly across samples from different countries. We implemented machine-learning algorithms to evaluate the prediction power of neurocognitive biomarkers (behavioral and imaging measures) for classifying two neurodegenerative conditions -Alzheimer Disease (AD) and behavioral variant frontotemporal dementia (bvFTD)- across three different countries (>200 participants). We use machine-learning tools integrating multimodal measures such as cognitive scores (executive functions and cognitive screening) and brain atrophy volume (voxel based morphometry from fronto-temporo-insular regions in bvFTD, and temporo-parietal regions in AD) to identify the most relevant features in predicting the incidence of the diseases. In the Country-1 cohort, predictions of AD and bvFTD became maximally improved upon inclusion of cognitive screenings outcomes combined with atrophy levels. Multimodal training data from this cohort allowed predicting both AD and bvFTD in the other two novel datasets from other countries with high accuracy (>90%), demonstrating the robustness of the approach as well as the differential specificity and reliability of behavioral and neural markers for each condition. In sum, this is the first study, across centers and countries, to validate the predictive power of cognitive signatures combined with atrophy levels for contrastive neurodegenerative conditions, validating a benchmark for future assessments of reliability and reproducibility.

A multidimensional and multi-feature framework for cardiac interoception.

Interoception (the sensing of inner-body signals) is a multi-faceted construct with major relevance for basic and clinical neuroscience research. However, the neurocognitive signatures of this domain (cutting across behavioral, electrophysiological, and fMRI connectivity levels) are rarely reported in convergent or systematic fashion. Additionally, various controversies in the field might reflect the caveats of standard interoceptive accuracy (IA) indexes, mainly based on heartbeat detection (HBD) tasks. Here we profit from a novel IA index (md) to provide a convergent multidimensional and multi-feature approach to cardiac interoception. We found that outcomes from our IA-md index are associated with -and predicted by- canonical markers of interoception, including the hd-EEG-derived heart-evoked potential (HEP), fMRI functional connectivity within interoceptive hubs (insular, somatosensory, and frontal networks), and socio-emotional skills. Importantly, these associations proved more robust than those involving current IA indexes. Furthermore, this pattern of results persisted when taking into consideration confounding variables (gender, age, years of education, and executive functioning). This work has relevant theoretical and clinical implications concerning the characterization of cardiac interoception and its assessment in heterogeneous samples, such as those composed of neuropsychiatric patients.

Profile of Chlorophyll Catabolites in Senescent Leaves of Epipremnun aureum Includes a Catabolite Esterified with Hydroxytyrosol 1-O-Glucoside.

Despite the fact that chlorophyll degradation is a physiological phenomenon occurring daily in all photosynthetic tissues, chlorophyll catabolites are not fully identified. Three new forms (1, 3, and 4) of linear chlorophyll catabolites (phyllobilins) have been characterized in senescent leaves of Epipremnun aureum with spectroscopic data. Compound 1 is a hypermodified blue fluorescent chlorophyll catabolite (hmFCC) esterified with the potent antioxidant hydroxytyrosol. The sequestration of this phenol by a chlorophyll catabolite could explain the physiological meaning of the persistence of hmFCCs in some senescent plants. Compound 3, a yellow chlorophyll catabolite (YCC) originated from the oxidation at C-15 of 1. YCCs have been identified previously and are exclusively formed in the plant vacuole from the final nonfluorescent chlorophyll catabolites (NCCs). The presence of 3 in leaves implies a new reaction in chlorophyll catabolism, as the characterization of 3 implies that YCCs can be also be oxidized in the cytosol from FCCs. Finally, phyllobilin 4 represents a new type of YCC characterized by an inflexible bicyclo glucosyl moiety linked through an intramolecular esterification of the propionic acid residue with the C-3 hydroxy group. The corresponding NCC precursor was recently identified and now the characterization of 4 shows that even this rigid structure can be further oxidized. Undoubtedly, the characterization of phyllobilins is essential to completely comprehend chlorophyll degradation.

Chemical Profile and Antibacterial Activity of a Novel Spanish Propolis with New Polyphenols also Found in Olive Oil and High Amounts of Flavonoids.

Propolis is a natural product obtained from hives. Its chemical composition varies depending on the flora of its surroundings, but nevertheless, common for all types of propolis, they all exhibit remarkable biological activities. The aim of this study was to investigate the chemical composition and antimicrobial activity of a novel Spanish Ethanolic Extract of Propolis (SEEP). It was found that this new SEEP contains high amounts of polyphenols (205 ± 34 mg GAE/g), with unusually more than half of this of the flavonoid class (127 ± 19 mg QE/g). Moreover, a detailed analysis of its chemical composition revealed the presence of olive oil compounds (Vanillic acid, 1-Acetoxypinoresinol, p-HPEA-EA and 3,4-DHPEA-EDA) never detected before in propolis samples. Additionally, relatively high amounts of ferulic acid and quercetin were distinguished, both known for their important therapeutic benefits. Regarding the antimicrobial properties of SEEP, the minimal inhibitory and bactericidal concentrations (MIC and MBC) against Staphylococcus epidermidis strains were found at the concentrations of 240 and 480 µg/mL, respectively. Importantly, subinhibitory concentrations were also found to significantly decrease bacterial growth. Therefore, the results presented here uncover a new type of propolis rich in flavonoids with promising potential uses in different areas of human health.