Defining Alzheimer's Disease through Proteomic CSF Profiling.

Alzheimer disease (AD) is the main cause of dementia, and its complexity is not yet completely understood. Proteomic profiles can provide useful information to explore the pathways involved and the heterogeneity among AD patients. A proteomic analysis was performed in cerebrospinal fluid (CSF) samples from mild cognitive impairment due to AD (MCI-AD) and control individuals; both groups were classified by amyloid ß42/amyloid ß40 levels in CSF (data available in BioStudies database (S-BSST1456)). The analysis based on PLS regression and volcano plot identified 7 proteins (FOLR2, PPP3CA, SMOC2, STMN1, TAGLN3, TMEM132B, and UCHL1) mainly related to protein phosphorylation, structure maintenance, inflammation, and protein degradation. Enrichment analysis revealed the involvement of different biological processes related to neuronal mechanisms and synapses, lipid and carbohydrate metabolism, immune system and inflammation, vascular, hormones, and response to stimuli, and cell signaling and adhesion. In addition, the proteomic profile showed some association with the levels of AD biomarkers in CSF. Regarding the subtypes, two MCI-AD subgroups were identified: one could be related to synapsis and neuronal functions and the other to innate immunity. The study of the proteomic profile in the CSF of AD patients reflects the heterogeneity of biochemical pathways involved in AD.

Lactoferrin modulates oxidative stress and inflammatory cytokines in a murine model of dysbiosis induced by clindamycin.

Antibiotics, specifically clindamycin, cause intestinal dysbiosis, reducing the microbiota with anti-inflammatory properties. Furthermore, clindamycin can induce alterations in the immune responses and oxidative stress. Lactoferrin, among other activities, participates in the maintenance of intestinal homeostasis and reduces dysbiosis induced by antibiotic treatment. The aim of this study was to analyze the effect of native and iron-saturated bovine LF in a murine model of dysbiosis induced by clindamycin. Six groups of male C57BL/6 mice were treated with saline (control), clindamycin (Clin), native lactoferrin (nLF), iron-saturated lactoferrin (sLF), nLF/Clin or sLF/Clin. Oxidation caused in the intestinal cells of the ileum of animals subjected to different treatments was analyzed, focusing on lipid peroxidation and protein carbonyl content. The expression of inflammatory mediators was determined by qRT-PCR. Treatment with clindamycin did not modify lipid peroxidation, but significantly increased protein carbonyl levels up to almost 5-fold respect to the control, an effect that was reversed by orally administering sLF to mice. Furthermore, clindamycin increased the expression of interleukin-6 and TNF-α by 1- and 2-fold change, respectively. This effect was reversed by treatment with nLF and sLF, decreasing the expression to basal levels. In conclusion, this study indicates that lactoferrin can prevent some of the effects of clindamycin on intestinal cells and their associated immune system.

Neuroprotective effects of whey and buttermilk-based formulas on a DSS-induced colitis murine model.

Inflammatory bowel disease is a gut-brain axis disorder that comprises chronic inflammatory conditions affecting the gastrointestinal tract, where alterations in the mood of patients are common. Gut-brain axis is a bidirectional communication that link gut and brain. The close association between inflammatory bowel disease and neuroinflammation has far-reaching implications, as is increasingly recognized as a contributing factor to neuropsychiatric and neurodegenerative diseases. The increasing prevalence and high economic cost, together with the loss of life quality of people suffering from these diseases, point to the need to find alternatives to alleviate them. Exploring new therapeutic avenues prompts us to consider the potential benefits of milk fractions, taking advantage of the use of dairy by-products, such as whey and buttermilk. This study examines the impact of cow's whey- and buttermilk-based formulas supplemented with bovine lactoferrin and milk fat globule membrane on the expression of cytokines, as well as on the components of immune and serotonergic system of the brain in a murine model of DSS-induced colitis. Our results show the potential of these dairy by-products, especially whey, as functional foods in ameliorating neuroinflammation and safeguarding the central nervous system function amid the neurological complications induced or concomitant with intestinal inflammatory processes.

ASEBIR Quality Special Interest Group guidance for quality in assisted reproduction technology.

Assisted human reproduction has undergone rapid advances since its inception 45 years ago. To keep pace with these advances, assisted reproduction laboratories should adhere to a quality management system that addresses staffing and training, physical space and air quality, equipment maintenance and other operational matters, and ensures gamete and embryo handling in accordance with the latest quality and safety standards. Accordingly, this review aims to provide a reference document that highlights the critical aspects to consider when establishing and operating an ART laboratory. The review collates and expands upon published national and international guidelines and consensus documents, providing easier access to this large body of important information.

Subclinical synovitis impact on the progression of lupus joint disease: A 10-year longitudinal multicenter study.

OBJECTIVE: To determine the effect of subclinical synovitis on the progression of joint disease in a cohort of patients with systemic lupus erythematosus over a mean follow-up of 10 years. METHODS: A longitudinal follow-up of 96 patients diagnosed with lupus was performed. All patients were considered clinically free of joint disease or with minimal joint impairment at baseline and were studied through ultrasound study of their dominant hand to assess the prevalence of subclinical synovitis. Now, over 10 years after we contacted them and reviewed their evolution to determine the impact of had or had not been diagnosed with subclinical synovitis in their current joint condition. RESULTS: Thirty-one of the 91 reached patients developed clinical progression in their joint manifestations (at least one ordinal degree of worsening). Of these, 23 (74,9%) had demonstrated subclinical synovitis at baseline. In the group of patients who did not progress clinically, 46 (76,6%) did not have this finding at the start of follow-up (p < .01, OR 9,44 95%CI 3,46-25,74). The patients in whom clinical progression was demonstrated had worse combined ultrasound scores than the rest of the patients: 6,41 SD 1,45 vs. 1,15 SD 0,97 (p < .01). CONCLUSIONS: The finding of subclinical synovitis in patients with systemic lupus erythematosus is associated with the development of joint disease progression both clinically and ultrasonographically.

An industry perspective on current QSP trends in drug development.

2023 marks the 10th anniversary of Natpara's submission to the US FDA, which led to the first recorded regulatory interaction where a decision was supported by Quantitative and Systems Pharmacology (QSP) simulations. It had taken about 5 years for the timid QSP discipline to emerge as an effective Model-Informed Drug Development (MIDD) tool with visible impact in the pharmaceutical industry. Since then, the presence of QSP in the regulatory environment has continued to increase, to the point that the Agency reported 60 QSP submissions in 2020 alone, representing ~ 4% of their annual IND submissions [1]. What sort of industry mindset has enabled QSP to reach this level of success? How does QSP fit within the MIDD paradigm? Does QSP mean the same to Discovery and to Clinical Development projects? How do 'platforms' compare to 'fit-for-purpose' QSP models in an industrial setting? Can QSP and empirical Pharmacokinetic-Pharmacodynamic (PKPD) modelling be complementary? What level of validation is required to inform drug development decisions? This article reflects on all these questions, in particular addressing those audiences with limited line-of-sight into the drug industry decision-making machinery.

Relationship between Plasma Lipid Profile and Cognitive Status in Early Alzheimer Disease.

Alzheimer disease (AD) is a heterogeneous and complex disease in which different pathophysiological mechanisms are involved. This heterogenicity can be reflected in different atrophy patterns or clinical manifestations. Regarding biochemical pathways involved in early AD, lipid metabolism plays an important role; therefore, lipid levels have been evaluated as potential AD diagnosis biomarkers, and their levels could be related to different AD clinical manifestations. Therefore, the aim of this work is to study AD lipid profiles from early AD patients and evaluate their clinical significance. For this purpose, untargeted plasma lipidomic analysis was carried out in early AD patients (n = 31) diagnosed with cerebrospinal fluid (CSF) biomarkers. Cluster analysis was carried out to define early AD subgroups according to the lipid levels. Then, the clinical significance of each lipid profile subgroup was studied, analyzing differences for other variables (cognitive status, CSF biomarkers, medication, comorbidities, age, and gender). The cluster analysis revealed two different groups of AD patients. Cluster 1 showed higher levels of plasma lipids and better cognitive status than Cluster 2. However, no differences were found for the other variables (age, gender, medication, comorbidities, cholesterol, and triglycerides levels) between both groups. Plasma lipid levels could differentiate two early AD subgroups, which showed different cognitive statuses. However, further research with a large cohort and longitudinal study evaluating the clinical evolution of these patients is required. In general, it would involve a relevant advance in the knowledge of AD pathological mechanisms, potential treatments, and precision medicine.

The Expression of Genes Related to Reverse Cholesterol Transport and Leptin Receptor Pathways in Peripheral Blood Mononuclear Cells Are Decreased in Morbid Obesity and Related to Liver Function.

Obesity is frequently accompanied by non-alcoholic fatty liver disease (NAFLD). These two diseases are associated with altered lipid metabolism, in which reverse cholesterol transport (LXRα/ABCA1/ABCG1) and leptin response (leptin receptor (Ob-Rb)/Sam68) are involved. The two pathways were evaluated in peripheral blood mononuclear cells (PBMCs) from 86 patients with morbid obesity (MO) before and six months after Roux-en-Y gastric bypass (RYGB) and 38 non-obese subjects. In the LXRα pathway, LXRα, ABCA1, and ABCG1 mRNA expressions were decreased in MO compared to non-obese subjects (p < 0.001, respectively). Ob-Rb was decreased (p < 0.001), whereas Sam68 was increased (p < 0.001) in MO. RYGB did not change mRNA gene expressions. In the MO group, the LXRα pathway (LXRα/ABCA1/ABCG1) negatively correlated with obesity-related variables (weight, body mass index, and hip), inflammation (C-reactive protein), and liver function (alanine-aminotransferase, alkaline phosphatase, and fatty liver index), and positively with serum albumin. In the Ob-R pathway, Ob-Rb and Sam68 negatively correlated with alanine-aminotransferase and positively with albumin. The alteration of LXRα and Ob-R pathways may play an important role in NAFLD development in MO. It is possible that MO patients may require more than 6 months following RYBGB to normalize gene expression related to reverse cholesterol transport or leptin responsiveness.

Quantitative Systems Pharmacology and Machine Learning: A Match Made in Heaven or Hell?

As pharmaceutical development moves from early-stage in vitro experimentation to later in vivo and subsequent clinical trials, data and knowledge are acquired across multiple time and length scales, from the subcellular to whole patient cohort scale. Realizing the potential of this data for informing decision making in pharmaceutical development requires the individual and combined application of machine learning (ML) and mechanistic multiscale mathematical modeling approaches. Here we outline how these two approaches, both individually and in tandem, can be applied at different stages of the drug discovery and development pipeline to inform decision making compound development. The importance of discerning between knowledge and data are highlighted in informing the initial use of ML or mechanistic quantitative systems pharmacology (QSP) models. We discuss the application of sensitivity and structural identifiability analyses of QSP models in informing future experimental studies to which ML may be applied, as well as how ML approaches can be used to inform mechanistic model development. Relevant literature studies are highlighted and we close by discussing caveats regarding the application of each approach in an age of constant data acquisition. SIGNIFICANCE STATEMENT: We consider when best to apply machine learning (ML) and mechanistic quantitative systems pharmacology (QSP) approaches in the context of the drug discovery and development pipeline. We discuss the importance of prior knowledge and data available for the system of interest and how this informs the individual and combined application of ML and QSP approaches at each stage of the pipeline.

Clinical usefulness of cerebrospinal fluid biomarkers in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a complex disease that shares clinical features with other dementias. It is important to establish a specific and reliable diagnosis. Nowadays, AD diagnosis is based on cerebrospinal fluid (CSF) biomarkers. However, the corresponding cut-offs differ amongst studies. This study aims to evaluate the CSF biomarkers in the AD differential diagnosis. METHODS: Clinical relevant biomarkers (amyloid ß42 (Aß42), t-Tau, p-Tau, amyloid ß40 (Aß40), neurofilament light chain (NfL)) were determined in CSF samples from participants classified as AD (n = 124) and non-AD (n = 148) patients from the Neurology Unit. They were included and evaluated consecutively (August 2018-October 2020). The clinical utility of these biomarkers was evaluated by AUC-ROC curves and the corresponding cut-off points were defined. RESULTS: The results showed satisfactory accuracy (AUC-ROC 0.91 for Aß42, 0.890 for t-Tau and 0.933 for p-Tau); whilst Aß40 and NfL did not show good discriminatory capacity (AUC-ROC 0.557 and 0.738, respectively). The ratios Aß42/Aß40 and t-Tau/Aß42 improved the diagnosis indices of each individual biomarker, with AUC-ROC of 0.980 and 0.971, respectively. Also, elevated levels of NfL were found in the frontotemporal dementia group compared with the other participant groups. CONCLUSIONS: The ratio Aß42/Aß40 showed the highest discriminating capacity between AD and non-AD patients and might be useful in clinical practice. Regarding NfL, it is not a specific biomarker for AD; however, it might be helpful for the differential diagnosis of frontotemporal dementia. Nevertheless, further analysis in an external cohort is required in order to validate these results.

Effect of in vitro gastrointestinal digestion on the antibacterial activity of bioactive dairy formulas supplemented with lactoferrin against Cronobacter sakazakii.

Milk is a source of proteins with high nutritional value and relevant biological activities. Bioactive milk proteins, like lactoferrin, are important for newborn development and can also be used as ingredients in functional products to improve health. Lactoferrin is essential in infant's diet, since protects against infections and promotes immune system maturation. Bovine lactoferrin is used to supplement formula milk in order to strengthen baby's defences against some pathogenic bacteria. Thus, lactoferrin supplemented formula can be a barrier against emergent pathogens, such as Cronobacter sakazakii, which has caused great concern in the last few years. Milk proteins generate bioactive peptides in the digestion process, and it is known that industrial processing can modify their susceptibility to digestion. Treatments such as heating have been shown to denature whey proteins and make them more easily digestible. Therefore, the aim of this study was to analyze the effect of technological treatments and gastrointestinal digestion on the antibacterial activity against C. sakazakii of proteins present in dairy formulas supplemented with lactoferrin. Commercial bovine lactoferrin has been shown to have antibacterial activity against C. sakazakii, both in the native state and after static in vitro gastrointestinal digestion. In addition, the digests obtained from dairy formulas subjected to technological treatments, either homogenization or pasteurization, have higher antibacterial activity than non-treated formulas. The release of low molecular weight peptides during the in vitro gastric digestion is probably the cause that would explain the enhanced antibacterial activity of the digested dairy formulas.

Bioactivity of Fucoidan-Rich Extracts from Fucus vesiculosus against Rotavirus and Foodborne Pathogens.

Marine algae are sources of bioactive components with defensive properties of great value against microbial infections. This study investigated the bioactivity of extracts from brown algae Fucus vesiculosus against rotavirus, the worldwide leading cause of acute gastroenteritis in infants and young children. Moreover, one of the extracts was tested against four foodborne bacteria: Campylobacter jejuni, Escherichia coli, Salmonella Typhimurium, and Listeria monocytogenes, and the non-pathogenic: E. coli K12. In vitro tests using MA104 cells revealed that both whole algae extracts and crude fucoidan precipitates neutralized rotavirus in a dose-responsive manner. The maximum neutralization activity was observed when the rotavirus was incubated with 100 µg mL-1 of the hydrochloric acid-obtained crude fucoidan (91.8%), although crude fucoidan extracted using citric acid also demonstrated high values (89.5%) at the same concentration. Furthermore, molecular weight fractionation of extracts decreased their antirotaviral activity and high molecular weight fractions exhibited higher activity compared to those of lower molecular weight. A seaweed extract with high antirotaviral activity was also found to inhibit the growth of C. jejuni, S. Typhimurium, and L. monocytogenes at a concentration of 0.2 mg mL-1. Overall, this study expands the current knowledge regarding the antimicrobial mechanisms of action of extracts from F. vesiculosus.

Assessment of Plasma and Cerebrospinal Fluid Biomarkers in Different Stages of Alzheimer's Disease and Frontotemporal Dementia.

Alzheimer's disease (AD) is the primary type of dementia, followed by frontotemporal lobar degeneration (FTLD). They share some clinical characteristics, mainly at the early stages. So, the identification of early, specific, and minimally invasive biomarkers is required. In this study, some plasma biomarkers (Amyloid ß42, p-Tau181, t-Tau, neurofilament light (NfL), TAR DNA-binding protein 43 (TDP-43)) were determined by single molecule array technology (SIMOA®) in control subjects (n = 22), mild cognitive impairment due to AD (MCI-AD, n = 33), mild dementia due to AD (n = 12), and FTLD (n = 11) patients. The correlations between plasma and cerebrospinal fluid (CSF) levels and the accuracy of plasma biomarkers for AD early diagnosis and discriminating from FTLD were analyzed. As result, plasma p-Tau181 and NfL levels correlated with the corresponding CSF levels. Additionally, plasma p-Tau181 showed good accuracy for distinguishing between the controls and AD, as well as discriminating between AD and FTLD. Moreover, plasma NfL could discriminate dementia-AD vs. controls, FTLD vs. controls, and MCI-AD vs. dementia-AD. Therefore, the determination of these biomarkers in plasma is potentially helpful in AD spectrum diagnosis, but also discriminating from FTLD. In addition, the accessibility of these potential early and specific biomarkers may be useful for AD screening protocols in the future.

Early Alzheimer's Disease Screening Approach Using Plasma Biomarkers.

Alzheimer's disease (AD) is the most prevalent dementia, but it shows similar initial symptoms to other neurocognitive diseases (Lewy body disease (LBD) and frontotemporal dementia (FTD)). Thus, the identification of reliable AD plasma biomarkers is required. The aim of this work is to evaluate the use of a few plasma biomarkers to develop an early and specific AD screening method. Plasma p-Tau181, neurofilament light (NfL), and glial fibrillary acid protein (GFAP) were determined by Single Molecule Assay (SIMOA® Quanterix, Billerica, MA, USA) in patients with mild cognitive impairment due to AD (MCI-AD, n = 50), AD dementia (n = 10), FTD (n = 20), LBD (n = 5), and subjective cognitive impairment (SCI (n = 21)). Plasma p-Tau181 and GFAP showed the highest levels in AD dementia, and significant correlations with clinical AD characteristics; meanwhile, NfL showed the highest levels in FTD, but no significant correlations with AD. The partial least squares (PLS) diagnosis model developed between the AD and SCI groups showed good accuracy with a receiver operating characteristic (ROC) area under curve (AUC) of 0.935 (CI 95% 0.87-0.98), sensitivity of 86%, and specificity of 88%. In a first screen, NfL plasma levels could identify FTD patients among subjects with cognitive impairment. Then, the developed PLS model including p-Tau181 and GFAP levels could identify AD patients, constituting a simple, early, and specific diagnosis approach.

Epidemiology and clinical characteristics of psoriatic arthritis-related uveitis in Madrid, Spain.

PURPOSE: To describe the epidemiology and clinical characteristics of psoriatic arthritis (PsA) related uveitis in Madrid, Spain. METHODS: A case series nested in a retrospective single-center cohort of 494 patients with PsA was performed. Patients older than 18 years old whit a clinical diagnosis PsA-related uveitis who attended the Ramon y Cajal University Hospital in Madrid, Spain, between 1st January 2017 and 31st December 2019 were included in the study. Epidemiological and clinical data were retrieved from the electronic medical records. RESULTS: Thirteen cases of psoriatic arthritis-related uveitis (6 men and 7 women) were included. PsA-related uveitis showed an incidence of 0.05 cases per 100,000 persons/year (CI95 0.00-0.35), and a prevalence of 2.19 cases per 100,000 persons (CI95 1.24-3.79). The prevalence of active uveitis in the cohort of PsA patients was 2.6%. The first episode of uveitis (mean age of 48.15 ± 15.41 years) was anterior and unilateral in 92.31% of the cases. Most of the patients had a recurrent course (69.2%) with 0.92 flare-ups per patient/year (CI95 0.85-0.96). The uveitis preceded the diagnosis of psoriatic arthritis in 62.5% of the patients. In patients with PsA-related uveitis, HLA-B27 was present in 23.1%, HLA-Cw6 in 7.7%. CONCLUSIONS: Uveitis is a PsA manifestation that affects roughly 1 in 37 PsA patients, and that may precede the articular symptoms. It generally presents as a unilateral acute anterior uveitis and has a recurrent course. The most frequent observed complications are elevated intraocular pressure and cataracts.

Oncological safety of hysteroscopy in endometrial cancer.

OBJECTIVE: It has been suggested that the manipulation of neoplastic tissue during hysteroscopy may lead to dissemination of tumor cells into the peritoneal cavity and worsen prognosis and overall survival. The goal of this study was to assess the oncological safety comparing hysteroscopy to Pipelle blind biopsy in the presurgical diagnosis of patients with endometrial cancer. METHODS: We performed a retrospective multicentric study among patients who had received primary surgical treatment for endometrial cancer. A multivariate statistical analysis model was used to compare relapse and survival rates in patients who had been evaluated preoperatively either by hysteroscopy or Pipelle biopsy. The relapse rate, disease-free survival, and overall survival were assessed as the main outcomes. The histological type, tumor size, myometrial invasion, International Federation of Gynecology and Obstetrics (FIGO) stage, surgical approach, use of a uterine manipulator, and adjuvant treatment were also included in the analysis. RESULTS: A total of 1731 women from 15 centers were included: 1044 in the hysteroscopy group and 687 in the Pipelle sampling group. 225 patients relapsed during the 10 year follow-up period: 139 (13.3%) in the hysteroscopy group and 86 (12.4%) in the Pipelle sampling group. There is no evidence of an association between the use of hysteroscopy as a diagnostic method and relapse rate (HR 1.24, 95% CI 0.92 to 1.66; p=0.16), lower disease-free survival (HR 1.23, 95% CI 0.92 to 1.66; p=0.15), or overall survival (HR 0.95, 95% CI 0.70 to 1.29; p=0.76). CONCLUSION: Hysteroscopy is a safe diagnostic method for patients with endometrial cancer with no impact on oncological outcomes when compared with sampling by Pipelle.

Current practices for QSP model assessment: an IQ consortium survey.

Quantitative Systems Pharmacology (QSP) modeling is increasingly applied in the pharmaceutical industry to influence decision making across a wide range of stages from early discovery to clinical development to post-marketing activities. Development of standards for how these models are constructed, assessed, and communicated is of active interest to the modeling community and regulators but is complicated by the wide variability in the structures and intended uses of the underlying models and the diverse expertise of QSP modelers. With this in mind, the IQ Consortium conducted a survey across the pharmaceutical/biotech industry to understand current practices for QSP modeling. This article presents the survey results and provides insights into current practices and methods used by QSP practitioners based on model type and the intended use at various stages of drug development. The survey also highlights key areas for future development including better integration with statistical methods, standardization of approaches towards virtual populations, and increased use of QSP models for late-stage clinical development and regulatory submissions.

Artificial Intelligence on FDG PET Images Identifies Mild Cognitive Impairment Patients with Neurodegenerative Disease.

The purpose of this project is to develop and validate a Deep Learning (DL) FDG PET imaging algorithm able to identify patients with any neurodegenerative diseases (Alzheimer's Disease (AD), Frontotemporal Degeneration (FTD) or Dementia with Lewy Bodies (DLB)) among patients with Mild Cognitive Impairment (MCI). A 3D Convolutional neural network was trained using images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The ADNI dataset used for the model training and testing consisted of 822 subjects (472 AD and 350 MCI). The validation was performed on an independent dataset from La Fe University and Polytechnic Hospital. This dataset contained 90 subjects with MCI, 71 of them developed a neurodegenerative disease (64 AD, 4 FTD and 3 DLB) while 19 did not associate any neurodegenerative disease. The model had 79% accuracy, 88% sensitivity and 71% specificity in the identification of patients with neurodegenerative diseases tested on the 10% ADNI dataset, achieving an area under the receiver operating characteristic curve (AUC) of 0.90. On the external validation, the model preserved 80% balanced accuracy, 75% sensitivity, 84% specificity and 0.86 AUC. This binary classifier model based on FDG PET images allows the early prediction of neurodegenerative diseases in MCI patients in standard clinical settings with an overall 80% classification balanced accuracy.

Comparative effect of bovine buttermilk, whey, and lactoferrin on the innate immunity receptors and oxidative status of intestinal epithelial cells.

Milk contains bioactive molecules with important functions as defensive proteins; among them are the whey protein lactoferrin and proteins of the milk fat globule membrane (MFGM) present in buttermilk. The aim of this study has been to investigate the effects of lactoferrin, whey, and buttermilk as modulators of intestinal innate immunity and oxidative stress on intestinal epithelial cells, to evaluate its potential use for the development of functional foods. The mRNA expression levels of innate immune system Toll-like receptors (TLR2, TLR4, and TLR9), lipid peroxidation (malondialdehyde + 4-hydroxyalkenals) and protein expression levels of carbonyl were analyzed in enterocyte-like Caco-2/TC7 cells treated for 24 h with different concentrations of lactoferrin, whey, or buttermilk. None of the substances analyzed caused oxidative damage; however, whey significantly decreased the levels of lipid peroxidation. Furthermore, both lactoferrin and whey reduced the oxidative stress induced by lipopolysaccharide. With respect to TLR receptors, lactoferrin, whey, and buttermilk specifically altered the expression of TLR2, TLR4, and TLR9 receptors, with a strong decrease in the expression levels of TLR4. These results suggest that lactoferrin, whey, and buttermilk are potentially interesting ingredients for functional foods because they seem to modulate oxidative stress and the inflammatory response induced by the activation of TLRs.

Impact of uterine manipulator on oncological outcome in endometrial cancer surgery.

BACKGROUND: There are limited data available to indicate whether oncological outcomes might be influenced by the uterine manipulator, which is used at the time of hysterectomy for minimally invasive surgery in patients with endometrial cancer. The current evidence derives from retrospective studies with limited sample sizes. Without substantial evidence to support its use, surgeons are required to make decisions about its use based only on their personal choice and surgical experience. OBJECTIVE: To evaluate the use of the uterine manipulator on oncological outcomes after minimally invasive surgery, for apparent early-stage endometrial cancer. STUDY DESIGN: We performed a retrospective multicentric study to assess the oncological safety of uterine manipulator use in patients with apparent early-stage endometrial cancer, treated with minimally invasive surgery. The type of manipulator, surgical staging, histology, lymphovascular space invasion, International Federation of Gynecology and Obstetrics stage, adjuvant treatment, recurrence, and pattern of recurrence were evaluated. The primary objective was to determine the relapse rate. The secondary objective was to determine recurrence-free survival, overall survival, and the pattern of recurrence. RESULTS: A total of 2661 women from 15 centers were included; 1756 patients underwent hysterectomy with a uterine manipulator and 905 without it. Both groups were balanced with respect to histology, tumor grade, myometrial invasion, International Federation of Gynecology and Obstetrics stage, and adjuvant therapy. The rate of recurrence was 11.69% in the uterine manipulator group and 7.4% in the no-manipulator group (P<.001). The use of the uterine manipulator was associated with a higher risk of recurrence (hazard ratio, 2.31; 95% confidence interval, 1.27-4.20; P=.006). The use of uterine manipulator in uterus-confined endometrial cancer (International Federation of Gynecology and Obstetrics [FIGO] I-II) was associated with lower disease-free survival (hazard ratio, 1.74; 95% confidence interval, 0.57-0.97; P=.027) and higher risk of death (hazard ratio, 1.74; 95% confidence interval, 1.07-2.83; P=.026). No differences were found regarding the pattern of recurrence between both groups (chi-square statistic, 1.74; P=.63). CONCLUSION: In this study, the use of a uterine manipulator was associated with a worse oncological outcome in patients with uterus-confined endometrial cancer (International Federation of Gynecology and Obstetrics I-II) who underwent minimally invasive surgery. Prospective trials are essential to confirm these results.