Multiple mechanisms contribute to acquired TRAIL resistance in multiple myeloma.

Multiple Myeloma (MM) prognosis has recently improved thanks to the incorporation of new therapies to the clinic. Nonetheless, it is still a non-curable malignancy. Targeting cancer cells with agents inducing cell death has been an appealing alternative investigated over the years, as is the case of TRAIL, an agonist of DR4 and DR5 death receptors. This pathway, involved in apoptosis triggering, has demonstrated efficacy on MM cells. In this research, we have investigated the sensitivity of a panel of MM cells to this agent and generated TRAIL-resistant models by continuous culture of sensitive cells with this peptide. Using genomic and biochemical approaches, the mechanisms underlying resistance were investigated. In TRAIL-resistant cells, a strong reduction in cell-surface receptor levels was detected and impaired the apoptotic machinery to respond to the treatment, enabling cells to efficiently form the Death Inducing Signalling Complex. In addition, an upregulation of the inhibitory protein c-FLIP was detected. Even though the manipulation of these proteins was able to modify cellular responses to TRAIL, it was not complete, pointing to other mechanisms involved in TRAIL resistance.

Remodeling p38 signaling in muscle controls locomotor activity via IL-15.

Skeletal muscle has gained recognition as an endocrine organ releasing myokines upon contraction during physical exercise. These myokines exert both local and pleiotropic health benefits, underscoring the crucial role of muscle function in countering obesity and contributing to the overall positive effects of exercise on health. Here, we found that exercise activates muscle p38γ, increasing locomotor activity through the secretion of interleukin-15 (IL-15). IL-15 signals in the motor cortex, stimulating locomotor activity. This activation of muscle p38γ, leading to an increase locomotor activity, plays a crucial role in reducing the risk of diabetes and liver steatosis, unveiling a vital muscle-brain communication pathway with profound clinical implications. The correlation between p38γ activation in human muscle during acute exercise and increased blood IL-15 levels highlights the potential therapeutic relevance of this pathway in treating obesity and metabolic diseases. These findings provide valuable insights into the molecular basis of exercise-induced myokine responses promoting physical activity.

Standardization of body composition parameters between GE Lunar iDXA and Hologic Horizon A and their clinical impact.

Body composition (BC) measured by DXA differs between devices. We aimed to compare regional and total BC measurements assessed by the Hologic Horizon A and the GE Lunar iDXA devices; to determine device-specific calibration equations for each BC parameter; and to assess the impact of this standardization procedure on the assessment of sarcopenia, lipedema, obesity, and cardiovascular risk with DXA. A total of 926 postmenopausal women (aged 72.9 ± 6.9 yr, height 160.3 ± 6.6 cm, weight 66.1 ± 12.7 kg) underwent BC assessment on each device within 1 h, following the ISCD guidelines. The included sample was split into 80% train and 20% test datasets stratified by age, height, and weight. Inter-device differences in BC parameters were assessed with Bland-Altman analysis, Pearson or Spearman correlation coefficients, and t-tests or Wilcoxon tests. The equations were developed in the train dataset using backward stepwise multiple linear regressions and were evaluated in the test dataset with the R-squared and mean absolute error. We compared the abovementioned BC-derived health conditions before and after standardization in the test set with respect to relative risk, accuracy, Kappa score, and McNemar tests. Total and regional body masses were similar (p>.05) between devices. BMC was greater for all regions in the Lunar device (p<.05), while fat and lean masses differed among regions. Regression equations showed high performance metrics in both datasets. The BC assessment from Hologic classified 2.13 times more sarcopenic cases (McNemar: p<.001), 1.39 times more lipedema (p<.001), 0.40 times less high cardiovascular risk (p<.001), and similarly classified obesity (p>.05), compared to Lunar. After standardization, the differences disappeared (p>.05), and the classification metrics improved. This study discusses how hardware and software differences impact BC assessments. The provided standardization equations address these issues and improve the agreement between devices. Future studies and disease definitions should consider these differences.

Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancer.

Neratinib is a tyrosine kinase inhibitor that is used for the therapy of patients with HER2+ breast tumors. However, despite its clinical benefit, resistance to the drug may arise. Here we have created cellular models of neratinib resistance to investigate the mechanisms underlying such resistance. Chronic neratinib exposure of BT474 human HER2+ breast cancer cells resulted in the selection of several clones resistant to the antiproliferative action of the drug. The clones were characterized biochemically and biologically using a variety of techniques. These clones retained HER2 levels similar to parental cells. Knockdown experiments showed that the neratinib-resistant clones retained oncogenic dependence on HER2. Moreover, the tyrosine phosphorylation status of BT474 and the resistant clones was equally sensitive to neratinib. Transcriptomic and Western analyses showed that peptidylarginine deiminase 3 was overexpressed in the three neratinib-resistant clones studied but was undetectable in BT474 cells. Experiments performed in the neratinib-resistant clones showed that reduction of PADI3 or inhibition of its function restored sensitivity to the antiproliferative action of neratinib. Moreover, overexpression of FLAG-tagged PADI3 in BT474 cells provoked resistance to the antiproliferative action of neratinib. Together, these results uncover a role of PADI3 in the regulation of sensitivity to neratinib in breast cancer cells overexpressing HER2 and open the possibility of using PADI3 inhibitors to fight resistance to neratinib.

Ocoxin Oral Solution Triggers DNA Damage and Cell Death in Ovarian Cancer.

Ovarian cancer is the most fatal of all the reproductive cancers within the female population, mainly due to its late diagnosis that limits surgery and medical treatment. Classically, ovarian cancer therapy has included conventional chemotherapy, and other therapeutic approaches are now being used to treat these patients, but the outcomes of the disease are still poor. Therefore, new strategies are needed to improve life expectancy and life quality of ovarian cancer patients. Considering that, we investigated the effect of the nutritional supplement Ocoxin Oral Solution (OOS) in ovarian cancer models. OOS contains several nutritional supplements, some of them with demonstrated antitumoral action. In vitro studies showed that OOS inhibited the proliferation of several ovarian cancer cell lines, especially of those representative of the endometrioid subtype, in a time- and dose-dependent manner. A fast cell death induction after OOS treatment was observed, and when the molecular mechanisms leading to this effect were investigated, an activation of the DNA damage checkpoint was detected, as shown by activation (phosphorylation) of CHK1 and CHK2 kinases that was followed by the phosphorylation of the target protein histone H2AX. When tested in animal models of ovarian cancer, OOS reduced tumor growth without any observed secondary effects. Moreover, such reduction in tumor proliferation was caused by the induction of DNA damage as corroborated by the in vivo phosphorylation of CHK2 and Histone H2AX. Finally, OOS potentiated the action of carboplatin or olaparib, the standard of care treatments used in ovarian clinics, opening the possibility of including OOS in combination with those standard of care agents in patients with ovarian cancer.

Development and reporting of artificial intelligence in osteoporosis management.

An abundance of medical data and enhanced computational power have led to a surge in Artificial Intelligence (AI) applications. Published studies involving AI in bone and osteoporosis research have increased exponentially, raising the need for transparent model development and reporting strategies. This review offers a comprehensive overview and systematic quality assessment of AI articles in osteoporosis while highlighting recent advancements. A systematic search in the PubMed database, from December 17th, 2020, to February 1st, 2023 was conducted to identify AI articles that relate to osteoporosis. The quality assessment of the studies relied on the systematic evaluation of 12 quality items derived from the MI-CLAIM checklist. The systematic search yielded 97 articles that fell into five areas; bone properties assessment (11 articles), osteoporosis classification (26 articles), fracture detection/classification (25 articles), risk prediction (24 articles) and bone segmentation (11 articles). The average quality score for each study area was 8.9 (range: 7-11) for bone properties assessment, 7.8 (range: 5-11) for osteoporosis classification, 8.4 (range: 7-11) for fracture detection, 7.6 (range: 4-11) for risk prediction, and 9.0 (range: 6-11) for bone segmentation. A 6th area, AI-driven clinical decision support, identified the studies from the five preceding areas which aimed to improve clinician efficiency, diagnostic accuracy and patient outcomes through AI-driven models and opportunistic screening by automating or assisting with specific clinical tasks in complex scenarios. The current work highlights disparities in study quality and a lack of standardized reporting practices. Despite these limitations, a wide range of models and examination strategies have shown promising outcomes to aid in the earlier diagnosis and improve clinical decision making. Through careful consideration of sources of bias in model performance assessment, the field can build confidence in AI-based approaches, ultimately leading to improved clinical workflows and patient outcomes.

This review covers the recent advancements in artificial intelligence (AI) for managing osteoporosis, an increasingly prevalent condition that weakens bone tissues and increases fracture risk. Analyzing 97 studies from December 2020 to February 2023, the present work highlights how AI enhances bone properties assessment, osteoporosis classification, fracture detection and classification, risk prediction, and bone segmentation. A systematic qualitative assessment of the studies revealed improvements in study quality compared with the earlier review period, supported by innovative and more explainable AI approaches. AI shows promise in clinical decision support by offering novel screening tools that can help in the earlier identification of the disease, improve clinical workflows and patient prognosis. New pre-processing strategies and advanced model architectures have played a critical role in these improvements. Researchers have enhanced the accuracy and predictive performance of traditional methods by integrating clinical data with imaging data through advanced multi-factorial AI techniques. These innovations, paired with standardized development and validation processes, promise to personalize medicine and enhance patient care in osteoporosis management.

Painful sexual intercourse, quality of life and sexual function in patients with endometriosis: not just deep dyspareunia.

PURPOSE: To evaluate the prevalence of deep and superficial dyspareunia in women with diagnosis of endometriosis. Secondly, to assess the temporal relation between deep and superficial dyspareunia in women reporting both symptoms (concomitant dyspareunia) and the impact on quality of life (QoL) and sexual function. METHODS: This is a cross-sectional cohort study that included fertile women with diagnosis of endometriosis. Enrolled subjects reported pain symptoms including dyspareunia and its temporal onset and completed two one-time validated questionnaires regarding sexual function (Female Sexual Function Index) and QoL (International QoL Assessment SF-36). RESULTS: Among the 334 enrolled patients, 75.7% (95%) reported dyspareunia. Women were divided into four groups according to the presence and type of dyspareunia: isolated superficial dyspareunia (6.3%), isolated deep dyspareunia (26.0%), concomitant dyspareunia (43.4%) and no dyspareunia (24.3%). Women with concomitant dyspareunia reported higher NRS scores than women with isolated dyspareunia or no dyspareunia (P ≤ 0.001). The majority of women with concomitant dyspareunia (56.6%) reported that deep dyspareunia developed before superficial dyspareunia. Women with concomitant dyspareunia reported worse QoL and worse sexual function than women with isolated dyspareunia or without dyspareunia (P ≤ 0.001). CONCLUSION: Dyspareunia is a common symptom in women with endometriosis, with many reporting concomitant deep and superficial dyspareunia. Concomitant dyspareunia can significantly impact sexual function and quality of life (QoL). Therefore, it is crucial to investigate dyspareunia thoroughly and differentiate between its types to tailor effective therapeutic strategies.

The influence of nationwide COVID-19 lockdown on the functional impairment and long-term survival of dependent people for carrying out basic activities of daily living in a neighborhood of the city of Madrid, Spain: Orcasitas Cohort Longitudinal Study.

Background: Prolonged confinement can lead to personal deterioration at various levels. We studied this phenomenon during the nationwide COVID-19 lockdown in a functionally dependent population of the Orcasitas neighborhood of Madrid, Spain, by measuring their ability to perform basic activities of daily living and their mortality rate. Methods: A total of 127 patients were included in the Orcasitas cohort. Of this cohort, 78.7% were female, 21.3% were male, and their mean age was 86 years. All participants had a Barthel index of ≤ 60. Changes from pre- to post-confinement and 3 years afterward were analyzed, and the effect of these changes on survival was assessed (2020-2023). Results: The post-confinement functional assessment showed significant improvement in independence over pre-confinement for both the Barthel score (t = -5.823; p < 0.001) and the classification level (z = -2.988; p < 0.003). This improvement progressively disappeared in the following 3 years, and 40.9% of the patients in this cohort died during this period. These outcomes were associated with the Barthel index (z = -3.646; p < 0.001) and the level of dependence (hazard ratio 2.227; CI 1.514-3.276). Higher mortality was observed among men (HR 1.745; CI 1.045-2.915) and those with severe dependence (HR 2.169; CI 1.469-3.201). Setting the cutoff point of the Barthel index at 40 provided the best detection of the risk of death associated with dependence. Conclusions: Home confinement and the risk of death due to the COVID-19 pandemic awakened a form of resilience in the face of adversity among the population of functionally dependent adults. The Barthel index is a good predictor of medium- and long-term mortality and is a useful method for detecting populations at risk in health planning. A cutoff score of 40 is useful for this purpose. To a certain extent, the non-institutionalized dependent population is an invisible population. Future studies should analyze the causes of the high mortality observed.

Enzymatic Modulation of the Pulmonary Glycocalyx Enhances Susceptibility to Streptococcus pneumoniae.

The pulmonary epithelial glycocalyx is rich in glycosaminoglycans such as hyaluronan and heparan sulfate. Despite their presence, the importance of these glycosaminoglycans in bacterial lung infections remains elusive. To address this, we intranasally inoculated mice with Streptococcus pneumoniae in the presence or absence of enzymes targeting pulmonary hyaluronan and heparan sulfate, followed by characterization of subsequent disease pathology, pulmonary inflammation, and lung barrier dysfunction. Enzymatic degradation of hyaluronan and heparan sulfate exacerbated pneumonia in mice, as evidenced by increased disease scores and alveolar neutrophil recruitment. However, targeting epithelial hyaluronan in combination with Streptococcus pneumoniae infection further exacerbated systemic disease, indicated by elevated splenic bacterial load and plasma levels of pro-inflammatory cytokines. In contrast, enzymatic cleavage of heparan sulfate resulted in increased bronchoalveolar bacterial burden, lung damage and pulmonary inflammation in mice infected with Streptococcus pneumoniae. Accordingly, heparinase-treated mice also exhibited disrupted lung barrier integrity as evidenced by higher alveolar edema scores and vascular protein leakage into the airways. This finding was corroborated in a human alveolus-on-a-chip platform, confirming that heparinase treatment also disrupts the human lung barrier during Streptococcus pneumoniae infection. Notably, enzymatic pre-treatment with either hyaluronidase or heparinase also rendered human epithelial cells more sensitive to pneumococcal-induced barrier disruption, as determined by transepithelial electrical resistance measurements, consistent with our findings in murine pneumonia. Taken together, these findings demonstrate the importance of intact hyaluronan and heparan sulfate in limiting pneumococci-induced damage, pulmonary inflammation, and epithelial barrier function and integrity.

The invisible problem of early adolescent pregnancy in the Dominican Republic: a descriptive analysis.

Study objectives: The aim of this article is to describe the problem of pregnancy in girls under 15 years of age in the Dominican Republic in the period 2000-2021, to develop a specific indicator for this age group and describing the related factors. Methods: This is an exploratory ecological study, based on secondary data sources, such as birth records from the National Statistics Office (NSO) and the Ministry of Public Health (MPH). We calculated the rates of fertility and pregnancy in early adolescence, as well as analyzed their main determining factors and consequences. Results: Fertility Rate in Early Adolescence (FREA) decreases from 6.27 to 1.04 per thousand in the period 2001-2021. The average FREA for 2015-2021 was 1.78. The average Estimated Rate of Pregnancy in Early Adolescence (ERPEA) for the same period was 3.39. Disability-Adjusted Life Years (DALYs) were 11,620 years. Years of Life Lost (YLL) were 9,665.9 years. The prevalence of Low Birth Weight (LBW) in the under 15-year-old age group was 14.2 %. Conclusions: Pregnancy in childhood implies risks for both the mother and the child, including low birth weight. The official fertility rate is substantially underreported (2.84 vs. 1.79).The fertility rate indicator traditionally used does not accurately measure the number of pregnancies in women, particularly in specific age groups or populations where pregnancies may be interrupted by various factors. Therefore, the use of ERPEA is recommended.We emphasize the need for implementing the proposed indicator for the target group, as well as monitoring Sustainable Development Goal indicator 3.7.2.

Chemical Composition, Antioxidant Activities, Antidepressant Effect, and Lipid Peroxidation of Peruvian Blueberry: Molecular Docking Studies on Targets Involved in Oxidative Stress and Depression.

Blueberries (Vaccinium corymbosum L.) are cultivated worldwide and are among the best dietary sources of bioactive compounds with beneficial health effects. This study aimed to investigate the components of Peruvian blueberry using high-performance liquid chromatography coupled to electrospray ionization and quadrupole time-of-flight mass spectrometry (HPLC-ESI-QTOF-MS/MS), identifying 11 compounds. Furthermore, we assessed in vitro the antioxidant activity and in vivo the antidepressant effect using a rat model and protective effect on lipid peroxidation (in the serum, brain, liver, and stomach). We also conducted molecular docking simulations with proteins involved in oxidative stress and depression for the identified compounds. Antioxidant activity was assessed by measuring total phenolic and flavonoid contents, as well as using 1,1-diphenyl-2-picrylhydrazin (DPPH), 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS•+), and ferric-reducing antioxidant power (FRAP) assays. Peruvian blueberries demonstrated higher antioxidant activity than Vaccinium corymbosum fruits from Chile, Brazil, the United States, Turkey, Portugal, and China. The results showed that oral administration of Peruvian blueberries (10 and 20 mg/kg) for 28 days significantly (p < 0.001) increased swimming and reduced immobility in the forced swimming test (FST). Additionally, at doses of 40 and 80 mg/kg, oxidative stress was reduced in vivo (p < 0.001) by decreasing lipid peroxidation in brain, liver, stomach, and serum. Molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions were performed. In the molecular docking studies, quercitrin and 3,5-di-O-caffeoylquinic acid showed the best docking scores for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, superoxide dismutase, and xanthine oxidase; while 3,5-dicaffeoylquinic acid methyl ester and caffeoyl coumaroylquinic acid had the best docking scores for monoamine oxidase and serotonin receptor 5-HT2. In summary, our results suggest that the antidepressant and protective effects against lipid peroxidation might be related to the antioxidant activity of Peruvian Vaccinium corymbosum L.

Pulmonary function and bronchopulmonary dysplasia classification: insights from the Spanish Registry.

In 2016, the Spanish Research Group on Bronchopulmonary Dysplasia (BPD) (GEIDIS) established a national registry with participation of 66 hospitals to collect information on clinical characteristics and long-term outcomes of BPD infants into adulthood. The aim of this observational study is to examine forced spirometry data in early childhood and to assess their correlation with the respiratory support required at 36 weeks postmenstrual age (PMA). The study analyzed data from preterm infants with BPD born between January 2016 and December 2017 who underwent forced spirometry at 5-7 years of age. Statistical analyses were conducted to investigate the relationships between spirometry results, perinatal factors, and the required respiratory support at 36 weeks PMA. The study involved 143 patients with a median gestational age (GA) of 27.3 weeks (range 25.7-28.7) and a median weight of 880 g (range 740-1135). Abnormal spirometry results were observed in 39.2% (56) of the patients. Among patients diagnosed with BPD type 3, those requiring over 30% oxygen at 36 weeks PMA exhibited an increased risk of abnormal spirometry results (OR 4.48; 95% CI 1.11-18.13) compared to those requiring positive pressure with less than 30% oxygen. In addition, this subgroup had a higher risk of developing a restrictive-mixed pattern compared to those with BPD type 1 (OR 10.65; 95% CI 2.06-54.98) and BPD type 2 (OR 6.76; 95% CI 1.09-42.06). No significant differences were found in the incidence of an obstructive pattern between BPD types.      Conclusion: The requirement of more than 30% oxygen at 36 weeks PMA serves as a risk indicator for pulmonary function impairment in school-aged children with BPD. These findings suggest persistent airway and parenchymal injury in this specific patient population, and highlight the importance of careful monitoring to evaluate their long-term effects on lung function. What is Known: • Premature patients with bronchopulmonary dysplasia (BPD) may present abnormalities in pulmonary function tests during school age. However, the predictive accuracy of consensus BPD severity classification remains uncertain. What is New: • The requirement of more than 30% oxygen at 36 weeks postmenstrual age (PMA) indicates a potential risk of pulmonary function impairment in school-aged children with BPD. Additionally, a significant correlation has been observed between a restrictive-mixed pattern with exposure to mechanical ventilation and the development of severe forms of BPD.

Practical tool to identify Spasticity-Plus Syndrome amongst patients with multiple sclerosis. Algorithm development based on a conjoint analysis.

Introduction: The Spasticity-Plus Syndrome (SPS) in multiple sclerosis (MS) refers to a combination of spasticity and other signs/symptoms such as spasms, cramps, bladder dysfunction, tremor, sleep disorder, pain, and fatigue. The main purpose is to develop a user-friendly tool that could help neurologists to detect SPS in MS patients as soon as possible. Methods: A survey research based on a conjoint analysis approach was used. An orthogonal factorial design was employed to form 12 patient profiles combining, at random, the eight principal SPS signs/symptoms. Expert neurologists evaluated in a survey and a logistic regression model determined the weight of each SPS sign/symptom, classifying profiles as SPS or not. Results: 72 neurologists participated in the survey answering the conjoint exercise. Logistic regression results of the survey showed the relative contribution of each sign/symptom to the classification as SPS. Spasticity was the most influential sign, followed by spasms, tremor, cramps, and bladder dysfunction. The goodness of fit of the model was appropriate (AUC = 0.816). Concordance between the experts' evaluation vs. model estimation showed strong Pearson's (r = 0.936) and Spearman's (r = 0.893) correlation coefficients. The application of the algorithm provides with a probability of showing SPS and the following ranges are proposed to interpret the results: high (> 60%), moderate (30-60%), or low (< 30%) probability of SPS. Discussion: This study offers an algorithmic tool to help healthcare professionals to identify SPS in MS patients. The use of this tool could simplify the management of SPS, reducing side effects related with polypharmacotherapy.

Prospective associations between breast feeding, metabolic health, inflammation and bone density in women with prior gestational diabetes mellitus.

INTRODUCTION: The aim of the study is to investigate prospective associations between breastfeeding and metabolic outcomes, inflammation, and bone density in women with prior gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: We prospectively included 171 women with GDM from the MySweetheart trial. Women were followed during pregnancy (from 24 up to 32 weeks' gestational age) up to 1 year postpartum. Outcomes included weight, weight retention, body composition, insulin resistance and secretion indices, C reactive protein (CRP), and bone density. We compared differences in the associations between breastfeeding and health outcomes between women who breast fed <6 months vs ≥6 months. Analyses were adjusted for potential medical and sociodemographic confounders. RESULTS: Breastfeeding initiation was 94.2% (n=161) and mean breastfeeding duration was 6.6 months. Breastfeeding duration was independently associated with lower weight, weight retention, body fat, visceral adipose tissue, lean mass, CRP, insulin resistance (Homeostatic Model Assessment for Insulin Resistance), and insulin secretion (Homeostatic Model Assessment of ß-cell index) at 1 year postpartum (all p≤0.04) after adjusting for confounders. Breastfeeding was associated with higher insulin resistance-adjusted insulin secretion (Insulin Secretion-Sensitivity Index-2) in the unadjusted analyses only. There was no association between breastfeeding duration and bone density. Compared with <6 months, breastfeeding duration ≥6 months was associated with lower weight, weight retention, body fat, fat-free mass as well as lower CRP at 1 year postpartum (all p<0.05) after adjusting for confounders. CONCLUSIONS: Longer breastfeeding duration among women with prior GDM was associated with lower insulin resistance, weight, weight retention, body fat and inflammation, but not lower bone density at 1 year postpartum. Breastfeeding for ≥6 months after GDM can help to improve cardiometabolic health outcomes 1 year after delivery.

Lack of p38 activation in T cells increases IL-35 and protects against obesity by promoting thermogenesis.

Obesity is characterized by low-grade inflammation, energy imbalance and impaired thermogenesis. The role of regulatory T cells (Treg) in inflammation-mediated maladaptive thermogenesis is not well established. Here, we find that the p38 pathway is a key regulator of T cell-mediated adipose tissue (AT) inflammation and browning. Mice with T cells specifically lacking the p38 activators MKK3/6 are protected against diet-induced obesity, leading to an improved metabolic profile, increased browning, and enhanced thermogenesis. We identify IL-35 as a driver of adipocyte thermogenic program through the ATF2/UCP1/FGF21 pathway. IL-35 limits CD8+ T cell infiltration and inflammation in AT. Interestingly, we find that IL-35 levels are reduced in visceral fat from obese patients. Mechanistically, we demonstrate that p38 controls the expression of IL-35 in human and mouse Treg cells through mTOR pathway activation. Our findings highlight p38 signaling as a molecular orchestrator of AT T cell accumulation and function.

Release of Angiostrongylus cantonensis larvae from live intermediate hosts under stress.

The metastrongyloid nematode Angiostrongylus cantonensis causes eosinophilic meningitis in a variety of homeothermic hosts including humans. Third-stage infectious larvae develop in gastropods as intermediate hosts. Humans are usually infected by intentional or incidental ingestion of an infected mollusk or paratenic host (poikilothermic vertebrates and invertebrates). The infection may also hypothetically occur through ingestion of food or water contaminated by third-stage larvae spontaneously released from gastropods. Larvae are thought to be released in greater numbers from the intermediate host exposed to stress. This study aimed to compare larval release from stressed with unstressed gastropods. Experimentally infected Limax maximus and Lissachatina fulica were exposed to a stress stimulus (shaking on an orbital shaker). The mucus was collected before and after the stress and examined microscopically and by qPCR for the presence of A. cantonensis larvae and their DNA. In the case of L. maximus, no larvae were detected microscopically in the mucus, but qPCR analysis confirmed the presence of A. cantonensis DNA in all experimental replicates, without clear differences between stressed and non-stressed individuals. In contrast, individual larvae of A. cantonensis were found in mucus from Li. fulica after stress exposure, which also reflects an increased number of DNA-positive mucus samples after stress. Stress stimuli of intensity similar to the transport or handling of mollusks can stimulate the release of larvae from highly infected intermediate hosts. However, these larvae are released in small numbers. The exact number of larvae required to trigger neuroangiostrongyliasis is unknown. Therefore, caution is essential when interacting with potential intermediate hosts in regions where A. cantonensis is endemic.

The Quality Evaluation of Avocado Fruits (Persea americana Mill.) of Hass Produced in Different Localities on the Island of Tenerife, Spain.

The effect of the production area on the quality of Hass avocados grown on the island of Tenerife was studied. For this purpose, several physicochemical parameters, such as fruit weight, percentage of pulp, seed and skin, proximate composition, minerals, total phenolic compounds (TP), total flavonoid compounds (TF), α-tocopherol, antioxidant capacity, and fatty acid profile were analyzed. The location of the orchards significantly influenced avocado weight; pulp and seed percentage; and fat, fiber, ash, α-tocopherol, TP, phosphorus, potassium, calcium, iron, zinc, and oleic and palmitoleic acid contents. Buenavista (BU) avocados were the smallest (185 g) and presented the highest percentage of pulp (77.1%) and lowest percentage of fiber (5.43%). The highest levels of dry matter (33.8%) and fat (20.4%) were found in avocados harvested in Los Silos (SI) and Santiago del Teide (SA), respectively. Compared with those at the other locations, the avocados harvested in Güímar (GU) had high levels of α-tocopherol (52.2 µg g-1) and phenolic compounds (56.0 mg GAE 100 g-1). Avocados from Los Realejos (RE) had the highest percentage of oleic acid and the lowest percentage of palmitoleic acid. Numerous significant correlations were found between the variables studied, especially those between TP, TF, and antioxidant capacity (DPPH) and between fat percentage and dry matter.

Sustainable extraction methods of carotenoids from mango (Mangifera indica L. 'Kent') pulp: Ultrasound assisted extraction and green solvents.

Mango is a good source of carotenoids for use in food, cosmetic, and pharmaceutical products because of their organoleptic and health-promoting properties. Safe and sustainable methods for their extraction is required. The present investigation was aimed to study concentration and carotenoid profile of 'Kent' mango pulp through a conventional extraction (CE) and ultrasound-assisted extraction (UAE) using traditional solvents (tetrahydrofuran-THF and diethyl ether: petroleum ether-DE:PE) and green solvents (GS) (2-metiltetrahydrofuran, 2 m-THF; cyclopentyl methyl ether, CPME). Mango showed (µg/g d.w.) ß-carotene (29.4), zeaxanthin (1.28), ß-cryptoxanthin (2.8), phytoene (18.68) and phytofluene (7.45) in a CE using DE:PE. Similar results were obtained applying DE:PE in UAE and GS in a CE, so CPME and 2-mTHF seem suitable solvents to replace DE:PE in CE. The yield of total carotenes, xanthophylls and carotenoids using GS combined with UAE was lower than with CE, but important enough to be used as a sustainable procedure for obtaining carotenoids from mango pulp.

Trastuzumab deruxtecan in breast cancer.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) consisting of a humanised, anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody covalently linked to a topoisomerase I inhibitor cytotoxic payload (DXd). The high drug-to-antibody ratio (8:1) ensures a high DXd concentration is delivered to target tumour cells, following internalisation of T-DXd and subsequent cleavage of its tetrapeptide-based linker. DXd's membrane-permeable nature enables it to cross cell membranes and potentially exert antitumour activity on surrounding tumour cells regardless of HER2 expression. T-DXd's unique mechanism of action is reflected in its efficacy in clinical trials in patients with HER2-positive advanced breast cancer (in heavily pretreated populations and in those previously treated with a taxane and trastuzumab), as well as HER2-low metastatic breast cancer. Thus, ADCs such as T-DXd have the potential to change the treatment paradigm of targeting HER2 in metastatic breast cancer, including eventually within the adjuvant/neoadjuvant setting.

Nitrate modulates the physiological tolerance responses of the halophytic species Sarcocornia fruticosa to copper excess.

Coexistence impact of pollutants of different nature on halophytes tolerance to metal excess has not been thoroughly examined, and plant functional responses described so far do not follow a clear pattern. Using the Cu-tolerant halophyte Sarcocornia fruticosa as a model species, we conducted a greenhouse experiment to evaluate the impact of two concentration of copper (0 and 12 mM CuSO4) in combination with three nitrate levels (2, 14 and 50 mM KNO3) on plant growth, photosynthetic apparatus performance and ROS-scavenging enzymes system. The results revealed that S. fruticosa was able to grow adequately even when exposed to high concentrations of copper and nitrate. This response was linked to the plant capacity to uptake and retain a large amount of copper in its roots (up to 1500 mg kg-1 Cu), preventing its transport to aerial parts. This control of translocation was further magnified with nitrate concentration increment. Likewise, although Cu excess impaired S. fruticosa carbon assimilation capacity, the plant was able to downregulate its light-harvesting complexes function, as indicated its lowers ETR values, especially at 12 mM Cu + 50 mM NO3. This downregulation would contribute to avoid excess energy absorption and transformation. In addition, this strategy of avoiding excess energy was accompanied by the upregulation of all ROS-scavenging enzymes, a response that was further enhanced by the increase in nitrate concentration. Therefore, we conclude that the coexistence of nitrate would favor S. fruticosa tolerance to copper excess, and this effect is mediated by the combined activation of several tolerance mechanisms.