Antiproliferative potential of essential oil from the leaves of Croton floribundus (Euphorbiaceae) against human metastatic melanoma cell lines.

Melanoma is a cancer type with high lethality, metastatic capacity, and limited therapeutic options. Different essential oils have been reported with antitumoral potential.  Thus, the essential oil (EO) of the leaves of C. floribundus was obtained by hydrodistillation and analyzed by GC-MS. The majority of substances annotated were ß-selinene, E-Caryophyllene, and Premnaspirodiene. The cytotoxic activity of EO was evaluated on three melanoma cell lines SKMEL-147, WM-1366, and CHL-1, which are representative of metastatic melanoma with different mutation profiles. The IC50 values found for EO were lower than temozolomide (reference drug) in all melanoma cell lines. In addition, the selectivity of EO was upward when compared to the reference drug. Interestingly, the WM-1366 cell line was the most responsive, and these findings are very promising considering that it has shown high resistance to the plethora of compounds. Thus,  the C. floribundus EO is a promising source to drive further studies for the development of new treatments for metastatic melanoma, which is urgently relevant given the resistance of this pathology to current treatments.

Noninvasive Surrogate for Physiologic Dead Space Using the Carbon Dioxide Ventilatory Equivalent: Testing in a Single-Center Cohort, 2017-2023.

OBJECTIVES: We sought to evaluate the association between the carbon dioxide (co2) ventilatory equivalent (VEqco2 = minute ventilation/volume of co2 produced per min), a marker of dead space that does not require a blood gas measurement, and mortality risk. We compared the strength of this association to that of physiologic dead space fraction (VD/Vt = [Paco2-mixed-expired Pco2]/Paco2) as well as to other commonly used markers of dead space (i.e., the end-tidal alveolar dead space fraction [AVDSf = (Paco2-end-tidal Pco2)/Paco2], and ventilatory ratio [VR = (minute ventilation × Paco2)/(age-adjusted predicted minute ventilation × 37.5)]). DESIGN: Retrospective cohort data, 2017-2023. SETTING: Quaternary PICU. PATIENTS: One hundred thirty-one children with acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All dead space markers were calculated at the same 1-minute timepoint for each patient within the first 72 hours of using invasive mechanical ventilation. The 131 children had a median (interquartile range, IQR) age of 5.8 (IQR 1.4, 12.6) years, oxygenation index (OI) of 7.5 (IQR 4.6, 14.3), VD/Vt of 0.47 (IQR 0.38, 0.61), and mortality was 17.6% (23/131). Higher VEqco2 (p = 0.003), VD/Vt (p = 0.002), and VR (p = 0.013) were all associated with greater odds of mortality in multivariable models adjusting for OI, immunosuppressive comorbidity, and overall severity of illness. We failed to identify an association between AVDSf and mortality in the multivariable modeling. Similarly, we also failed to identify an association between OI and mortality after controlling for any dead space marker in the modeling. For the 28-day ventilator-free days outcome, we failed to identify an association between VD/Vt and the dead space markers in multivariable modeling, although OI was significant. CONCLUSIONS: VEqco2 performs similarly to VD/Vt and other surrogate dead space markers, is independently associated with mortality risk, and may be a reasonable noninvasive surrogate for VD/Vt.

Genomic Insights into Cyanide Biodegradation in the Pseudomonas Genus.

Molecular studies about cyanide biodegradation have been mainly focused on the hydrolytic pathways catalyzed by the cyanide dihydratase CynD or the nitrilase NitC. In some Pseudomonas strains, the assimilation of cyanide has been linked to NitC, such as the cyanotrophic model strain Pseudomonas pseudoalcaligenes CECT 5344, which has been recently reclassified as Pseudomonas oleovorans CECT 5344. In this work, a phylogenomic approach established a more precise taxonomic position of the strain CECT 5344 within the species P. oleovorans. Furthermore, a pan-genomic analysis of P. oleovorans and other species with cyanotrophic strains, such as P. fluorescens and P. monteilii, allowed for the comparison and identification of the cioAB and mqoAB genes involved in cyanide resistance, and the nitC and cynS genes required for the assimilation of cyanide or cyanate, respectively. While cyanide resistance genes presented a high frequency among the analyzed genomes, genes responsible for cyanide or cyanate assimilation were identified in a considerably lower proportion. According to the results obtained in this work, an in silico approach based on a comparative genomic approach can be considered as an agile strategy for the bioprospection of putative cyanotrophic bacteria and for the identification of new genes putatively involved in cyanide biodegradation.

Dose-escalated SBRT for borderline and locally advanced pancreatic cancer. Feasibility, safety and preliminary clinical results of a multicenter study.

Background: Pancreatic Stereotactic Body Radiotherapy (SBRT) allows for the administration of a higher biologically effective doses (BED), that would be essential to achieve durable tumor control. Escalating treatment doses need a very accurate tumor positioning and motion control during radiotherapy.The aim of this study to assess the feasibility and safety of a Simultaneous Integrated Boost (SIB) dose-escalated protocol at 45 Gy, 50 Gy and 55 Gy in 5 consecutive daily fractions, in Border Line Resectable Pancreatic Cancer (BRCP) /Locally Advanced Pancreatic Cancer (LAPC) by means of a standard LINAC platform. Methods: Patients diagnosed of BRPC/LAPC, candidates for neoadjuvant chemotherapy and SBRT, in four university hospitals of the province of Las Palmas (Canary Islands, Spain) were included in this prospective study. Radiotherapy was administered using standard technology (LINACS) with advanced positioning (Lipiodol® and metallic stent used as fiducial markers) and tumor motion control (4D, DBH, Calypso®). There were 3 planned dose-escalated SIB groups, 45 Gy/5f (9 patients) 50 Gy/5f (9 + 9 patients) and 55 Gy/5f (9 patients). The defined primary end points of the study were the safety and feasibility of the proposed treatment protocol. Secondary endpoints included radiological tumor response after SBRT, local control and survival. Results: From June 2017 to December 2022, sixty-two patients were initially assessed for eligibility in the study in the four participating centers, and 49 were candidates for chemotherapy (CHT). Forty-one were referred to radiotherapy after CHT and 33 finally were treated by escalated-dose SIB, 45 Gy (9 patients) 50 Gy (16 patients), 55 Gy(8 patients). All patients completed the scheduled treatment and no acute or late severe (≥grade3) gastrointestinal toxicity was observed.Local response was analyzed by CT/MRI two months after the end of SBRT. Ten patients (31,25 %) achieved objective response (2/9:45 Gy, 5/15:50 Gy, 3/8:55 Gy). Follow-up was closed as July 2023. Freedom from local progression at 1-2y were 89,3% (95 %CI:83,4-95,2%) and 66 % (95 %CI:54,6-77,4%) respectively. The 1-2y survival rates were 95,7% (95 %CI:91,4-100 % and 48,6% (95 %CI:37,7-59,5%) respectively. Conclusion: These promising results should be confirmed by further studies with larger sample size and extended follow-up period.

Bacterial tolerance and detoxification of cyanide, arsenic and heavy metals: Holistic approaches applied to bioremediation of industrial complex wastes.

Cyanide is a highly toxic compound that is found in wastewaters generated from different industrial activities, such as mining or jewellery. These residues usually contain high concentrations of other toxic pollutants like arsenic and heavy metals that may form different complexes with cyanide. To develop bioremediation strategies, it is necessary to know the metabolic processes involved in the tolerance and detoxification of these pollutants, but most of the current studies are focused on the characterization of the microbial responses to each one of these environmental hazards individually, and the effect of co-contaminated wastes on microbial metabolism has been hardly addressed. This work summarizes the main strategies developed by bacteria to alleviate the effects of cyanide, arsenic and heavy metals, analysing interactions among these toxic chemicals. Additionally, it is discussed the role of systems biology and synthetic biology as tools for the development of bioremediation strategies of complex industrial wastes and co-contaminated sites, emphasizing the importance and progress derived from meta-omic studies.

Adaptation of sea turtles to climate warming: Will phenological responses be sufficient to counteract changes in reproductive output?

Sea turtles are vulnerable to climate change since their reproductive output is influenced by incubating temperatures, with warmer temperatures causing lower hatching success and increased feminization of embryos. Their ability to cope with projected increases in ambient temperatures will depend on their capacity to adapt to shifts in climatic regimes. Here, we assessed the extent to which phenological shifts could mitigate impacts from increases in ambient temperatures (from 1.5 to 3°C in air temperatures and from 1.4 to 2.3°C in sea surface temperatures by 2100 at our sites) on four species of sea turtles, under a "middle of the road" scenario (SSP2-4.5). Sand temperatures at sea turtle nesting sites are projected to increase from 0.58 to 4.17°C by 2100 and expected shifts in nesting of 26-43 days earlier will not be sufficient to maintain current incubation temperatures at 7 (29%) of our sites, hatching success rates at 10 (42%) of our sites, with current trends in hatchling sex ratio being able to be maintained at half of the sites. We also calculated the phenological shifts that would be required (both backward for an earlier shift in nesting and forward for a later shift) to keep up with present-day incubation temperatures, hatching success rates, and sex ratios. The required shifts backward in nesting for incubation temperatures ranged from -20 to -191 days, whereas the required shifts forward ranged from +54 to +180 days. However, for half of the sites, no matter the shift the median incubation temperature will always be warmer than the 75th percentile of current ranges. Given that phenological shifts will not be able to ameliorate predicted changes in temperature, hatching success and sex ratio at most sites, turtles may need to use other adaptive responses and/or there is the need to enhance sea turtle resilience to climate warming.

Prehospitalization Trauma and Physiologic Factors Associated with the Presence of Post-traumatic Stress 3 Months After PICU Discharge.

BACKGROUND: Children admitted to the pediatric intensive care unit (PICU) have post-traumatic stress (PTS) rates up to 64%, and up to 28% of them meet criteria for PTS disorder (PTSD). We aim to examine whether a prior trauma history and increased physiologic parameters due to a heightened sympathetic response are associated with later PTS. Our hypothesis was children with history of prehospitalization trauma, higher heart rates, blood pressures, cortisol, and extrinsic catecholamine administration during PICU admission are more likely to have PTS after discharge. METHODS: This is a prospective, observational study of children admitted to the PICU at an urban, quaternary, academic children's hospital. Children aged 8 to 17 years old without developmental delay, severe psychiatric disorder, or traumatic brain injury were included. Children's prehospitalization trauma history was assessed with a semistructured interview. All in-hospital variables were from the electronic medical record. PTS was present if children had 4 of the Diagnostic and Statistical Manual of Mental Disorders IV criteria for PTSD. Student's t- and chi-squared tests were used to compare the presence or absence of prior trauma and all of the PICU-associated variables. RESULTS: Of the 110 children at baseline, 67 had 3-month follow-up. In the latter group, 46% met the criteria for PTS, mean age of 13 years (SD 3), 57% male, a mean PRISM III score of 4.9 (SD 4.3), and intensive care unit length of stay 6.5 days (SD 7.8). There were no statistically significant differences in the demographics of the children with and without PTS. The only variable to show significance was trauma history; children with prehospitalization trauma were more likely to have PTS at 3-month follow-up (P = .02). CONCLUSIONS: Prehospitalization trauma history was associated with the presence of PTS after admission to the PICU. This study suggests future studies should shift to the potential predictive benefit of screening children for trauma history upon PICU admission.

Application of an Ultra-Low-Cost Passive Sampler for Light-Absorbing Carbon in Mongolia.

Low-cost, long-term measures of air pollution concentrations are often needed for epidemiological studies and policy analyses of household air pollution. The Washington passive sampler (WPS), an ultra-low-cost method for measuring the long-term average levels of light-absorbing carbon (LAC) air pollution, uses digital images to measure the changes in the reflectance of a passively exposed paper filter. A prior publication on WPS reported high precision and reproducibility. Here, we deployed three methods to each of 10 households in Ulaanbaatar, Mongolia: one PurpleAir for PM2.5; two ultrasonic personal aerosol samplers (UPAS) with quartz filters for the thermal-optical analysis of elemental carbon (EC); and two WPS for LAC. We compared multiple rounds of 4-week-average measurements. The analyses calibrating the LAC to the elemental carbon measurement suggest that 1 µg of EC/m3 corresponds to 62 PI/month (R2 = 0.83). The EC-LAC calibration curve indicates an accuracy (root-mean-square error) of 3.1 µg of EC/m3, or ~21% of the average elemental carbon concentration. The RMSE values observed here for the WPS are comparable to the reported accuracy levels for other methods, including reference methods. Based on the precision and accuracy results shown here, as well as the increased simplicity of deployment, the WPS may merit further consideration for studying air quality in homes that use solid fuels.

Lifestyle Patterns in the Late Postoperative Period of Bariatric Surgery: a Descriptive Analysis of the CINTO Study.

BACKGROUND: The behavior of patients undergoing metabolic bariatric surgery (MBS) has been widely investigated to better understand their attitudes and to formulate effective advisory strategies. Although these elements have been studied separately, the magnitude of these behaviors still needs to be determined from a combined factors approach. This study aimed to identify the lifestyle patterns of patients who underwent MBS 5 or more years ago. METHODS: In this observational study, 123 patients who underwent MBS at least 5 years ago were included. Anthropometric data, sociodemographic profile, dietary intake, physical activity level, sleeping, smoking, and alcohol consumption were collected for all participants. Lifestyle pattern was evaluated using principal component analysis (PCA) and the Kaiser-Meyer-Olkin (KMO) index was applied to evaluate data factorability. RESULTS: PCA identified two patterns of behavior adopted by the participants in the late postoperative (PO) period (more than 5 years PO) of MBS. In the first pattern, a positive correlation was found between consumption of ultra-processed foods (r = 0.459), risky consumption of alcoholic beverages (r = 0.630), and tobacco use (r = 0.584). In the second, a positive correlation was observed between the consumption of unprocessed or minimally processed foods (r = 0.692) and more sleep time per day (r = 0.654). CONCLUSION: After 5 years of PO, combined behavior analysis revealed healthy and unhealthy lifestyle patterns, which points to the relevance of permanent clinical follow-up of these patients to ensure the best health status.

Quantitative Proteomic Analysis of Cyanide and Mercury Detoxification by Pseudomonas pseudoalcaligenes CECT 5344.

The cyanide-degrading bacterium Pseudomonas pseudoalcaligenes CECT 5344 uses cyanide and different metal-cyanide complexes as the sole nitrogen source. Under cyanotrophic conditions, this strain was able to grow with up to 100 µM mercury, which was accumulated intracellularly. A quantitative proteomic analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been applied to unravel the molecular basis of the detoxification of both cyanide and mercury by the strain CECT 5344, highlighting the relevance of the cyanide-insensitive alternative oxidase CioAB and the nitrilase NitC in the tolerance and assimilation of cyanide, independently of the presence or absence of mercury. Proteins overrepresented in the presence of cyanide and mercury included mercury transporters, mercuric reductase MerA, transcriptional regulator MerD, arsenate reductase and arsenical resistance proteins, thioredoxin reductase, glutathione S-transferase, proteins related to aliphatic sulfonates metabolism and sulfate transport, hemin import transporter, and phosphate starvation induced protein PhoH, among others. A transcriptional study revealed that from the six putative merR genes present in the genome of the strain CECT 5344 that could be involved in the regulation of mercury resistance/detoxification, only the merR2 gene was significantly induced by mercury under cyanotrophic conditions. A bioinformatic analysis allowed the identification of putative MerR2 binding sites in the promoter regions of the regulatory genes merR5, merR6, arsR, and phoR, and also upstream from the structural genes encoding glutathione S-transferase (fosA and yghU), dithiol oxidoreductase (dsbA), metal resistance chaperone (cpxP), and amino acid/peptide extruder involved in quorum sensing (virD), among others. IMPORTANCE Cyanide, mercury, and arsenic are considered very toxic chemicals that are present in nature as cocontaminants in the liquid residues generated by different industrial activities like mining. Considering the huge amounts of toxic cyanide- and mercury-containing wastes generated at a large scale and the high biotechnological potential of P. pseudoalcaligenes CECT 5344 in the detoxification of cyanide present in these industrial wastes, in this work, proteomic, transcriptional, and bioinformatic approaches were used to characterize the molecular response of this bacterium to cyanide and mercury, highlighting the mechanisms involved in the simultaneous detoxification of both compounds. The results generated could be applied for developing bioremediation strategies to detoxify wastes cocontaminated with cyanide, mercury, and arsenic, such as those generated at a large scale in the mining industry.

Clinical utility of a personalized and long-term monitoring device for Parkinson's disease in a real clinical practice setting: An expert opinion survey on STAT-ON™.

BACKGROUND: STAT-ON™ is an objective tool that registers ON-OFF fluctuations making possible to know the state of the patient at every moment of the day in normal life. Our aim was to analyze the opinion of different Parkinson's disease experts about the STAT-ON™ tool after using the device in a real clinical practice setting (RCPS). METHODS: STAT-ON™ was provided by the Company Sense4Care to Spanish neurologists for using it in a RCPS. Each neurologist had the device for at least three months and could use it in PD patients at his/her own discretion. In February 2020, a survey with 30 questions was sent to all participants. RESULTS: Two thirds of neurologists (53.8% females; mean age 44.9±9 years old) worked in a Movement Disorders Unit, the average experience in PD was 16±6.9 years, and 40.7% of them had previously used other devices. A total of 119 evaluations were performed in 114 patients (range 2-9 by neurologist; mean 4.5±2.3). STAT-ON™ was considered "quite" to "very useful" by 74% of the neurologists with an overall opinion of 6.9±1.7 (0, worst; 10, best). STAT-ON™ was considered better than diaries by 70.3% of neurologists and a useful tool for the identification of patients with advanced PD by 81.5%. Proper identification of freezing of gait episodes and falls were frequent limitations reported. CONCLUSION: STAT-ON™ could be a useful device for using in PD patients in clinical practice.

Prospective Pilot study of Quality of Life in patients with severe late-radiation-toxicity treated by Low hyperbaric-oxigen-therapy.

Background/purpose: The aim of this study is to assess for the first time the immediate and long term impact on quality-of-life of HBO treatments(HBOT) at 1.45 ATA (Absolute Atmospheric Pressure) Medical Hyperbaric chamber. Methods: Patients over 18 years-old, suffering of grade 3 Common Terminology Criteria for Adverse Events (CTCAE) 4.0 radiation induced late toxicity and progressing to standard support therapy were included in this prospective study. HBOT was given daily, sixty minutes per session by a Medical Hyperbaric Chamber Biobarica System at 1.45 ATA at 100% O2. Forty sessions were prescribed for all patients given in 8 weeks. Patients reported outcomes (PROs) was assessed by the QLQ-C30 questionnaire, before starting, in the last week of the treatment, as well as during follow up. Results: Between February-2018/June-2021, 48 patients fulfilled the inclusion criteria. A total of 37 patients (77%) completed the treatment prescribed HBOT sessions. Patients with anal fibrosis (9/37) and brain necrosis (7/37) were the most frequently treated. The most common symptoms were pain (65%) and bleeding (54%). In addition, thirty out of the 37 patients who completed the pre- and post-treatment Patients Reported Outcomes (PROs) assessment also completed the follow up European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire C30 (EORTC-QLQ-C30), and were evaluated in the present study. Mean follow up was 22,10 (6-39) months.The Median score of the EORTC-QLQ-C30, at the end of HBOT and during follow-up, was improved in all assessed domains, except in the cognitive aspect (p = 0.106). Conclusions: HBOT at 1.45 ATA is a feasible and well tolerated treatment, improving long term quality of life in terms of physical function, daily activities and general health subjective state of patients suffering severe late radiation-induced toxicity.

Proteomic Analysis of Arsenic Resistance during Cyanide Assimilation by Pseudomonas pseudoalcaligenes CECT 5344.

Wastewater from mining and other industries usually contains arsenic and cyanide, two highly toxic pollutants, thereby creating the need to develop bioremediation strategies. Here, molecular mechanisms triggered by the simultaneous presence of cyanide and arsenite were analyzed by quantitative proteomics, complemented with qRT-PCR analysis and determination of analytes in the cyanide-assimilating bacterium Pseudomonas pseudoalcaligenes CECT 5344. Several proteins encoded by two ars gene clusters and other Ars-related proteins were up-regulated by arsenite, even during cyanide assimilation. Although some proteins encoded by the cio gene cluster responsible for cyanide-insensitive respiration decreased in the presence of arsenite, the nitrilase NitC required for cyanide assimilation was unaffected, thus allowing bacterial growth with cyanide and arsenic. Two complementary As-resistance mechanisms were developed in this bacterium, the extrusion of As(III) and its extracellular sequestration in biofilm, whose synthesis increased in the presence of arsenite, and the formation of organoarsenicals such as arseno-phosphoglycerate and methyl-As. Tetrahydrofolate metabolism was also stimulated by arsenite. In addition, the ArsH2 protein increased in the presence of arsenite or cyanide, suggesting its role in the protection from oxidative stress caused by both toxics. These results could be useful for the development of bioremediation strategies for industrial wastes co-contaminated with cyanide and arsenic.

Novel unconventional radiotherapy techniques: Current status and future perspectives - Report from the 2nd international radiation oncology online seminar.

•Improvement of therapeutic ratio by novel unconventional radiotherapy approaches.•Immunomodulation using high-dose spatially fractionated radiotherapy.•Boosting radiation anti-tumor effects by adding an immune-mediated cell killing.

Systemic Therapy for Advanced Hepatocellular Carcinoma: Current Stand and Perspectives.

Hepatocellular carcinoma often develops in the context of chronic liver disease. It is the sixth most frequently diagnosed cancer and the third most common cause of cancer-related mortality worldwide. Although the mainstay of therapy is surgical resection, most patients are not eligible because of liver dysfunction or tumor extent. Sorafenib was the first tyrosine kinase inhibitor that improved the overall survival of patients who failed to respond to local therapies or had advanced disease, and for many years, it was the only treatment approved for the first-line setting. However, in recent years, trials have demonstrated an improvement in survival with treatments based on immunotherapy and new targeting agents, thereby extending the treatment options. A phase III trial showed that a combination of immunotherapy and targeted therapy, including atezolizumab plus bevacizumab, improved survival in the first-line setting, and is now considered the new standard of care. Other agents and combinations are being tested, including the combination of nivolumab plus ipilimumab and tremelimumab plus durvalumab, and they reportedly have clinical benefits. The aim of this manuscript is to review the latest approved therapeutic options in first- and second-line settings for advanced HCC and discuss future perspectives.

Holistic view of biological nitrogen fixation and phosphorus mobilization in Azotobacter chroococcum NCIMB 8003.

Nitrogen (N) and phosphorus (P) deficiencies are two of the most agronomic problems that cause significant decrease in crop yield and quality. N and P chemical fertilizers are widely used in current agriculture, causing environmental problems and increasing production costs. Therefore, the development of alternative strategies to reduce the use of chemical fertilizers while maintaining N and P inputs are being investigated. Although dinitrogen is an abundant gas in the atmosphere, it requires biological nitrogen fixation (BNF) to be transformed into ammonium, a nitrogen source assimilable by living organisms. This process is bioenergetically expensive and, therefore, highly regulated. Factors like availability of other essential elements, as phosphorus, strongly influence BNF. However, the molecular mechanisms of these interactions are unclear. In this work, a physiological characterization of BNF and phosphorus mobilization (PM) from an insoluble form (Ca3(PO4)2) in Azotobacter chroococcum NCIMB 8003 was carried out. These processes were analyzed by quantitative proteomics in order to detect their molecular requirements and interactions. BNF led to a metabolic change beyond the proteins strictly necessary to carry out the process, including the metabolism related to other elements, like phosphorus. Also, changes in cell mobility, heme group synthesis and oxidative stress responses were observed. This study also revealed two phosphatases that seem to have the main role in PM, an exopolyphosphatase and a non-specific alkaline phosphatase PhoX. When both BNF and PM processes take place simultaneously, the synthesis of nitrogenous bases and L-methionine were also affected. Thus, although the interdependence is still unknown, possible biotechnological applications of these processes should take into account the indicated factors.

Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region.

BACKGROUND: Overweight and obesity are defined by an anomalous or excessive fat accumulation that may compromise health. To find single-nucleotide polymorphisms (SNPs) influencing metabolic phenotypes associated with the obesity state, we analyze multiple anthropometric and clinical parameters in a cohort of 790 healthy volunteers and study potential associations with 48 manually curated SNPs, in metabolic genes functionally associated with the mechanistic target of rapamycin (mTOR) pathway. RESULTS: We identify and validate rs2291007 within a conserved region in the 3'UTR of folliculin-interacting protein FNIP2 that correlates with multiple leanness parameters. The T-to-C variant represents the major allele in Europeans and disrupts an ancestral target sequence of the miRNA miR-181b-5p, thus resulting in increased FNIP2 mRNA levels in cancer cell lines and in peripheral blood from carriers of the C allele. Because the miRNA binding site is conserved across vertebrates, we engineered the T-to-C substitution in the endogenous Fnip2 allele in mice. Primary cells derived from Fnip2 C/C mice show increased mRNA stability, and more importantly, Fnip2 C/C mice replicate the decreased adiposity and increased leanness observed in human volunteers. Finally, expression levels of FNIP2 in both human samples and mice negatively associate with leanness parameters, and moreover, are the most important contributor in a multifactorial model of body mass index prediction. CONCLUSIONS: We propose that rs2291007 influences human leanness through an evolutionarily conserved modulation of FNIP2 mRNA levels.

Association of Peripheral Blood and Cutaneous Eosinophils With Bullous Pemphigoid Disease Severity and Treatment Outcomes / Asociación entre eosinófilos de sangre periférica y cutáneos con la gravedad del penfigoide ampolloso y los resultados terapéuticos

Background and aims A dermal inflammatory infiltrate rich in eosinophils is a prominent histological feature of bullous pemphigoid (BP) and peripheral blood eosinophilia has been documented in 50–60% of BP patients. Nevertheless, the impact of circulating and dermal infiltrate eosinophil levels on BP remains poorly understood. The main objective of this work was to investigate the association of peripheral blood and dermal infiltrate eosinophil levels with clinical and immunological characteristics of the disease. Material and methods Retrospective cohort study including all patients diagnosed with BP between 2011 and 2020. Results The study cohort included 233 patients with BP. The mean baseline peripheral blood eosinophil count was 956.3±408.6×106/L and the mean number of tissue eosinophils at the dermal hot spot area was 30.5±19.0. Patients with disseminated presentation (i.e. BSA>50%) had significantly higher peripheral blood eosinophil counts (P=0.028). Mucosal involvement was significantly associated with lower dermal eosinophil count (P=0.001). Requiring inpatient care and relapsing were significantly associated with high peripheral blood eosinophil count (P=0.025; P=0.020, respectively). Among the 68 patients who experienced a relapse, 31 had peripheral blood eosinophilia (i.e. >500×106/L) at relapse (44.2%). Peripheral blood eosinophil counts at baseline and at relapse were significantly correlated (r=0.82, P<0.001). Conclusion Peripheral blood and cutaneous eosinophils levels may be useful biomarkers for disease activity and treatment outcomes in BP. Monitoring peripheral blood eosinophil counts may allow early detection of relapse (AU)

Antecedentes y objetivos El infiltrado inflamatorio dérmico rico en eosinófilos es una característica histológica destacada de penfigoide ampolloso (PA) y eosinofilia en sangre periférica, que se ha documentado en el 50-60% de los pacientes con esta enfermedad. Sin embargo, el impacto de los niveles de eosinófilos circulantes y en infiltrados dérmicos en el PA sigue sin comprenderse. El objetivo principal de este estudio fue investigar la asociación entre los niveles de eosinófilos en sangre periférica y en infiltrados dérmicos y las características clínicas e inmunológicas de esta enfermedad. Material y métodos Estudio de cohorte retrospectivo que incluyó a todos los pacientes con PA entre 2011 y 2020. Resultados El estudio de cohorte incluyó 233 pacientes con PA. El recuento de eosinófilos basal medio en sangre periférica fue de 956,3 ± 408,6 x106/L y el número medio de eosinófilos tisulares en la zona dérmica clave fue de 30,5 ± 19. Los pacientes con presentación diseminada (es decir, BSA >50%) tuvieron conteos de eosinófilos en sangre periférica significativamente superiores (p = 0,028). El compromiso mucoso estuvo significativamente asociado a un conteo de eosinófilos cutáneo inferior (p = 0,001). La necesidad de cuidados hospitalarios y las recaídas estuvieron significativamente asociadas a conteos de eosinófilos en sangre periférica más elevados (p = 0,025; p = 0,020, respectivamente). Entre los 68 pacientes que experimentaron recidiva, 31 tuvieron eosinofilia en sangre periférica (es decir, > 500 x 106/L) en recaída (44,2%). Los conteos de eosinófilos en sangre periférica basales y en recaída se correlacionaron significativamente (r = 0,82, p < 0,001). Conclusione Los niveles de eosinófilos en sangre periférica y cutáneos pueden constituir biomarcadores útiles para la actividad de la enfermedad y los resultados terapéuticos en el PA. Supervisar los conteos de eosinófilos en sangre periférica puede ayudar a detectar la recidiva tempranamente (AU)

[Artículo traducido] Asociación entre eosinófilos de sangre periférica y cutáneos con la gravedad del penfigoide ampolloso y los resultados terapéuticos / Association of Peripheral Blood and Cutaneous Eosinophils With Bullous Pemphigoid Disease Severity and Treatment Outcomes

Antecedentes y objetivos El infiltrado inflamatorio dérmico rico en eosinófilos es una característica histológica destacada de penfigoide ampolloso (PA) y eosinofilia en sangre periférica, que se ha documentado en el 50-60% de los pacientes con esta enfermedad. Sin embargo, el impacto de los niveles de eosinófilos circulantes y en infiltrados dérmicos en el PA sigue sin comprenderse. El objetivo principal de este estudio fue investigar la asociación entre los niveles de eosinófilos en sangre periférica y en infiltrados dérmicos y las características clínicas e inmunológicas de esta enfermedad. Material y métodos Estudio de cohorte retrospectivo que incluyó a todos los pacientes con PA entre 2011 y 2020. Resultados El estudio de cohorte incluyó 233 pacientes con PA. El recuento de eosinófilos basal medio en sangre periférica fue de 956,3 ± 408,6 x106/L y el número medio de eosinófilos tisulares en la zona dérmica clave fue de 30,5 ± 19. Los pacientes con presentación diseminada (es decir, BSA >50%) tuvieron conteos de eosinófilos en sangre periférica significativamente superiores (p = 0,028). El compromiso mucoso estuvo significativamente asociado a un conteo de eosinófilos cutáneo inferior (p = 0,001). La necesidad de cuidados hospitalarios y las recaídas estuvieron significativamente asociadas a conteos de eosinófilos en sangre periférica más elevados (p = 0,025; p = 0,020, respectivamente). Entre los 68 pacientes que experimentaron recidiva, 31 tuvieron eosinofilia en sangre periférica (es decir, > 500 x 106/L) en recaída (44,2%). Los conteos de eosinófilos en sangre periférica basales y en recaída se correlacionaron significativamente (r = 0,82, p < 0,001). Conclusione Los niveles de eosinófilos en sangre periférica y cutáneos pueden constituir biomarcadores útiles para la actividad de la enfermedad y los resultados terapéuticos en el PA. Supervisar los conteos de eosinófilos en sangre periférica puede ayudar a detectar la recidiva tempranamente (AU)

Background and aims A dermal inflammatory infiltrate rich in eosinophils is a prominent histological feature of bullous pemphigoid (BP) and peripheral blood eosinophilia has been documented in 50–60% of BP patients. Nevertheless, the impact of circulating and dermal infiltrate eosinophil levels on BP remains poorly understood. The main objective of this work was to investigate the association of peripheral blood and dermal infiltrate eosinophil levels with clinical and immunological characteristics of the disease. Material and methods Retrospective cohort study including all patients diagnosed with BP between 2011 and 2020. Results The study cohort included 233 patients with BP. The mean baseline peripheral blood eosinophil count was 956.3±408.6×106/L and the mean number of tissue eosinophils at the dermal hot spot area was 30.5±19.0. Patients with disseminated presentation (i.e. BSA>50%) had significantly higher peripheral blood eosinophil counts (P=0.028). Mucosal involvement was significantly associated with lower dermal eosinophil count (P=0.001). Requiring inpatient care and relapsing were significantly associated with high peripheral blood eosinophil count (P=0.025; P=0.020, respectively). Among the 68 patients who experienced a relapse, 31 had peripheral blood eosinophilia (i.e. >500×106/L) at relapse (44.2%). Peripheral blood eosinophil counts at baseline and at relapse were significantly correlated (r=0.82, P<0.001). Conclusion Peripheral blood and cutaneous eosinophils levels may be useful biomarkers for disease activity and treatment outcomes in BP. Monitoring peripheral blood eosinophil counts may allow early detection of relapse (AU)

National and Intraurban Air Pollution Exposure Disparity Estimates in the United States: Impact of Data-Aggregation Spatial Scale.

Air pollution exposure disparities by race/ethnicity and socioeconomic status have been analyzed using data aggregated at various spatial scales. Our research question is this: To what extent does the spatial scale of data aggregation impact the estimated exposure disparities? We compared disparities calculated using data spatially aggregated at five administrative scales (state, county, census tract, census block group, census block) in the contiguous United States in 2010. Specifically, for each of the five spatial scales, we calculated national and intraurban disparities in exposure to fine particles (PM2.5) and nitrogen dioxide (NO2) by race/ethnicity and socioeconomic characteristics using census demographic data and an empirical statistical air pollution model aggregated at that scale. We found, for both pollutants, that national disparity estimates based on state and county scale data often substantially underestimated those estimated using tract and finer scales; in contrast, national disparity estimates were generally consistent using tract, block group, and block scale data. Similarly, intraurban disparity estimates based on tract and finer scale data were generally well correlated for both pollutants across urban areas, although in some cases intraurban disparity estimates were substantially different, with tract scale data more frequently leading to underestimates of disparities compared to finer scale analyses.