Efficacy of haematopoietic stem cell boost as a rescue for poor graft function after haematopoietic stem cell transplantation: A multicentre retrospective study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC).

Haematopoietic stem cell reinjection may be a curative option for poor graft function after haematopoietic stem cell transplantation; however, literature supporting its use remains limited. We conducted a multicentre retrospective study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy, including 55 patients. We demonstrated response rates of nearly 40% and two-year survival of more than 60% in the context of an otherwise deadly complication and we observed that the timing of injection and the degree of cytopenia are strongly associated with outcomes. This study shows the feasibility of the procedure informing on its epidemiology, outcomes and prognostic factors, setting the stage for future guidelines.

Are seven amino acid substitutions sufficient to explain the evolution of high l-DOPA 4,5-dioxygenase activity leading to betalain pigmentation? Revisiting the gain-of-function mutants of Bean et al. (2018).

This work revisits a publication by Bean et al. (2018) that reports seven amino acid substitutions are essential for the evolution of l-DOPA 4,5-dioxygenase (DODA) activity in Caryophyllales. In this study, we explore several concerns which led us to replicate the analyses of Bean et al. (2018). Our comparative analyses, with structural modelling, implicate numerous residues additional to those identified by Bean et al. (2018), with many of these additional residues occurring around the active site of BvDODAα1. We therefore replicated the analyses of Bean et al. (2018) to re-observe the effect of their original seven residue substitutions in a BvDODAα2 background, that is the BvDODAα2-mut3 variant. Multiple in vivo assays, in both Saccharomyces cerevisiae and Nicotiana benthamiana, did not result in visible DODA activity in BvDODAα2-mut3, with betalain production always 10-fold below BvDODAα1. In vitro assays also revealed substantial differences in both catalytic activity and pH optima between BvDODAα1, BvDODAα2 and BvDODAα2-mut3 proteins, explaining their differing performance in vivo. In summary, we were unable to replicate the in vivo analyses of Bean et al. (2018), and our quantitative in vivo and in vitro analyses suggest a minimal effect of these seven residues in altering catalytic activity of BvDODAα2. We conclude that the evolutionary pathway to high DODA activity is substantially more complex than implied by Bean et al. (2018).

Randomized phase II BGOG/ENGOT-cx1 study of paclitaxel-carboplatin with or without nintedanib in first-line recurrent or advanced cervical cancer.

OBJECTIVE: Nintedanib is an oral tyrosine kinase inhibitor targeting, among others, vascular endothelial growth factor receptor. The aim was to establish the role of nintedanib in addition to paclitaxel and carboplatin in first-line recurrent/metastatic cervical cancer. METHODS: Double-blind phase II randomized study in patients with first-line recurrent or primary advanced (FIGO stage IVB) cervical cancer. Patients received carboplatin-paclitaxel with oral nintedanib 200 mg BID/placebo. The primary endpoint was progression-free survival (PFS) at 1.5 years and α = 0.15, ß = 80%, one sided. RESULTS: 120 patients (62 N, 58C) were randomized. Median follow-up was 35 months. Baseline characteristics were similar in both groups (total population: squamous cell carcinoma 62%, prior radiotherapy 64%, primary advanced 25%, recurrent 75%). The primary endpoint was met with a PFS at 1.5 years of 15.1% versus 12.8% in favor of the nintedanib arm (p = 0.057). Median overall survival (OS) was 21.7 and 16.4 months for N and C, respectively. Confirmed RECIST response rate was 48% for N and 39% for C. No new adverse events were noted for N. However, N was associated with numerically more serious adverse events for anemia and febrile neutropenia. Global health status during and at the end of the study was similar in both arms. CONCLUSION: The study met its primary endpoint with a prolonged PFS in the N arm. No new safety signals were observed.

A randomized, non-inferiority trial on the DuoStim strategy in PGT-A cycles.

RESEARCH QUESTION: Is the DuoStim strategy an effective alternative to two conventional ovarian stimulation cycles in poor-prognosis patients undergoing preimplantation genetic testing for aneuploidies (PGT-A) to improve euploidy rates and obtain the first euploid embryo in less time? DESIGN: This randomized controlled trial was performed at IVI Madrid between June 2017 and December 2020 and included 80 patients with a suboptimal profile aged 38 or older undergoing PGT-A cycles. Patients were blindly randomized into two groups: 39 women underwent two ovarian stimulations in consecutive cycles (control group), whereas the double stimulation strategy was applied to 41 women (DuoStim group). The main outcome was the euploidy rate in each group. The secondary outcomes were the time it took to obtain a euploid embryo and the main cycle outcomes. RESULTS: The baseline characteristics of the patients were similar. No differences were found between the control group and the DuoStim group in the mean days of stimulation (21.3 ± 1.6 versus 23.0 ± 1.4, P = 0.10), total gonadotrophins (4005 ± 450 versus 4245 ± 430, P = 0.43), metaphase II oocytes (8.7 ± 1.8 versus 6.8 ± 1.7, P = 0.15) or euploid embryos obtained (0.8 ± 0.4 versus 0.6 ± 0.4, P = 0.45). The euploid rate per randomized patient (ITT) was 16.1% in the control group versus 22.7% in the DuoStim group, with P-values of 0.371, and the euploidy rate per patient treated was 39.0% versus 45.7% in the control versus DuoStim groups. However, there was a significant difference in the average number of days it took to obtain a euploid blastocyst, favouring the DuoStim group (44.1 ± 2.0 versus 23.3 ± 2.8, P < 0.001). CONCLUSIONS: The use of the DuoStim strategy in poor-prognosis patients undergoing PGT-A cycles maintains a similar euploidy rate while reducing the time required to obtain a euploid blastocyst.

Clinical and molecular signature of survival and resistance to olaparib plus pegylated liposomal doxorubicin in platinum-resistant ovarian cancer: a stratified analysis from the phase II clinical trial ROLANDO, GEICO-1601.

OBJECTIVE: To determine the potential prognostic value of clinical and molecular biomarkers in the survival of patients with platinum-resistant ovarian cancer treated with olaparib and pegylated liposomal doxorubicin. METHODS: ROLANDO was a single-arm phase II trial that included patients with high-grade serous or endometrioid tumors and at least one previous platinum-resistant recurrence regardless of BRCA status. Patients received 6 cycles of pegylated liposomal doxorubicin every 28 days plus olaparib 300 mg twice daily. followed by olaparib 300 mg twice daily; monotherapy until progression or unacceptable toxicity. Prognostic factors including previous lines (and platinum-containing ones), BRCA mutation status, previous bevacizumab, CA-125 levels, and the neutrophil/lymphocyte ratio, lymphocyte/monocyte ratio, and platelet/lymphocyte ratio calculated at inclusion were analyzed through a multivariate logistic regression and factor analysis of mixed data. RESULTS: Thirty-one patients were included. Median age was 57 years (range 43-75), Eastern Cooperative Oncolgy Group performance status 0/1: 32.3%/67.7% and BRCA mutated: 16.1%. Prior treatment lines were >2 lines: 14 (45.2%) patients, ≥2 platinum lines: 21 patients (67.7%) and previous bevacizumab 19 (61.3%) patients. CA-125 was >2 upper limit normal in 24 (77.4%) patients. A high neutrophil/lymphocyte ratio was associated with worse overall survival by univariate/multivariate regression model (HR=11.18; 95% CI 1.1 to 114.5; p=0.042). No other factors were associated with overall survival in the multivariate model. A multifactorial signature based on clinical and molecular baseline characteristics was capable of defining six patient clusters. Three of these clusters had significantly better prognosis, with a median overall survival of 21.3 months (95% CI 12.2 to not reached). CONCLUSIONS: High neutrophil/lymphocyte ratio at platinum-resistant relapse indicated poor prognosis in patients treated with olaparib plus pegylated liposomal doxorubicin. A multifactorial clinical signature was more precise than single variables for implying the prognosis and may help in therapeutic assignment after further validation in large prospective cohorts.

Virtual Reality for Upper Limb Rehabilitation in Patients With Obstetric Brachial Palsy: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Obstetric brachial palsy (OBP) is a pathology caused by complications during childbirth because of cervical spine elongation, affecting the motor and sensory innervation of the upper limbs. The most common lesion occurs on the C5 and C6 nerve branches, known as Erb-Duchenne palsy. The least common lesion is when all nerve roots are affected (C5-T1), which has the worst prognosis. Virtual reality (VR) is commonly used in neurological rehabilitation for the evaluation and treatment of physical deficits. OBJECTIVE: This systematic review aims to assess the efficacy of VR in the rehabilitation of upper limb function in patients with OBP. METHODS: A search was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines in several scientific databases-PubMed, Web of Science, PEDro, Cochrane, MEDLINE, Scopus, and CINAHL-without language or date restrictions and including articles published up to April 2023. The inclusion criteria were established according to the population, intervention, comparison, outcome, and study (PICOS) design framework: children aged <18 years diagnosed with OBP, VR therapy used in addition to conventional therapy or isolated, VR therapy compared with conventional therapy, outcomes related to OBP rehabilitation therapy, and randomized controlled trials (RCTs). The PEDro scale was used to assess the methodological quality of the RCTs, and the Cochrane Collaboration tool was used to assess the risk of bias. The Review Manager statistical software (version 5.4; The Cochrane Collaboration) was used to conduct the meta-analysis. The results were synthesized through information extraction and presented in tables and forest plots. RESULTS: In total, 5 RCTs were included in this systematic review, with 3 (60%) providing information for the meta-analysis. A total of 138 participants were analyzed. All the studies used semi-immersive or nonimmersive VR systems. The statistical analysis showed no favorable results for all outcomes except for the hand-to-mouth subtest of the Mallet scoring system (functional activity; standardized mean difference -0.97, 95% CI -1.67 to -0.27; P=.007). CONCLUSIONS: The evidence for the use of VR therapy for upper limb rehabilitation outcomes in patients with OBP was insufficient to support its efficacy and strongly recommend its use. Nevertheless, scientific literature supports the use of VR technologies for rehabilitation as it provides several advantages, such as enhancing the patient's motivation, providing direct feedback, and focusing the patient's attention during the intervention. Thus, the use of VR for upper limb rehabilitation in patients with OBP is still in its first stages. Small sample sizes; limited long-term analysis; lack of testing of different doses; and absence of International Classification of Functioning, Disability, and Health-related outcomes were present in the included RCTs, so further research is needed to fully understand the potential of VR technologies as a therapeutic approach for patients with OBP. TRIAL REGISTRATION: PROSPERO CRD42022314264; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=314264.

Environmental and economic impacts of combining backfill materials for novel circular narrow trenches.

Over the last few years, several policies and new technological solutions have targeted the construction sector with the aim of reducing the sector's impacts on the environment. Among the different technological advances proposed, the reuse of materials in construction has been reported as a promising solution for an increase in sustainability and circularity. In particular, a type of cities' undergrounds assets for which materials' reuse is being explored are trenches for protecting services (i.e., water and gas transport pipelines, and optic fibre and other telecommunications services). Nonetheless, the economic and environmental benefits and impact of this type of system is still insufficiently quantified. In this research study, the economic and environmental impacts of four scenarios of trenches were assessed by using Life Cycle Costing (LCC) and Life Cycle Assessment (LCA). The four alternatives analysed consisted of: (1) the classical solution; (2) the classical solution with the reuse of soil; (3) the control low-strength material, and (4) the eco-trench. The results allowed concluding that in the eco-trench system, for which all material is reused, the environmental and economic impacts could be reduced by more than 80% and 50%, respectively. A parametric study for which the dimensions of the trenches were varied, permitted to reinforce these results and to quantify the impact's change along with the width and depth of the trench. Overall, this study provides a comprehensive view of the high-impact potential of reusing material for the construction of trenches in cities. The outcomes allow also remarking that the eco-trench system could be an attractive and advantageous solution for urban infrastructure stakeholders, both from an economic and environmental perspective.

EPA Consensus Project Paper: Shifting from the "Analogic Virtual Patient" to the "Digital Virtual Patient" in Prosthodontics. A Scoping Review.

AIMS: To determine whether the use of single or combined mechanical and virtual articulators, as well as facebows, jaw motion trackers, face scanners, and related devices, actually improve the efficacy of the prosthesis obtained in terms of lifespan and patient-related outcomes. To coin the terms Analogic and Digital Virtual Patients (AVP and DVP) as an attempt to analyze, clarify and synthesize terminology and workflows related to previously so-called devices. MATERIALS AND METHODS: A scoping review was accomplished involving different databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-ScR) checklist and JBI guidance were followed to extract data regarding the Population, Context and Concept established. RESULTS: Available literature on the efficacy of using devices and techniques related to both AVP and DVP workflows showed arguable study designs, great heterogeneity, and questionable quality. CONCLUSIONS: The terms AVP and DVP have been coined as a first step to clarify and simplify concepts and workflows related to the use of both mechanical and virtual articulators, as well as facebows, or facial and intraoral scanners, among others. This scoping review cannot claim that an AVP approach leads to more effective and efficient prosthetic restorations.

[Risk of thrombosis recurrence among patients with COVID-19- and surgery-associated venous thromboembolism]. / Riesgo de recurrencia de la trombosis en pacientes con tromboembolia venosa asociada a COVID-19 y a cirugía.

Introduction: Recent surgery is a well-known major transient risk factor for venous thromboembolism (VTE) due to the low risk of VTE recurrence after anticoagulation is discontinued. On the other hand, the risk of VTE recurrence among patients with COVID-19-associated VTE is unknown. This study aimed to compare the risk of VTE recurrence between patients with COVID-19- and surgery-associated VTE. Methods: A prospective observational single-center study was performed including consecutive patients diagnosed with VTE in a tertiary hospital from January 2020 to May 2022 and followed up for at least 90 days. Baseline characteristics, clinical presentation, and outcomes were assessed. The incidence of VTE recurrence, bleeding, and death was compared between both groups. Results: A total of 344 patients were included in the study: 111 patients with surgery-associated VTE and 233 patients with COVID-19-associated VTE. Patients with COVID-19-associated VTE were more frequently men (65.7% vs 48.6%, p = 0.003). VTE recurrence was 3% among COVID-19 patients and 5.4% among surgical patients, with no significant differences (p = 0.364). The incidence rate of recurrent VTE was 1.25 per 1000 person-months in COVID-19 patients and 2.29 person-months in surgical patients, without significant differences (p = 0.29). In the multivariate analysis, COVID-19 was associated with higher mortality (HR 2.34; 95% CI 1.19-4.58), but not with a higher risk of recurrence (HR 0.52; 95% CI 0.17-1.61). No differences were found in recurrence in the multivariate competing risk analysis (SHR 0.82; 95% CI 0.40 - 2.05). Conclusions: In patients with COVID-19 and surgery-associated VTE, the risk of recurrence was low, with no differences between both groups.

Effects of acute intravenous lipopolysaccharide administration on the plasma lipidome and metabolome in lactating Holstein cows experiencing hyperlipidemia.

INTRODUCTION: The effects of lipopolysaccharides (i.e., endotoxin; LPS) on metabolism are poorly defined in lactating dairy cattle experiencing hyperlipidemia. OBJECTIVES: Our objective was to explore the effects of acute intravenous LPS administration on metabolism in late-lactation Holstein cows experiencing hyperlipidemia induced by intravenous triglyceride infusion and feed restriction. METHODS: Ten non-pregnant lactating Holstein cows (273 ± 35 d in milk) were administered a single bolus of saline (3 mL of saline; n [Formula: see text] 5) or LPS (0.375 [Formula: see text]g of LPS/kg of body weight; n [Formula: see text] 5). Simultaneously, cows were intravenously infused a triglyceride emulsion and feed restricted for 16 h to induce hyperlipidemia in an attempt to model the periparturient period. Blood was sampled at routine intervals. Changes in circulating total fatty acid concentrations and inflammatory parameters were measured. Plasma samples were analyzed using untargeted lipidomics and metabolomics. RESULTS: Endotoxin increased circulating serum amyloid A, LPS-binding protein, and cortisol concentrations. Endotoxin administration decreased plasma lysophosphatidylcholine (LPC) concentrations and increased select plasma ceramide concentrations. These outcomes suggest modulation of the immune response and insulin action. Lipopolysaccharide decreased the ratio of phosphatidylcholine to phosphatidylethanomanine, which potentially indicate a decrease in the hepatic activation of phosphatidylethanolamine N-methyltransferase and triglyceride export. Endotoxin administration also increased plasma concentrations of pyruvic and lactic acids, and decreased plasma citric acid concentrations, which implicate the upregulation of glycolysis and downregulation of the citric acid cycle (i.e., the Warburg effect), potentially in leukocytes. CONCLUSION: Acute intravenous LPS administration decreased circulating LPC concentrations, modified ceramide and glycerophospholipid concentrations, and influenced intermediary metabolism in dairy cows experiencing hyperlipidemia.

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001.

BACKGROUND: Pembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy. PRIMARY OBJECTIVE: To compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease. STUDY HYPOTHESIS: Pembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers). TRIAL DESIGN: Phase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no). MAJOR INCLUSION/EXCLUSION CRITERIA: Adults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded. PRIMARY ENDPOINTS: Progression-free and overall survival (dual primary endpoints). SAMPLE SIZE: About 875 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Enrollment is expected to take approximately 24 months, with presentation of results in 2022. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03884101.

Laparoscopic cytoreductive surgery and HIPEC: a comparative matched analysis.

BACKGROUND: Cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is a procedure that has had encouraging results for peritoneal metastases (PM) from diverse tumour origins, but it is not exempt from high morbidity. Recently, the important role of laparoscopy in oncologic surgeries and its benefits have been evaluated for CRS + HIPEC in selected patients, which has yielded promising results. The aim of our study is to analyse the use of laparoscopy for CRS + HIPEC in patients with limited peritoneal disease. METHODS: We have conducted a retrospective study from a prospective database in our tertiary referral hospital within the period of January 2009 to July 2019, which includes 825 patients who had PM from varying tumour origins. We have compared the patients treated with the laparoscopic approach (L-CRS-HIPEC) to a matched population who have undergone the open approach (O-CRS-HIPEC) and fulfil the same selection criteria. We have analysed the postoperative outcomes and survival results. RESULTS: We have confirmed the homogeneity between the sample of the O-CRS + HIPEC (n = 42) and the L-CRS + HIPEC (n = 18) regarding preoperative and intraoperative features. The L-CRS + HIPEC group had shorter hospital stays, (median of 4 [2-10] days versus 9 [2-19] days) and reduced wait time to return to chemotherapy (median of 4 [3-7] weeks and a median of 8 [4-36] weeks) than the O-CRS + HIPEC group. No differences were found regarding the need for perioperative blood transfusion, surgery time or postoperative morbi-mortality. No early locoregional relapse occurred in the L-CRS + HIPEC group and short term disease-free survival did not differ between groups. CONCLUSIONS: Laparoscopy for CRS + HIPEC is feasible and safe in highly selected patients, with no significant differences concerning postoperative morbi-mortality or early oncological results. We have found that patients who have undergone laparoscopic operations have shorter hospital stays and that they return to adjuvant chemotherapy sooner. Further investigation is required to confirm the benefits of minimally invasive procedures for the management of PM.

[Usefulness and acceptance of telephone monitoring by a virtual assistant for patients with COVID-19 following discharge]. / Utilidad y aceptación del seguimiento telefónico de un asistente virtual a pacientes COVID-19 tras el alta.

COVID-19 has placed a significant burden on the healthcare system, making it necessary to implement new tools that allow patients to be monitored remotely and guarantee quality and continuity of care. The usefulness and acceptance by patients of a virtual caregiver designed for follow-up in the month following hospital discharge for COVID-19 are evaluated. The virtual assistant, based on voice and artificial intelligence technology, made telephone calls at 48 hours, seven days, 15 days, and 30 days after discharge and asked five questions about the patient's health. If the answer to any of the questions was affirmative, it generated an alert that was transferred to a healthcare professional One hundred patients were included in the project and 85 alerts were generated in 45 of the patients, most at one month after hospital discharge. The nursing staff resolved 94% of them by telephone. Patient satisfaction with the virtual caregiver was high.

Application of a digital PCR method for WT1 to myeloid neoplasms in CR and deep ELN WT1 molecular response (< 10 copies).

Bone marrow WT1 mRNA levels assessed by the ELN method are useful to establish prognostic correlations in myeloid malignancies treated with chemotherapy or hematopoietic stem cell transplantation (HCT). Those patients with WT1 levels below ten copies have a good outcome. However, some of these patients relapse. To further characterize this group of cases, we applied a new and sensitive digital (ddPCR) WT1 method. A consecutive series of 49 patients with treated myeloid malignancies and with an ELN WT1 quantitation of < 10 copies were included in the study. All cases (47 AML and 2 MDS) have received intensive chemotherapy or HCT. One to four micrograms of total RNA were retrotranscribed to obtain ≥ 10,000 ABL1 copies using the ELN protocol. Only those cases with a good quality cDNA were used in the ddPCR WT1 test. The ddPCR Gene Expression WT1 Assay of Bio-Rad© was used to perform the PCR amplification, and the microdroplets were quantified in the Bio-Rad's QX200 droplet reader. Eighteen patients showed a negative WT1 ddPCR assay (0 copies/µl), whereas 31 cases were positive (results ranged from 1 to 15.2 copies/µl). Survival analysis showed statistically significant differences in terms of OS between both groups, 83 ± 8% vs. 46 ± 9% (p = 0.024). A statistically significant correlation was also found between ddPCRWT1 results and CD123+ cell number detected by flow cytometry (p = 0.024). Larger series of patients tested with the current ddPCRWT1 method will solve whether it could be used to stratify patients with myeloid malignancies achieving deep WT1 molecular response (< 10 copies).

An olaparib window-of-opportunity trial in patients with early-stage endometrial carcinoma: POLEN study.

OBJECTIVE: Olaparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP)-1, 2, and 3 with potential activity in endometrial cancer (EC). METHODS: In this window-of-opportunity trial, women with operable type 1 EC received olaparib oral tablets (300mg) twice daily for 28days before surgery. The primary objective was to evaluate the effects of olaparib on EC in tissue samples taken at baseline and at treatment completion. Signal of activity was defined as significant changes in the expression of the cell cycle-related proteins cyclin D1, Ki67, and cleaved caspase-3. RESULTS: A total of 31 patients were included in the biomarker analysis. The median time of olaparib exposure was 24 days (1-39). Significant inhibition was found for cyclin D1 (p < 0.01), but not for Ki67 and active caspase 3 immunostaining. PARP-1 levels positively correlated with cyclin D1 levels (rho = 0.661, p = 0.0001). Both PARP-1 and cyclin D1 levels were significantly lower (p = 0.022 and p = 0.004, respectively) in patients with ARID1A[-] tumors than ARID1A[+] tumors. A significant relationship between plasma olaparib concentrations and decreased GLUT1 activity was observed (r = -0.5885; p < 0.05). Drug-related toxicity consisted mostly of gastrointestinal and grade 1 or 2 adverse events. CONCLUSIONS: Olaparib reduced expression of cyclin D1, which positively correlated with PARP-1 levels. This effect was more evident in ARID1A-deficient tumors. Olaparib further induced inhibition of GLUT1 plasma activity. Our findings could have noteworthy implications in predicting which patients with EC would benefit from olaparib-based strategies.

Antimicrobial activity of Citrus spp. and Anethum graveolens components against Candida metapsilosis in ranch sauce.

In this paper, a study was carried out to test the inhibitory effect of a natural food compound (NFC), based on flavonoids (naringenin, hesperetin, tangeritin, luteolin, apigenin and kaempferol) from citrus and dill, in ranch sauce. A strain of C. metapsilosis, isolated from a spoiled sample of ranch sauce, was used as target pathogen microorganism. The inhibitory effect of NFC was compared with a common mixture of chemical preservatives used in this type of sauces: potassium sorbate and sodium benzoate (S/B). An in vitro test was performed by the microtiter plate assay at 10, 25 and 37 °C for 24 h in modified Tryptic Soy Broth. An additive antimicrobial effect had been observed in the combination of acetic acid and NFC. The results of the microtiter assay were validated in a challenge test in ranch sauce at 5, 25 and 37 °C for 10 weeks. NFC showed partial fungicidal effect against C. metapsilosis, reducing two logarithmic units at 5 °C for 10 weeks. At 5 °C, the traditional doses of S/B used in ranch sauce decreased viable cells to non-detectable counts from the second week of the experiment. At 25 and 37 °C, the use of S/B mixture or the use of NFC showed the same fungicidal effect. The incorporation of NFC, alone or in combination with acetic acid, opens the possibility of formulating clean label sauces with good protection against the development of the acid resistant yeast C. metapsilosis.

Recruitment of activated neutrophils correlates with disease severity in adult Crohn's disease.

Neutrophils are detected in inflamed colon in Crohn's disease (CD). However, whether the frequency and/or activation of circulating or gut tissue neutrophils correlate with endoscopic severity remains to be investigated. A cohort of 73 CD patients was prospectively enrolled according to endoscopic severity and treatment history. Individuals with active disease were stratified using the Montreal classification. Harvey-Bradshaw Index (HBI) and Simple Endoscopic Score for Crohn's Disease (SES-CD) were performed at the time of ileocolonoscopy. Frequency of neutrophils and their expression of CD66b and CD64 were assessed in paired blood and colonic biopsies using flow cytometry. The percentage of neutrophils increased in inflamed colon and correlated with SES-CD in the entire cohort of patients examined, as well as in the subgroup with inflammatory (B1) active disease. SES-CD further correlated with neutrophil CD66b expression in mucosa but not blood and, conversely, with neutrophil CD64 expression in blood but not mucosa. However, the evaluation of neutrophil activation in mucosa when compared to blood reflected disease activity more clearly. Finally, a neutrophil activation power index (CD66b in mucosa X CD64 in blood) that correlated with SES-CD discriminated between patients with mild and severe disease. In conclusion, the frequency and activation of colonic neutrophils correlated with SES-CD, highlighting that mucosal neutrophils are associated with disease severity in CD.

[Psychosomatic symptoms as an expression of the deterioration of the health-related quality of life in adolescents]. / Síntomas psicosomáticos como expresión del deterioro de la calidad de vida relacionada con la salud en adolescentes.

AIM: To analyze, in a population of adolescents in school, the relationship between psychosomatic symptoms and the perception of health-related quality of life (HRQoL), differentiating by gender and age group. DESIGN: Transversal study. LOCATION: Five Secondary Schools. PARTICIPANTS: Eight hundred and forty four adolescents between the ages of 15 and 18 in secondary school. MAIN MEASUREMENTS: HRQoL using KIDSCREEN-52 and psychosomatic symptoms with the psychosomatic problems scale (PSP). RESULTS: Girls and adolescents aged 17-18 years presented significantly higher psychosomatic symptoms, both groups also scored worse in all dimensions of HRQoL, although only the dimensions related to physical and mental wellness, mood and stress reached significance. All psychosomatic symptoms were inversely associated with the ten dimensions of KIDSCREEN-52. The regression models showed that sadness, concentrating difficulties and sleeping difficulties were the predictors of worse HRQoL in both sexes and age groups and these variables explained between 30 and 41% of the HRQoL variance of the adolescents. CONCLUSIONS: Psychosomatic symptoms are frequent especially in girls and in older adolescents and predictors of worse HRQoL. It is important to distinguish them from medical conditions to avoid unnecessary interventions. As expressions of emotional discomfort they must be evaluated and treated in an integral way because they interfere with daily life and increase the vulnerability proper of adolescence.

Kinetic study of sulforaphane stability in blanched and un-blanched broccoli (Brassica oleracea var. italica) florets during storage at low temperatures.

Sulforaphane is a health-promoting compound found in broccoli. Given its high thermo-lability, its preservation through high-temperature processes seems inconvenient. Accordingly, storage at low temperature is an alternative. There are no studies about the evolution of sulforaphane content during storage at low temperatures. The change of sulforaphane content in blanched and un-blanched broccoli florets during storage at 10, - 1, - 21 and - 45 °C for 83 days was studied. In blanched broccoli, sulforaphane content followed a first-order degradation kinetics (R2 ≥ 0.95). A two-consecutive irreversible reactions model described adequately the evolution of sulforaphane content in un-blanched broccoli (R2 ≥ 0.94). Activation energies from Arrhenius equation resulted in 19.4 kJ/mol for blanched and 30 kJ/mol (formation) and 58 kJ/mol (degradation) for un-blanched broccoli. Storage of un-blanched broccoli at - 45 °C for 40 days maximized sulforaphane content. These results could be useful to propose broccoli storage conditions that preserve or maximize sulforaphane content.

Phase Diagram of Fatty Acid Langmuir Monolayers from Rheological Measurements.

Langmuir monolayers of fatty acids and alcohols are two-dimensional systems with a rich equilibrium phase diagram. We have explored the temperature and surface-pressure-dependent shear response of monolayers formed by fatty acids of different chain lengths and a fatty alcohol. This has been accomplished with an interfacial shear rheometer utilizing magnetic tweezers and equipped with a refined temperature control and acquisition system. Our rheological results have allowed us to draw a phase diagram from the viscoelastic properties of these 2-D systems and show new phenomena that strongly depend on temperature: the existence of a maximum in viscosity at the L2' phase, the behavior of the elastic modulus to the storage modulus ratio at the L2 phase, and the increase or decrease in viscosity at the L2-LS phase transition. In addition, we unambiguously show that the LS phase displays a counterintuitive behavior in which the loss modulus increases with temperature. We demonstrate, through isothermal surface pressure sweeps and isobaric temperature sweeps, that the exponential dependence of the loss modulus on temperature at the LS phase appears for all hydrophobic tail lengths studied and for both acid and alcohol head groups.