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Epigenetic modifications are closely related to certain disorders of the organism, including the development of tumors. One of the main epigenetic modifications is the methylation of DNA cytosines, 5‐methyl‐2′‐deoxycycytidine. Furthermore, 5‐mdC can be oxidized to form three new modifications, 5‐(hydroxymethyl)‐2′‐deoxycytidine, 5‐formyl‐2′‐deoxycytidine, and 5‐carboxy‐2′‐deoxycytidine. The coupling of liquid chromatography with tandem mass spectrometry has been widely used for the total determination of methylated DNA cytosines in samples of biological and clinical interest. These methods are based on the measurement of the free compounds (e.g., urine) or after complete hydrolysis of the DNA (e.g., tissues) followed by a preconcentration, derivatization, and/or clean‐up step. This review highlights the main advances in the quantification of modified nucleotides and nucleosides by isotope dilution using isotopically labeled analogs combined with liquid or gas chromatography coupled to mass spectrometry reported in the last 20 years. The different possible sources of labeled compounds are indicated. Special emphasis has been placed on the different types of chromatography commonly used (reverse phase and hydrophilic interaction liquid chromatography) and the derivatization methods developed to enhance chromatographic resolution and ionization efficiency. We have also revised the application of bidimensional chromatography and indicated significant biological and clinical applications of these determinations. [ABSTRACT FROM AUTHOR]

Several species of ectoparasites, including chewing lice and mites are closely associated with their hosts. The Andean condor (Vultur gryphus) is globally listed as vulnerable by the IUCN and its population has been steadily declining in recent decades suggesting a potential extinction of associated entomofauna. The purpose of this study was to record the species of ectoparasites infesting three individuals of Andean condor found dead in the ‘Páramo del Almorzadero’ Santander Department, Northeastern Colombia. One juvenile (male) and two adults (male and female) Andean condors received for necropsy were carefully examined for ectoparasite infestation. Specimens were collected and preserved in ethanol (70%) for taxonomic studies. Morphologic identification and morphometric records were made under light microscopy. Some specimens were also prepared for scanning electron microscopy and others were subjected to DNA extraction to amplify and obtain sequences of the cytochrome‐C oxidase subunit I (COI) gene for phylogenetic analyses. Lice were collected from the juvenile condor and the adult female and identified as Falcolipeurus assesor (Phthiraptera: Ischnocera) in the juvenile condor (8 females, 19 males and 8 nymphs) and the adult (1 female); Colpocephalum trichosum (Phthiraptera: Amblycera) in the juvenile (19 females, 24 males and 1 nymph) and the adult (2 females, 2 males and 3 nymphs); and Cuculiphilus zonatus (Phthiraptera: Amblycera) in the juvenile (40 females, 43 males and 15 nymphs) and the adult (1 male and 2 nymphs). Moreover, one mite collected from the juvenile condor was identified as Ancyralges cathartinus (Acari: Astigmata) (1 female). Morphometric data was obtained for the adult stages of F. assesor (6 females and 13 males), C. trichosum (9 females and 9 males) and C. zonatus (10 females and 10 males). We obtained the first DNA sequences of COI for F. assessor, and C. trichosum, where phylogenetic tree analysis showed that F. assessor is more closely related to Falcolipeurus marginalis, and C. trichosum to Colpocephalum kelloggi. This represents the first record of parasites in Andean condor from Colombia and contributes to the knowledge of chewing lice and mites associated with an endemic and endangered bird species. Further studies on Andean condor ectoparasites should be focused on documenting host–parasite interactions and potential health impacts in these wild birds. [ABSTRACT FROM AUTHOR]

This article presents a case report of a 12-year-old girl with atypical Mowat-Wilson syndrome (aMOWS), a milder form of the rare developmental disorder characterized by distinct facial features, intellectual disability, and language impairment. The girl in the case had mild intellectual disability, dystonia, and choreoathetosis, which are movement disorders not typically associated with MOWS. The study emphasizes the need to consider aMOWS in patients with mild intellectual disability and movement disorders, challenging previous assumptions about the behavioral patterns of MOWS. [Extracted from the article]

Summary: Objectives: This study assessed the transparency and replicability of exercise‐based interventions following bariatric surgery by evaluating the content reporting of exercise‐based clinical trials. Design: The study design of the present article is a systematic review. Data sources PubMed, Scopus, Web of Sciences, PsycINFO, and Cochrane were searched from their inception to May 2023. Eligibility criteria: Eligible studies were clinical trials including exercise interventions in participants following bariatric surgery. There were 28 unique exercise interventions. Two independent reviewers applied the exercise prescription components of Frequency, Intensity, Time, and Type (FITT; four items) and the Consensus on Exercise Reporting Template (CERT; 19 items). Exercise interventions were organized into four major exercise components: aerobic training, resistance training, concurrent training, and "others." Results: The FITT assessment revealed that 53% of the trials did not report the training intensity, whereas 25% did not indicate the duration of the major exercise component within the training session. The mean CERT score was 5 out of a possible score of 19. No studies reached CERT score >10, while 13 out of the total 19 CERT items were not adequately reported by ≥75% of the studies. Conclusion: This study highlights that the exercise interventions following bariatric surgery are poorly reported, non‐transparent, and generally not replicable. This precludes understanding the dose–response association of exercise and health‐related effects and requires action to improve this scientific field. [ABSTRACT FROM AUTHOR]

The study of neurogenesis is essential to understanding fundamental developmental processes and for the development of cell replacement therapies for central nervous system disorders. Here, we designed an in vivo drug screening protocol in developing zebrafish to find new molecules and signalling pathways regulating neurogenesis in the ventral spinal cord. This unbiased drug screen revealed that 4 cyclooxygenase (COX) inhibitors reduced the generation of serotonergic interneurons in the developing spinal cord. These results fitted very nicely with available single‐cell RNAseq data revealing that floor plate cells show differential expression of 1 of the 2 COX2 zebrafish genes (ptgs2a). Indeed, several selective COX2 inhibitors and two different morpholinos against ptgs2a reduced the number of serotonergic neurons in the ventral spinal cord and led to locomotor deficits. Single‐cell RNAseq data and different pharmacological manipulations further revealed that COX2‐floor plate‐derived prostaglandin D2 promotes neurogenesis in the developing spinal cord by promoting mitotic activity in progenitor cells. Rescue experiments using a phosphodiesterase‐4 inhibitor suggest that intracellular changes in cAMP levels underlie the effects of COX inhibitors on neurogenesis and locomotion. Our study provides compelling in vivo evidence showing that prostaglandin signalling promotes neurogenesis in the ventral spinal cord. [ABSTRACT FROM AUTHOR]

The National Soil Strategy for Sustainable Agriculture (ENASAS) arises in response to the increasing need to organize, coordinate and strengthen the implementation of actions oriented to the sustainable management of Mexico's agricultural soils. The measures recommended in this paper allow the conservation and maintenance of soils' essential functions for agriculture, food security and population well‐being. The health and quality of agricultural soils are under constant pressure from several factors, mainly anthropogenic. One of ENASAS's objectives is to identify and stop the causes involved in land degradation processes using a systemic approach. From this perspective, the participation of various actors in sustainable soil management allows the integration of different systems, practices, techniques and knowledge that promotes awareness among the entire population about the importance of soil resources. On the other hand, given current limitations on the availability of information necessary to support decision‐making and evaluate the result of the actions implemented, ENASAS promotes the generation of tools that provide reliable and updated data regarding Mexico's agricultural soils. In the same sense, this strategy encourages the development of scientific and technological research and the transfer of knowledge that meets the needs of farmers, particularly those who carry out their activities on a smaller scale. This perspective describes ENASAS as a multi‐institutional initiative that will support sustainable soil management practices across the country's agricultural systems of Mexico and contribute to the adaptation and mitigation of global environmental change. [ABSTRACT FROM AUTHOR]

Introduction: The results of studies of tocilizumab (TCZ) in COVID‐19 are contradictory. Our study aims to update medical evidence from controlled observational studies and randomized clinical trials (RCTs) on the use of TCZ in hospitalized patients with COVID‐19. Methods: We searched the following databases from January 1, 2020 to April 13, 2021 (date of the last search): MEDLINE database through the PubMed search engine and Scopus, using the terms ("COVID‐19" [Supplementary Concept]) AND "tocilizumab" [Supplementary Concept]). Results: Sixty four studies were included in the present study: 54 were controlled observational studies (50 retrospective and 4 prospective) and 10 were RCTs. The overall results provided data from 20,616 hospitalized patients with COVID‐19: 7668 patients received TCZ in addition to standard of care (SOC) (including 1915 patients admitted to intensive care units (ICU) with reported mortality) and 12,948 patients only receiving SOC (including 4410 patients admitted to the ICU with reported mortality). After applying the random‐effects model, the hospital‐wide (including ICU) pooled mortality odds ratio (OR) of patients with COVID‐19 treated with TCZ was 0.73 (95% confidence interval (CI) = 0.56–0.93). The pooled hospital‐wide mortality OR was 1.25 (95% CI = 0.74–2.18) in patients admitted at conventional wards versus 0.66 (95% CI = 0.59–0.76) in patients admitted to the ICU. The pooled OR of hospital‐wide mortality (including ICU) of COVID‐19 patients treated with TCZ plus corticosteroids (CS) was 0.67 (95% CI = 0.54–0.84). The pooled in‐hospital mortality OR was 0.71 (95% CI = 0.35–1.42) when TCZ was early administered (≤10 days from symptom onset) versus 0.83 (95% CI 0.48–1.45) for late administration (>10 days from symptom onset). The meta‐analysis did not find significantly higher risk for secondary infections in COVID‐19 patients treated with TCZ. Conclusions: TCZ prevented mortality in patients hospitalized for COVID‐19. This benefit was seen to a greater extent in patients receiving concomitant CS and when TCZ administration occurred within the first 10 days after symptom onset. [ABSTRACT FROM AUTHOR]

Previous studies have indicated that diversity is a concern in soil science, including how this relates to gender equity. However, gender equity data for soil science are extremely limited, with only the USA having a current relatively extensive study published in the scientific literature. Therefore, this study was undertaken to gain a preliminary understanding of gender equity issues in a range of countries worldwide using the gender data of membership of national soil science societies, international conferences and journals. Data for 2020 membership was supplied by 44 soil science societies, providing a broad geographic representation. Thirty‐seven of the 44 societies had more male members than female. Only 32% of the soil science society members were women, although the highest percentage for an individual society was 69% female membership. Regionally, Asia had the lowest female membership at 22%, whereas Africa had the highest at 40%. Only 20% of the national soil science societies who are members of the International Union of Soil Sciences had female presidents, indicating that women are under‐represented in the top leadership roles in our professional societies. Women were under‐represented as keynote speakers at conferences and on many editorial boards. This initial scoping study demonstrates that there is an urgent global need to address gender equity within the soil science profession. However, gender equity extends beyond just the number of women in our profession: it also includes equal access to wages, leadership roles and decision making. We conclude that it is critical that individual countries undertake detailed studies of gender equity so we have a more complete picture of the national and international scale of this issue. Highlights: There is still gender inequity in soil scienceSoil science is a male‐dominated field in most countries worldwideGender equity is critical to advancing the discipline of soil scienceThere is a need for comprehensive national studies of gender equityEquity includes many issues beyond just equality in numbers of men and women in the profession. [ABSTRACT FROM AUTHOR]

Aim: Although circulatory impairment during the transitional circulation associates morbidity and mortality, its treatment remains controversial. In a pilot trial on circulatory impairment defined as low superior vena cava (SVC) flow, dobutamine (Db) versus placebo (PL) showed a trend towards improved short‐term outcomes. The purpose of this study was to report on the long‐term outcome of the infants who were observed for SVC flow patterns. Methods: Among the 126 infants <31 weeks of gestation prospectively scanned from birth, 28 presented low SVC flow within the first 24 h after birth and received Db (n = 16) or PL (n = 12). Follow‐up of survivors included motor assessment and Bayley Scales II or III at 2 years, and the Reynolds Intellectual Assessment Scale at 6 years. Neurodevelopmental impairment (NDI) was defined as: cerebral palsy (Gross Motor Function Classification System ≥ level 2), or a cognitive function score < −2 standard deviations; or moderate or severe hearing or visual impairment. Db group, PL group and normal‐flow group were compared. Results: Eighteen infants died (Db: 5; PL: 2; normal flow group: 11, P = 0.1). Follow‐up in survivors was accomplished in 80% and 55% of the cohort at 2 years and 6 years, respectively. No significant difference in the combined outcome (mortality or NDI) was found between the groups (42% Db, 36% PL, 30% normal flow group). Conclusions: This exploratory analysis did not show any differences in the long‐term outcome of infants according to SVC flow patterns or its treatment early after birth. [ABSTRACT FROM AUTHOR]

Aim: Our aim was to describe the clinical features of mothers infected with COVID‐19 and examine any potential vertical mother to newborn transmission. We also assessed how effective the discharge recommendations were in preventing transmission during the first month of life. Methods: This multicentre descriptive study involved 16 Spanish hospitals. We reviewed the medical records of 42 pregnant women diagnosed with COVID‐19 from March 13, 2020, to March 29, 2020, when they were in their third trimester of pregnancy. They and their newborn infants were monitored until the infant was 1 month old. Results: Over half (52.4%) of the women had a vaginal delivery. The initial clinical symptoms were coughing (66.6%) and fever (59.5%), and one mother died due to thrombo‐embolic events. We admitted 37 newborn infants to the neonatal unit (88%), and 28 were then admitted to intermediate care for organisational virus‐related reasons. No infants died, and no vertical transmission was detected during hospitalisation or follow‐up. Only six were exclusively breastfed at discharge. Conclusion: There was no evidence of COVID‐19 transmission in any of the infants born to COVID‐19 mothers, and the post‐discharge advice seemed effective. The measures to avoid transmission appeared to reduce exclusive breastfeeding at discharge. [ABSTRACT FROM AUTHOR]

Newly emerged proteomic methodologies, particularly data‐independent acquisition (DIA) analysis–related approaches, would improve current gene expression–based classifications of colorectal cancer (CRC). Therefore, this study was aimed to identify protein expression signatures using SWATH‐MS DIA and targeted data extraction, to aid in the classification of molecular subtypes of CRC and advance in the diagnosis and development of new drugs. For this purpose, 40 human CRC samples and 7 samples of healthy tissue were subjected to proteomic and bioinformatic analysis. The proteomic analysis identified three different molecular CRC subtypes: P1, P2 and P3. Significantly, P3 subtype showed high agreement with the mesenchymal/stem‐like subtype defined by gene expression signatures and characterized by poor prognosis and survival. The P3 subtype was characterized by decreased expression of ribosomal proteins, the spliceosome, and histone deacetylase 2, as well as increased expression of osteopontin, SERPINA 1 and SERPINA 3, and proteins involved in wound healing, acute inflammation and complement pathway. This was also confirmed by immunodetection and gene expression analyses. Our results show that these tumours are characterized by altered expression of proteins involved in biological processes associated with immune evasion and metastasis, suggesting new therapeutic options in the treatment of this aggressive type of CRC. [ABSTRACT FROM AUTHOR]

This translational multi‐centre study explored early changes in serologic variables following B lymphocyte depletion by rituximab (RTX) treatment in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients and investigated in vitro effects on the activity of other immune cells and the vascular endothelium. Eighty‐five SLE patients, seventy‐five RA patients and ninety healthy donors were enrolled. Two additional cohorts of selected SLE and RA patients were treated with RTX for 3 months. Changes in circulating levels of inflammatory mediators, oxidative stress markers and NETosis‐derived bioproducts were evaluated. Serum miRNomes were identified by next‐generation sequencing, and RTX‐induced changes were delineated. Mechanistic in vitro studies were performed to assess activity profiles. Altered inflammatory, oxidative and NETosis‐derived biomolecules were found in SLE and RA patients, closely interconnected and associated to specific miRNA profiles. RTX treatment reduced SLE and RA patients' disease activity, linked to a prominent alteration in those biomolecules and the reversal of altered regulating miRNAs. In vitro studies showed inhibition of NETosis and decline of pro‐inflammatory profiles of leucocytes and human umbilical vein endothelial cells (HUVECs) after B cell depletion. This study provides evidence supporting an early RTX‐induced re‐setting of the pro‐inflammatory status in SLE and RA, involving a re‐establishment of the homeostatic equilibrium in immune system and the vascular wall. [ABSTRACT FROM AUTHOR]

Thiamine is a crucial cofactor involved in the maintenance of carbohydrate metabolism and participates in multiple cellular metabolic processes within the cytosol, mitochondria, and peroxisomes. Currently, four genetic defects have been described causing impairment of thiamine transport and metabolism: SLC19A2 dysfunction leads to diabetes mellitus, megaloblastic anemia and sensory‐neural hearing loss, whereas SLC19A3, SLC25A19, and TPK1‐related disorders result in recurrent encephalopathy, basal ganglia necrosis, generalized dystonia, severe disability, and early death. In order to achieve early diagnosis and treatment, biomarkers play an important role. SLC19A3 patients present a profound decrease of free‐thiamine in cerebrospinal fluid (CSF) and fibroblasts. TPK1 patients show decreased concentrations of thiamine pyrophosphate in blood and muscle. Thiamine supplementation has been shown to improve diabetes and anemia control in Rogers' syndrome patients due to SLC19A2 deficiency. In a significant number of patients with SLC19A3, thiamine improves clinical outcome and survival, and prevents further metabolic crisis. In SLC25A19 and TPK1 defects, thiamine has also led to clinical stabilization in single cases. Moreover, thiamine supplementation leads to normal concentrations of free‐thiamine in the CSF of SLC19A3 patients. Herein, we present a literature review of the current knowledge of the disease including related clinical phenotypes, treatment approaches, update of pathogenic variants, as well as in vitro and in vivo functional models that provide pathogenic evidence and propose mechanisms for thiamine deficiency in humans. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) is characterized by high rates of metastasis and no available molecular targets. CTCs derived xenografts (CDX) have demonstrated to be a promising tool for understanding cancer biology. In our study, a CDX from a TNBC patient was developed for the first time. After CDX characterization, WNT signaling was found as the main mechanism related with this tumor biology and potential CTCs markers were identified and subsequently validated in TNBC patients. In this cohort high levels of MELK expression were associated with poorer survival rates. Overall, our study demonstrates that CTCs from TNBC are tumorigenic and CDXs are a useful model to obtain valuable information about the tumor. What's new? Circulating tumor cells (CTCs) hold promise as a liquid biopsy and model to study tumor biology. However, technical limitations toward CTCs molecular characterisation and ex vivo expansion remain. This work describes for the first time the development of a CTCs‐derived xenograft (CDX) from a metastatic Triple Negative Breast Cancer (TNBC) patient, with WNT signalling emerging as the main tumor mechanism. Potential prognostic markers and therapeutic targets were further identified in CTCs from TNBC patients. This study demonstrates that CTCs from TNBC are tumorigenic and highlights CDXs as a unique tool to better understand TNBC biology and develop novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: This study evaluated the effects of topically applied axitinib, a tyrosine kinase inhibitor, in an experimental model of corneal neovascularization (CNV). Methods: A total of 48 New Zealand rabbits were used. CNV was induced by placing five silk sutures in the upper cornea of one eye per rabbit. Rabbits were randomized into four groups (12 rabbits each): 0.9% saline (control group), 0.02 mg/mL axitinib, 0.35 mg/mL axitinib and 0.5 mg/mL axitinib groups. All treatments were administered three times daily for 14 days. Photographs were taken using a slit lamp on days 7 and 14. The area of neovascularization was measured in mm2, as the percentage of total corneal area and as the percentage of corneal surface covered by sutures (SCS). Results: On day 14, the CNV area in the control group (31.50 ± 7.47 mm2; 115.00 ± 22.55% of the corneal SCS) was larger than that in the 0.02 mg/mL axitinib group (19.20 ± 8.92 mm2; 73.89 ± 34.98%), the 0.35 mg/mL axitinib group (8.83 ± 3.92 mm2; 31.90 ± 13.59%) and the 0.5 mg/mL axitinib group (5.12 ± 3.97 mm2; 18.38 ± 13.65%). Compared with saline, CNV was inhibited 39.04% by 0.02 mg/mL axitinib, 71.96% by 0.35 mg/mL axitinib and 84.73% by 0.5 mg/mL axitinib. Conclusion: Topical administration of the three axitinib concentrations inhibited CNV in rabbits, blocking both vascular endothelial growth factor and platelet‐derived growth factor pathways. Axitinib at 0.5 mg/mL induced profound inhibition of corneal angiogenesis. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to examine the characteristics associated with the grieving process among a population with intellectual disability and the influence of particular variables. Materials and Methods: The sample was composed of 380 participants with intellectual disability, on whose behalf 149 professionals completed a 20‐item questionnaire with four Likert‐type answer options, developed to evaluate the grieving process: Inventory of Grief and Coping Strategies in Intellectual Disability (IGCS‐ID). Results: The IGCS‐ID shows adequate levels of reliability. It covers three dimensions: understanding of the concept of death, coping with the loss and post‐bereavement reactions. The level of intellectual disability, the time elapsed since the loss and the residential setting gave rise to significant differences in the three dimensions based on the participants. Conclusion: An assessment of the grieving process would help to put in place effective resources to help people with intellectual disability overcome the loss and cope with the changes that it brings. [ABSTRACT FROM AUTHOR]

We present a patient with a patch-test proven fixed drug eruption (FDE) from clindamycin who still tolerated lincomycin. Keywords: allergy; case report; clindamycin; fixed drug eruption; lincomycin; lincosamide; oral challenge test; patch test EN allergy case report clindamycin fixed drug eruption lincomycin lincosamide oral challenge test patch test 369 370 2 09/08/22 20221001 NES 221001 Clindamycin, a semisynthetic derivative of lincomycin, belongs to the lincosamide group, and is often prescribed to patients allergic to beta-lactam antibiotics. Allergy, case report, clindamycin, lincomycin, lincosamide, fixed drug eruption, patch test, oral challenge test. [Extracted from the article]

Zebrafish has become a popular research model in the last years, and several diseases affecting zebrafish research facilities have been reported. However, only one case of naturally occurring viral infections was described for this species. In 2015, infectious spleen and kidney necrosis virus (ISKNV) was detected in zebrafish from a research facility in Spain. Affected fish showed lethargy, loss of appetite, abnormal swimming, distention of the coelomic cavity and, in the most severe cases, respiratory distress, pale gills and petechial haemorrhages at the base of fins. Cytomegaly was the most relevant histopathological finding in organs and tissues, sometimes associated to degenerative and necrotic changes. ISKNV belongs to the relatively newly defined genus Megalocytivirus, family Iridoviridae, comprising large, icosahedral cytoplasmic DNA viruses. This is the first case of naturally occurring Megalocytivirus infection in zebrafish research facilities, associated with morbidity. The virus has been identified based on both pathologic and genetic evidence, to better understand the pathogenesis of the infection in zebrafish and the phylogenetic relationship with other iridoviruses. Given the ability of megalocytiviruses to cross-species boundaries, it seems necessary to implement stringent biosecurity practices as these infections may invalidate experimental data and have major impact on laboratory and cultured fish. [ABSTRACT FROM AUTHOR]

Background Currently, there are no predictive biomarkers for anti-angiogenic strategies in cancer, but response to anti-angiogenic drugs is associated with development of hypertension secondary to treatment. Therefore, this study explored the clinical relevance of genetic polymorphisms in some components of the renin-angiotensin system (RAS). Material and methods Genomic DNA was isolated from peripheral blood from 95 metastatic breast or colorectal cancer patients treated with bevacizumab, and AGTR1-A1166C (rs5186), AGT-M235T (rs699) SNPs and ACE I/D (rs4646994) polymorphisms were genotyped using RT-PCR. Circulating vascular endothelial grow factor and angiotensin converting enzyme (ACE) levels were analysed using ELISA kits. The antitumoral activity of bevacizumab was assayed in mice orthotopically xenografted with AGTR1-overexpressing breast cancer cells. Results The ACE IN/IN genotype was associated with a higher rate of disease progression compared to DEL/IN and DEL/DEL genotypes (36% vs. 11·1% P < 0·05). Similarly, AGTR1-1166A/A genotype was also associated with a higher rate of disease progression compared to AGTR1-1166A/C and AGTR1-1166C/C genotypes (24·4% vs. 2·7% P < 0·01). ACE IN/IN genotype was also found to be associated with shorter time to treatment failure compared to ACE IN/DEL and ACE DEL/DEL genotypes (14 weeks vs. 41·71, P = 0·033), whereas circulating ACE levels were found to be associated with a better response to bevacizumab treatment. Besides, in vivo experiments showed a significantly higher antitumoral activity of bevacizumab in tumours derived from AGTR1- overexpressing breast cancer cells. Conclusions A higher activity of ACE-angiotensin-II-AGTR1 axis is associated with a better response to bevacizumab, supporting that the RAS can be an important source of potential predictive markers of response to antiangiogenic drugs. [ABSTRACT FROM AUTHOR]

ABSTRACT High-voltage-activated calcium channels are hetero-oligomeric protein complexes that mediate multiple cellular processes, including the influx of extracellular Ca2+, neurotransmitter release, gene transcription, and synaptic plasticity. These channels consist of a primary α1 pore-forming subunit, which is associated with an extracellular α2δ subunit and an intracellular β auxiliary subunit, which alter the gating properties and trafficking of the calcium channel. The cellular localization of the α2δ3 subunit in the mouse and rat retina is unknown. In this study using RT-PCR, a single band at ∼305 bp corresponding to the predicted size of the α2δ3 subunit fragment was found in mouse and rat retina and brain homogenates. Western blotting of rodent retina and brain homogenates showed a single 123-kDa band. Immunohistochemistry with an affinity-purified antibody to the α2δ3 subunit revealed immunoreactive cell bodies in the ganglion cell layer and inner nuclear layer and immunoreactive processes in the inner plexiform layer and the outer plexiform layer. α2δ3 immunoreactivity was localized to multiple cell types, including ganglion, amacrine, and bipolar cells and photoreceptors, but not horizontal cells. The expression of the α2δ3 calcium channel subunit to multiple cell types suggests that this subunit participates widely in Ca-channel-mediated signaling in the retina. J. Comp. Neurol. 523:1443-1460, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

A detailed computational and kinetic analysis of the acetylation of 1-phenylethanol with acetic anhydride catalyzed by planar chiral 4-(dimethylamino)pyridine (DMAP) catalyst (−)- 1 is presented. The study includes a computational investigation of the potential-energy surface including the acylation and stereoselective transition states at the DFT level of theory. Experimentally, the kinetic study shows that the reaction proceeds in a first-order manner in catalyst, whereas both substrates, acetic anhydride and 1-phenylethanol, show fractional order, which is in accordance with steady-state conditions. The fractional order depends on an equilibrium between the free catalyst and the acetylated catalyst. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 87-year-old man with atypical photosensitivity reaction and eczema caused by triflusal, an antithrombotic agent which prevents platelet aggregation. He was completely diagnosed from a photoaggravated allergic reaction to triflusal with the doses of ultraviolet (UV) A and B.

Many of nitric oxide (NO) actions are mediated through the coupling of a nitroso moiety to a reactive cysteine leading to the formation of a S-nitrosothiol (SNO), a process known as S-nitrosylation or S-nitrosation. In many cases this reversible post-translational modification is accompanied by altered protein function and aberrant S-nitrosylation of proteins, caused by altered production of NO and/or impaired SNO homeostasis, has been repeatedly reported in a variety of pathophysiological settings. A growing number of studies are directed to the identification and characterization of those proteins that undergo S-nitrosylation and the analysis of S-nitrosoproteomes under pathological conditions is beginning to be reported. The study of these S-nitrosoproteomes has been fueled by advances in proteomic technologies that are providing researchers with improved tools for exploring this post-translational modification. Here we review novel refinements and improvements to these methods, and some recent studies of the S-nitrosoproteome in disease. Copyright © 2013 Wiley Periodicals, Inc. Rapid Commun. Mass Spectrom. 33: 7-20, 2014. [ABSTRACT FROM AUTHOR]

Purpose: Retinal degeneration compromises retinal metabolism and signaling, including lipid pathways. Fatty acids are highly enriched in the retina and they impact photoreceptor survival. In this study, we aimed to identify fatty acids that could be relevant in retinal degeneration. For this purpose, we analyzed the fatty acid profile of the retina of rd10 mice, model of retinitis pigmentosa. Methods: Fatty acids of the retina of C57BL/6J and rd10 mice were extracted by the Folch method and analyzed by GC/MS. Morphological changes were studied by immunohistochemistry. Results: In the retina of rd10 mice, there was a drop of photoreceptor rows compared to healthy retinas. Rhodopsin, a protein expressed in outer segments, was delocalized into the cell bodies of photoreceptors in dystrophic retinas, and axons and outer segments of cones were shortened. In these animals, we found a decrease of specific saturated, monounsaturated and polyunsaturated fatty acids. Remarkably, docosahexaenoic acid (DHA) experienced a marked drop, leading to a heightening of the n‐3/n‐6 ratio, an indicator of inflammation. We found a positive correlation of cerotic acid, hypogeic acid, and DHA with photoreceptor rows. Conclusions: Specific saturated and unsaturated fatty acids dropped in retinitis pigmentosa. Remarkably, diminished levels of the omega‐3 DHA could be contributing to the neurodegeneration process due to a shift to pro‐inflammatory pathways and a lack of neuroprotective signals, promoting photoreceptor death. Fatty acids could have decisive roles in the retinal degeneration outcome and should be considered to improve therapy. MICINN‐FEDER PID2019‐106230RB‐I00; RETICS‐FEDER RD16/0008/0016; ACIF/2020/203; IDIFEDER/2017/064; FPU16/04114; FPU18/02964. [ABSTRACT FROM AUTHOR]

Purpose: Intestinal dysbiosis has been linked with the pathogenesis of several degenerative diseases. Moreover, the consumption of high‐fat diets (HFD) can drove to significant changes in the gut microbiome. Our purpose was to investigate changes in gut microbiome and retinal degeneration associated with the ingestion of HFD in a mice model of retinitis pigmentosa (RP). Methods: C57BL/6J mice and rd10 mice were fed either with normal chow (5.5% fat kcal) or with a HFD (61.6% fat kcal) for two weeks since P19. Retinal function was analyzed by electroretinography and optomotor test. Immunohistochemistry was employed to evaluate the structure and integrity of the retinal tissue. 16S rRNA gene sequencing was made to evaluate the gut microbiome. Results: We found a higher retinal degeneration in rd10 mice as compared to C57BL/6J mice, both fed with normal chow. Rd10 mice exhibited significantly reduced retinal responsiveness, as well as diminished visual acuity. This loss of retina function went with a decrease in the number of photoreceptor rows, and the remaining photoreceptors showed morphologic anomalies. The photoreceptor degeneration was accompanied by an inflammatory response of the retina, characterized by the proliferation of microglial cells and reactive gliosis of Müller cells. Likewise, the gut microbiome analysis revealed differences in alpha and beta diversity at the genera, species, and amplicon sequence variants levels. HFD generated a significant dysbiosis in the gut microbiome increasing potentially pro‐inflammatory bacteria as Bilophila sp., Alistipes sp. and Mucispirillum schaedleri, and drived the exacerbation of the retinal degeneration. Conclusions: In retinitis pigmentosa, retinal dysfunction and degeneration are related to significant changes in the gut microbiome, which can be altered by diet, conducing to a worsening of the disease. Support: MINECOFEDER‐BFU2015‐67139‐R, FEDER‐PID2019‐106230RB‐I00, RETICS‐FEDER RD16/0008/0016, IDIFEDER/2017/064. [ABSTRACT FROM AUTHOR]

Purpose: Central choroidal dystrophies are retinal diseases characterized by progressive choriocapillaris atrophy and retinal degeneration that are usually associated with a single mutation in the PRPH2 gene. Thus, the purpose of this work was to generate a mouse model with the same p.Arg195Leu mutation described in diagnosed human patients. Methods: Prph2KI/WT and Prph2KI/KI mice have been designed and generated using the CRISPR system to introduce the Arg195Leu mutation. The retinal function was analyzed by electroretinography (ERG) and optomotor test. The structural integrity of the retinas was evaluated using optical coherence tomography and immunohistochemistry. Results: Genetic sequencing confirmed that both Prph2KI/WT and Prph2KI/KI mice presented the same codon mutation and degeneration pattern found in humans suffering from this dystrophy. A progressive loss of retinal function was found from 3 months of age, with significantly reduced mice visual acuity, measured by optomotor test. At 6 months of age, decreased a‐ and b‐wave amplitudes of the ERG responses were observed. Moreover, morphological analysis of the retinas correlated with functional findings, showing a decreased number of photoreceptor rows and retinal thickness, also presenting an increased inflammation with activation of microglia and Müller cells Conclusions: The new Prph2KI/WT and Prph2KI/KI mouse models show a similar degeneration pattern to human disease and may facilitate the study of the pathophysiological process, also displaying their potential to be a model for evaluation of different therapeutic strategies. Support: Ministerio de Ciencia e Innovación (FEDER‐ PID2019‐106230RB‐I00). Ministerio de Universidades (FPU16/04114, FPU18/02964). Instituto Carlos III (RETICS‐FEDER RD16/0008/0016). Retina Asturias/Cantabria. FARPE‐FUNDALUCE. Generalitat Valenciana (IDIFEDER/2017/064, ACIF/2020/203). Es Retina Asturias (2019/00286/001). [ABSTRACT FROM AUTHOR]

Abstract: Background: Risk factors for the hepatitis C virus (HCV) infection influence both the frequency and the progression of the liver disease. Routes of transmission and severity of the liver damage may differ by gender. We aimed to describe the risk factors for HCV infection and for the severity of the liver disease among women seroreactive to anti-HCV antibodies. Also, we tested the hypothesis that length of infection influences the levels of anti-HCV, in transfusion-associated hepatitis C. Methods: Eighty-six interferon-naive women, repeatedly seroreactive to anti-HCV antibodies, aged>20 years, were studied. Results: Surgeries (80%) and transfusion before 1993 (58%) were the main risk factors (52% cases had both). The main reason for practicing surgery was obstetric/gynecologic (74%). The main indication for transfusion was also obstetric/gynecologic (68%). Fifty-five (64%) women were positive to HCV RNA in serum, of them, coinfection with the hepatitis B virus (HBV) occurred in three (5%) cases, being occult hepatitis B (i.e., positive to HBV DNA, but negative to hepatitis B surface antigen) in two (4%). In multivariate analysis, determining factors of cirrhosis at histologic examination were age and the antecedent of transfusion before 1993. Anti-HCV levels correlated with the elapsed time from transfusion to diagnosis, but not with age. Conclusion: An obstetric/gynecologic indication was the most frequent reason for both surgery and transfusion. Hepatitis B coinfection had a low prevalence and did not influence the severity of the liver disease, as age and the antecedent of transfusion certainly did. Infection length influenced the levels of anti-HCV antibodies in transfusion-associated hepatitis C. [Copyright &y& Elsevier]

Hepatic injury by d-galactosamine ( d-GalN) is a suitable experimental model of hepatocellular injury. The induction of oxidative and nitrosative stress participates during d-GalN-induced cell death in cultured rat hepatocytes. This study aimed to identify protein expression changes during the induction of apoptosis and necrosis by d-GalN in cultured human hepatocytes. Methods: A proteomic approach was used to identify the proteins involved and those altered by tyrosine nitration. A high dose of d-GalN (40 mM) was used to induce apoptosis and necrosis in primary culture of human hepatocytes. Cellular lysates prepared at different times after addition of d-GalN were separated by two-dimensional electrophoresis. Gel spots with an altered expression and those matching nitrotyrosine-immunopositive proteins were excised and analyzed by mass spectrometry. Results: d-GalN treatment upregulated microsomal cytochrome b5, fatty acid binding protein and manganese superoxide dismutase, and enhanced annexin degradation. d-GalN increased tyrosine nitration of four cytosolic (Hsc70, Hsp70, annexin A4 and carbonyl reductase) and three mitochondrial (glycine amidinotransferase, ATP synthase β chain, and thiosulfate sulfurtransferase) proteins in human hepatocytes. Conclusions: The results provide evidences that oxidative stress and nitric oxide-derived reactive oxygen intermediates induce specific alterations in protein expression that may be critical for the induction of apoptosis and necrosis by d-GalN in cultured human hepatocytes. [ABSTRACT FROM AUTHOR]

Multimodal analgesia is defined as using several drugs or techniques simultaneously to target different pain pathways or receptors to avoid pain propagation. This study evaluated the pharmacokinetic profile and comparative bioavailability of etoricoxib 90 mg and tramadol 50 mg dosing alone (reference drugs) or in a novel fixed‐dose combination (test drug) under fasting conditions in Mexican healthy volunteers. This was a randomized, open‐label, 3‐way, crossover, single‐dose, prospective, and longitudinal study with a 14‐day washout period. Eligible subjects were healthy Mexican adult volunteers. The drugs were dosing orally, according to the randomization sequence, after 10 hours of fasting and 4 hours before breakfast with 250 mL of water at room temperature. Serial blood samples were collected before and after dosing, both drugs were quantified using high‐performance liquid chromatography coupled with tandem mass spectrometry. Forty‐two subjects were enrolled and 38 completed the study (28 men and 14 women, mean age 25.2 years, mean weight 66.6 kg). Test products were considered to have comparative bioavailability if confidence intervals of natural log‐transformed for (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration‐time curve form 0 up to last sampling time (AUC0‐t), and (area under the plasma drug concentration‐time curve from 0 up to infinity (AUC0‐∞) data were within the range of 80%‐125%. Non‐serious adverse events were observed. The results demonstrate that the pharmacokinetic profile and bioavailability of the etoricoxib/tramadol fixed‐dose combination are comparable to those of the reference products. [ABSTRACT FROM AUTHOR]

“Ruth” helps iron! A novel method for the non‐enzymatic dynamic kinetic resolution (DKR) of secondary aryl alcohols by the use of the planar chiral ferrocene derivative (+)‐1 in combination with the ruthenium racemization catalyst 2 yields acetylated alcohols in high enantioselectivity and yield. This development opens opportunities for new developments in the field of non‐enzymatic dynamic kinetic resolution. [ABSTRACT FROM AUTHOR]

„Ruth“ hilft Eisen! Eine neue Methode zur nichtenzymatischen dynamischen kinetischen Racematspaltung sekundärer Arylalkohole liefert mit dem planar ‐ chiralen Ferrocenderivat (+) ‐ 1 in Kombination mit dem Ruthenium ‐ Racemisierungskatalysator 2 acetylierte Alkohole mit hoher Enantioselektivität. Der Befund bietet Möglichkeiten für neue Entwicklungen auf dem Gebiet nichtenzymatischer Racematspaltungen. [ABSTRACT FROM AUTHOR]

Cellular senescence is a stress response that limits the proliferation of damaged cells by establishing a permanent cell cycle arrest. Different stimuli can trigger senescence but excessive production or impaired clearance of these cells can lead to their accumulation during aging with deleterious effects. Despite this potential negative side of cell senescence, its physiological role as a pro‐regenerative and morphogenetic force has emerged recently after the identification of programmed cell senescence during embryogenesis and during wound healing and limb regeneration. Here, we explored the conservation of tissue injury‐induced senescence in a model of complex regeneration, the zebrafish. Fin amputation in adult fish led to the appearance of senescent cells at the site of damage, and their removal impaired tissue regeneration. Despite many conceptual similarities, this tissue repair response is different from developmental senescence. Our results lend support to the notion that cell senescence is a positive response promoting tissue repair and homeostasis. [ABSTRACT FROM AUTHOR]