The potential of miRNA-based approaches in glioblastoma: An update in current advances and future perspectives.

Glioblastoma (GBM) is the most common malignant central nervous system tumor. The emerging field of epigenetics stands out as particularly promising. Notably, the discovery of micro RNAs (miRNAs) has paved the way for advancements in diagnosing, treating, and prognosticating patients with brain tumors. We aim to provide an overview of the emergence of miRNAs in GBM and their potential role in the multifaceted management of this disease. We discuss the current state of the art regarding miRNAs and GBM. We performed a narrative review using the MEDLINE/PUBMED database to retrieve peer-reviewed articles related to the use of miRNA approaches for the treatment of GBMs. MiRNAs are intrinsic non-coding RNA molecules that regulate gene expression mainly through post-transcriptional mechanisms. The deregulation of some of these molecules is related to the pathogenesis of GBM. The inclusion of molecular characterization for the diagnosis of brain tumors and the advent of less-invasive diagnostic methods such as liquid biopsies, highlights the potential of these molecules as biomarkers for guiding the management of brain tumors such as GBM. Importantly, there is a need for more studies to better examine the application of these novel molecules. The constantly changing characterization and approach to the diagnosis and management of brain tumors broaden the possibilities for the molecular inclusion of novel epigenetic molecules, such as miRNAs, for a better understanding of this disease.

Symptomatic spinal metastasis of a supratentorial glioblastoma in a pediatric patient: a case report and comprehensive review of the literature.

Spinal metastasis of Glioblastoma is a rare occurrence, especially in pediatric patients, and extremely rare to become symptomatic. The pathology is poorly understood and remains with unclear dissemination mechanisms. The treatment approaches are varied and multimodal therapy (surgery, chemotherapy, and radiotherapy) can be employed to manage this type of metastasis. We report a case of a 17-year-old female who underwent a gross-total resection of a right frontal glioblastoma and had adjuvant therapy with chemo- and radiotherapy. In the sixth month of follow-up, the patient presented a paraparesis, and a distant recurrence at T7-T8 was detected. The patient was treated with gross-total resection of the tumor through a laminectomy. The histopathological results were consistent with an isocitrate dehydrogenase (IDH) wildtype GBM metastasis. The patient was treated with multimodal therapy, including surgery, radiotherapy, and chemotherapy. A complementary comprehensive review of current available literature on this topic is also presented.

Shaping the curve from the microscopic transsphenoidal to the endoscopic endonasal approach for the sellar region.

OBJECTIVE: This study aimed to investigate the limitations, barriers, and complications in the early transition from the microscopic transsphenoidal approach (MTA) to the endonasal endoscopic approach (EEA) to the skull base in our institution. METHODS: Technical challenges, as well as clinical features and complications, were compared between MTA, EEA, and mixed cases during the early surgical curve. RESULTS: The period from the early learning curve was 1 year until the EEA protocol was used routinely. A total of 34 patients registered a resection using a transsphenoidal approach. Eighteen patients underwent EEA, 11 underwent MTA, and five underwent a mixed endonasal and microscopic approach. Non-significant differences were found in endocrine outcomes between the three groups. Patients with unchanged or improved visual function were higher in the EEA group (p = 0.147). Non-significant differences were found in terms of the extent of resection (EOR) between groups (p = 0.369). Only 1 (2.9%) patient in the whole series developed a post-operative CSF leaking that resolved with medical management, belonging to the EEA group (5.5%). CONCLUSIONS: The early phase of the learning curve did not affect our series significantly in terms of the EOR, endocrine status, and visual outcomes.

OBJETIVO: Investigar las limitaciones, las barreras y las complicaciones en la transición del abordaje transesfenoidal microscópico (ATM) al abordaje endonasal endoscópico (AEE) para la base del cráneo en nuestra institución. MÉTODO: Se compararon las características clínicas y las complicaciones entre ATM, AEE y casos mixtos durante la curva quirúrgica temprana. RESULTADOS: El periodo desde la curva de aprendizaje inicial fue de 1 año hasta que se utilizó el protocolo AEE de forma sistemática. Un total de 34 pacientes tuvieron una resección por vía transesfenoidal. A 18 pacientes se les realizó AEE, a 11 ATM y a 5 abordaje mixto endonasal y microscópico. Se encontraron diferencias no significativas en los resultados endocrinos entre los tres grupos. Los pacientes con función visual sin cambios o mejorada fueron más en el grupo AEE (p = 0.147). No se encontraron diferencias significativas respecto a la extensión de la resección (p = 0.369). Solo 1 (2.9%) paciente desarrolló una fístula de líquido cefalorraquídeo que se resolvió con manejo médico, perteneciente al grupo AEE (5.5%). CONCLUSIONES: La fase inicial de la curva de aprendizaje no afectó significativamente a nuestra serie en términos de extensión de la resección, estado endocrino y resultados visuales.

El Hierro Genome Study: A Genomic and Health Study in an Isolated Canary Island Population.

El Hierro is the smallest and westernmost island of the Canary Islands, whose population derives from an admixture of different ancestral components and that has been subjected to genetic isolation. We established the "El Hierro Genome Study" to characterize the health status and the genetic composition of ~10% of the current population of the island, accounting for a total of 1054 participants. Detailed demographic and clinical data and a blood sample for DNA extraction were obtained from each participant. Genomic genotyping was performed with the Global Screening Array (Illumina). The genetic composition of El Hierro was analyzed in a subset of 416 unrelated individuals by characterizing the mitochondrial DNA (mtDNA) and Y-chromosome haplogroups and performing principal component analyses (PCAs). In order to explore signatures of isolation, runs of homozygosity (ROHs) were also estimated. Among the participants, high blood pressure, hypercholesterolemia, and diabetes were the most prevalent conditions. The most common mtDNA haplogroups observed were of North African indigenous origin, while the Y-chromosome ones were mainly European. The PCA showed that the El Hierro population clusters near 1000 Genomes' European population but with a shift toward African populations. Moreover, the ROH analysis revealed some individuals with an important portion of their genomes with ROHs exceeding 400 Mb. Overall, these results confirmed that the "El Hierro Genome" cohort offers an opportunity to study the genetic basis of several diseases in an unexplored isolated population.

Gene therapy with AAV9-SGPL1 in an animal model of lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung that leads rapidly to respiratory failure. Novel approaches to treatment are urgently needed. The bioactive lipid sphingosine-1-phosphate (S1P) is increased in IPF lungs and promotes proinflammatory and profibrotic TGF-ß signaling. Hence, decreasing lung S1P represents a potential therapeutic strategy for IPF. S1P is degraded by the intracellular enzyme S1P lyase (SPL). Here we find that a knock-in mouse with a missense SPL mutation mimicking human disease resulted in reduced SPL activity, increased S1P, increased TGF-ß signaling, increased lung fibrosis, and higher mortality after injury compared to wild type (WT). We then tested adeno-associated virus 9 (AAV9)-mediated overexpression of human SGPL1 (AAV-SPL) in mice as a therapeutic modality. Intravenous treatment with AAV-SPL augmented lung SPL activity, attenuated S1P levels within the lungs, and decreased injury-induced fibrosis compared to controls treated with saline or only AAV. We confirmed that AAV-SPL treatment led to higher expression of SPL in the epithelial and fibroblast compartments during bleomycin-induced lung injury. Additionally, AAV-SPL decreased expression of the profibrotic cytokines TNFα and IL1ß as well as markers of fibroblast activation, such as fibronectin (Fn1), Tgfb1, Acta2, and collagen genes in the lung. Taken together, our results provide proof of concept for the use of AAV-SPL as a therapeutic strategy for the treatment of IPF. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Enhanced expression of natural cytotoxicity receptors on cytokine-induced memory-like natural killer cells correlates with effector function.

Introduction: Natural killer (NK) cells are a key component of the innate immune system, involved in defending the host against virus-infected cells and tumor immunosurveillance. Under in vitro culture conditions, IL-12/15/18 can induce a memory-like phenotype in NK cells. These cytokine-induced memory-like (CIML) NK cells possess desirable characteristics for immunotherapies, including a longer lifespan and increased cytotoxicity. Methods: In this study, NK cells were isolated from peripheral blood of healthy donors and stimulated with IL-12/15/18 to induce a memory-like phenotype or with IL-15 alone as a control. After seven days of culture, multiparametric flow cytometry analysis was performed to evaluate the phenotypic and functional profiles of CIML and control NK cells. Results: Our results showed a significantly higher expression of CD25, CD69, NKG2D, NKp30, NKp44, NKp46, TACTILE, and Granzyme B in CIML NK cells compared to control NK cells. In contrast, KIR2D expression was significantly lower in CIML NK cells than in control NK cells. Moreover, functional experiments demonstrated that CIML NK cells displayed enhanced degranulation capacity and increased intracellular IFN-γ production against the target cell line K562. Interestingly, the degranulation capacity of CIML NK cells was positively correlated with the expression of the activating receptors NKp46 and NKp30, as well as with the inhibitory receptor TACTILE. Discussion: In conclusion, this study provides a deep phenotypic characterization of in vitro-expanded CIML NK cells. Moreover, the correlations found between NK cell receptors and degranulation capacity of CIML NK cells allowed the identification of several biomarkers that could be useful in clinical settings.

Successful Treatment of a Cervical Injury and Myopathy Using Integrative Medicine Techniques in an Eclectus Parrot (Eclectus roratus) Following Cervical Entrapment.

A 2-year-old female eclectus parrot (Eclectus roratus) was presented for suspected cervical myopathy due to trauma. Severe ventroflexion of the cervical spine and mental depression were identified during the physical examination. The bird was responsive to stimuli but otherwise quiet. Plasma biochemistry results were suggestive of a myopathy, based on marked elevations of both aspartate transaminase (25 652 U/L) and creatine kinase (253 240 U/L). Whole-body radiographic images were unremarkable. Treatment was initiated with supportive therapy for presumptive shock, dehydration, pain, myopathy, and possible spinal swelling. Allopathic therapy included subcutaneous fluids; vitamins A, D, and E; dexamethasone sodium phosphate; hydromorphone; and gavage feeding to treat the acute inflammatory process and provide nutritional support during healing. Supportive care through the Integrative Medicine Department (Louisiana State University, Baton Rouge, LA, USA) was also performed on the patient. Photobiomodulation, acupuncture, Tui-na massage, and rehabilitation exercises were instituted to provide adjunct treatment for relieving pain, promoting muscle healing, improving patient demeanor, and improving cervical mobility. Integrative therapies were well tolerated by the patient, with no sedation required. By day 3, mentation had subjectively improved by 50% despite the persistent cervical ventroflexion. By day 8, the elevated serum enzyme activities had decreased, the patient could eat and drink on its own, and it could readily step up and seek attention during handling. The bird was able to lift its head and could hold it at approximately 50% of normal posture. Integrative therapies were continued throughout hospitalization. The bird was released from the hospital 20 days after initial intake, with head carriage in approximately 80% of the expected normal position and no apparent cervical pain based on palpation. This case demonstrates the benefits of integrative therapies as an adjunct treatment for cervical pain and myopathy in a psittacine species.

Preoperative tractography algorithm for safe resection of tumors located in the descending motor pathways zone.

Background: Diffusion tensor imaging (DTI) tractography facilitates maximal safe resection and optimizes planning to avoid injury during subcortical dissection along descending motor pathways (DMPs). We provide an affordable, safe, and timely algorithm for preoperative DTI motor reconstruction for gliomas adjacent to DMPs. Methods: Preoperative DTI reconstructions were extracted from a prospectively acquired registry of glioma resections adjacent to DMPs. The surgeries were performed over a 7-year period. Demographic, clinical, and radiographic data were extracted from patients' electronic medical records. Results: Nineteen patients (12 male) underwent preoperative tractography between January 1, 2013, and May 31, 2020. The average age was 44.5 years (range, 19-81 years). A complete radiological resection was achieved in nine patients, a subtotal resection in five, a partial resection in three, and a biopsy in two. Histopathological diagnoses included 10 patients with high-grade glioma and nine with low-grade glioma. A total of 16 perirolandic locations (10 frontal and six frontoparietal) were recorded, as well as two in the insula and one in the basal ganglia. In 9 patients (47.3%), the lesion was in the dominant hemisphere. The median preoperative and postoperative Karnofsky Performance Scores were 78 and 80, respectively. Motor function was unchanged or improved over time in 15 cases (78.9%). Conclusion: This protocol of DTI reconstruction for glioma removal near the DMP shows good results in low-term neurological functional outcomes.

Haptoglobin Gene Expression and Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors: A COG-ALTE03N1 Report.

Background: Anthracycline-related cardiomyopathy is a leading cause of premature death in childhood cancer survivors. The high interindividual variability in risk suggests the need to understand the underlying pathogenesis. Objectives: The authors interrogated differentially expressed genes (DEGs) to identify genetic variants serving regulatory functions or genetic variants not easily identified when using genomewide array platforms. Using leads from DEGs, candidate copy number variants (CNVs) and single-nucleotide variants (SNVs) were genotyped. Methods: Messenger RNA sequencing was performed on total RNA from peripheral blood of 40 survivors with cardiomyopathy (cases) and 64 matched survivors without cardiomyopathy (control subjects). Conditional logistic regression analysis adjusting for sex, age at cancer diagnosis, anthracycline dose, and chest radiation was used to assess the associations between gene expression and cardiomyopathy and between CNVs and SNVs and cardiomyopathy. Results: Haptoglobin (HP) was identified as the top DEG. Participants with higher HP gene expression had 6-fold greater odds of developing cardiomyopathy (OR: 6.4; 95% CI: 1.4-28.6). The HP2-specific allele among the HP genotypes (HP1-1, HP1-2, and HP2-2) had higher transcript levels, as did the G allele among SNVs previously reported to be associated with HP gene expression (rs35283911 and rs2000999). The HP1-2 and HP2-2 genotypes combined with the G/G genotype for rs35283911 and/or rs2000999 placed the survivors at 4-fold greater risk (OR: 3.9; 95% CI: 1.0-14.5) for developing cardiomyopathy. Conclusions: These findings provide evidence of a novel association between HP2 allele and cardiomyopathy. HP binds to free hemoglobin to form an HP-hemoglobin complex, thereby preventing oxidative damage from free heme iron, thus providing biological plausibility to the mechanistic basis of the present observation.

Menstrual blood-derived mesenchymal stromal cells: impact of preconditioning on the cargo of extracellular vesicles as potential therapeutics.

BACKGROUND: Mesenchymal stromal cells (MSCs) have been shown to exert their therapeutic effects through the secretion of broad spectrum of paracrine factors, including extracellular vesicles (EVs). Accordingly, EVs are being pursued as a promising alternative to cell-based therapies. Menstrual blood-derived stromal cells (MenSCs) are a type of MSC that, due to their immunomodulatory and regenerative properties, have emerged as an innovative source. Additionally, new strategies of cell priming may potentially alter the concentration and cargo of released EVs, leading to modification of their biological properties. In this study, we aimed to characterize the EVs released by MenSCs and compare their therapeutic potential under three different preconditioning conditions (proinflammatory stimuli, physioxia, and acute hypoxia). METHODS: MenSCs were isolated from five healthy women. Following culturing to 80% confluence, MenSCs were exposed to different priming conditions: basal (21% O2), proinflammatory stimuli (IFNγ and TNFα, 21% O2), physioxia (1-2% O2), and acute hypoxia (< 1% O2) for 48-72 h. Conditioned media from MenSCs was collected after 48 h and EVs were isolated by a combination of ultra-filtration and differential centrifugation. An extensive characterization ranging from nano-flow cytometry (nFC) to quantitative high-throughput shotgun proteomics was performed. Bioinformatics analyses were used to derive hypotheses on their biological properties. RESULTS: No differences in the morphology, size, or number of EVs released were detected between priming conditions. The proteome analysis associated with basal MenSC-EVs prominently revealed their immunomodulatory and regenerative capabilities. Furthermore, quantitative proteomic analysis of differentially produced MenSC-EVs provided sufficient evidence for the utility of the differential preconditioning in purpose-tailoring EVs for their therapeutic application: proinflammatory priming enhanced the anti-inflammatory, regenerative and immunomodulatory capacity in the innate response of EVs, physioxia priming also improves tissue regeneration, angiogenesis and their immunomodulatory capacity targeting on the adaptive response, while acute hypoxia priming, increased hemostasis and apoptotic processes regulation in MenSC-EVs, also by stimulating immunomodulation mainly through the adaptive response. CONCLUSIONS: Priming of MenSCs under proinflammatory and hypoxic conditions affected the cargo proteome of EVs released, resulting in different therapeutic potential, and thus warrants experimental exploration with the aim to generate better-defined MSC-derived bioproducts.

Standardization of Strategies to Perform a Parafascicular Tubular Approach for the Resection of Brain Tumors in Eloquent Areas.

OBJECTIVE: The aim of this work is to define a methodological strategy for the minimally invasive tubular retractor (MITR) parafascicular transulcal approach (PTA) for the management of brain tumors sited in eloquent areas. METHODS: An observational prospective study was designed to evaluate the benefits of PTA associated with MITRs, tractography and intraoperative cortical stimulation. They study was conducted from June 2018 to June 2021. Information regarding white matter tracts was processed, preventing a potential damage during the approach and/or resection. All patients older than 18 years who had a single brain tumor lesion were included in the study. Patients with a preoperative Karnofsky Performance Scale (KPS) score greater than 70% and a Glasgow Coma Scale (GCS) score > 14 points were included. RESULTS: 72 patients were included in the study, the mean age was 49.6, the most affected gender was male, 12.5% presented aphasia, 11.1% presented paraphasia, 41.6% had motor deficit, 9.7% had an affection in the optic pathway, the most frequently affected region was the frontal lobe (26.3%), the most frequent lesions were high-grade gliomas (34.7%) and the measurement of the incisions was on average 5.58 cm. Of the patients, 94.4% underwent a total macroscopic resection and 90.2% did not present new postoperative neurological deficits. In all cases, a PTA was used. CONCLUSION: Tubular minimally invasive approaches (MIAs) allow one to perform maximal safe resection of brain tumors in eloquent areas, through small surgical corridors. Future comparative studies between traditional and minimally invasive techniques are required to further investigate the potential of these surgical nuances.

Genome-Wide Association Study Identifies ROBO2 as a Novel Susceptibility Gene for Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors.

PURPOSE: Interindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests a modifying role of genetic susceptibility. Few previous studies have examined gene-anthracycline interactions. We addressed this gap using the Childhood Cancer Survivor Study (discovery) and the Children's Oncology Group (COG) study COG-ALTE03N1 (replication). METHODS: A genome-wide association study (Illumina HumanOmni5Exome Array) in 1,866 anthracycline-exposed Childhood Cancer Survivor Study participants (126 with heart failure) was used to identify single-nucleotide polymorphisms (SNPs) with either main or gene-environment interaction effect on anthracycline-related cardiomyopathy that surpassed a prespecified genome-wide threshold for statistical significance. We attempted replication in a matched case-control set of anthracycline-exposed childhood cancer survivors with (n = 105) and without (n = 160) cardiomyopathy from COG-ALTE03N1. RESULTS: Two SNPs (rs17736312 [ROBO2]) and rs113230990 (near a CCCTC-binding factor insulator [< 750 base pair]) passed the significance cutoff for gene-anthracycline dose interaction in discovery. SNP rs17736312 was successfully replicated. Compared with the GG/AG genotypes on rs17736312 and anthracyclines ≤ 250 mg/m2, the AA genotype and anthracyclines > 250 mg/m2 conferred a 2.2-fold (95% CI, 1.2 to 4.0) higher risk of heart failure in discovery and an 8.2-fold (95% CI, 2.0 to 34.4) higher risk in replication. ROBO2 encodes transmembrane Robo receptors that bind Slit ligands (SLIT). Slit-Robo signaling pathway promotes cardiac fibrosis by interfering with the transforming growth factor-ß1/small mothers against decapentaplegic (Smad) pathway, resulting in disordered remodeling of the extracellular matrix and potentiating heart failure. We found significant gene-level associations with heart failure: main effect (TGF-ß1, P = .007); gene*anthracycline interaction (ROBO2*anthracycline, P = .0003); and gene*gene*anthracycline interaction (SLIT2*TGF-ß1*anthracycline, P = .009). CONCLUSION: These findings suggest that high-dose anthracyclines combined with genetic variants involved in the profibrotic Slit-Robo signaling pathway promote cardiac fibrosis via the transforming growth factor-ß1/Smad pathway, providing credence to the biologic plausibility of the association between SNP rs17736312 (ROBO2) and anthracycline-related cardiomyopathy.

Postnatal Surgical Correction of Myelomeningoceles: Preoperative and Intraoperative Risk Factors Associated with Postoperative Neurologic Outcomes.

OBJECTIVE: Open spina bifida or myelomeningocele (MMC) is a congenital defect that results from failure of caudal neurulation. We present a case series of patients who were treated with postnatal surgical correction for MMC, evaluating the possible preoperative and intraoperative risk factors associated with neurologic outcomes. METHODS: A retrospective chart review of patients who underwent postnatal surgical correction for MMCs over 11 years at our institution was performed. MMCs were classified based on their morphologic configuration into 3 types. Type I includes defects without a sac and there is cerebrospinal fluid (CSF) leak. Type II includes where there is a sac ≤4 cm, with or without CSF leak. Type III includes defects with a sac that are greater than 4 cm. RESULTS: Fifty patients were included. The median age of gestation at surgery was 37.4 weeks. There were 30 females (60%). All mothers received adequate folate supplementation. All patients underwent surgical correction in the first 48 hours. Lower extremity motor function at the last clinical follow-up was normal in 34 patients (68%). CSF leak, infection, and mortality were 8%, 2%, and 0%, respectively. Twenty-one patients (42%) underwent ventriculoperitoneal shunt for hydrocephalus. CONCLUSIONS: Despite there being no statistically significant associations with a timely closure, all cases were treated within the first 48 hours and this could influence the low complication rate. Individuals of Hispanic background who received appropriate folate supplementation still had high rates of MMC and we posit that this may be caused in part by a genetic/molecular predisposition.

Extracellular matrix mechanobiology in cancer cell migration.

The extracellular matrix (ECM) is pivotal in modulating tumor progression. Besides chemically stimulating tumor cells, it also offers physical support that orchestrates the sequence of events in the metastatic cascade upon dynamically modulating cell mechanosensation. Understanding this translation between matrix biophysical cues and intracellular signaling has led to rapid growth in the interdisciplinary field of cancer mechanobiology in the last decade. Substantial efforts have been made to develop novel in vitro tumor mimicking platforms to visualize and quantify the mechanical forces within the tissue that dictate tumor cell invasion and metastatic growth. This review highlights recent findings on tumor matrix biophysical cues such as fibrillar arrangement, crosslinking density, confinement, rigidity, topography, and non-linear mechanics and their implications on tumor cell behavior. We also emphasize how perturbations in these cues alter cellular mechanisms of mechanotransduction, consequently enhancing malignancy. Finally, we elucidate engineering techniques to individually emulate the mechanical properties of tumors that could help serve as toolkits for developing and testing ECM-targeted therapeutics on novel bioengineered tumor platforms. STATEMENT OF SIGNIFICANCE: Disrupted ECM mechanics is a driving force for transitioning incipient cells to life-threatening malignant variants. Understanding these ECM changes can be crucial as they may aid in developing several efficacious drugs that not only focus on inducing cytotoxic effects but also target specific matrix mechanical cues that support and enhance tumor invasiveness. Designing and implementing an optimal tumor mimic can allow us to predictively map biophysical cue-modulated cell behaviors and facilitate the design of improved lab-grown tumor models with accurately controlled structural features. This review focuses on the abnormal changes within the ECM during tumorigenesis and its implications on tumor cell-matrix mechanoreciprocity. Additionally, it accentuates engineering approaches to produce ECM features of varying levels of complexity which is critical for improving the efficiency of current engineered tumor tissue models.

Gene-Level Analysis of Anthracycline-Induced Cardiomyopathy in Cancer Survivors: A Report From COG-ALTE03N1, BMTSS, and CCSS.

Background: Anthracyclines are highly effective in treating cancer, albeit with increased cardiomyopathy risk. Although risk is attributed to associations with single nucleotide polymorphisms (SNPs), multiple SNPs on a gene and their interactions remain unexamined. Objectives: This study examined gene-level associations with cardiomyopathy among cancer survivors using whole-exome sequencing data. Methods: For discovery, 278 childhood cancer survivors (129 cases; 149 matched control subjects) from the COG (Children's Oncology Group) study ALTE03N1 were included. Logic regression (machine learning) was used to identify gene-level SNP combinations for 7,212 genes and ordinal logistic regression to estimate gene-level associations with cardiomyopathy. Models were adjusted for primary cancer, age at cancer diagnosis, sex, race/ethnicity, cumulative anthracycline dose, chest radiation, cardiovascular risk factors, and 3 principal components. Statistical significance threshold of 6.93 × 10-6 accounted for multiple testing. Three independent cancer survivor populations (COG study, BMTSS [Blood or Marrow Transplant Survivor Study] and CCSS [Childhood Cancer Survivor Study]) were used to replicate gene-level associations and examine SNP-level associations from discovery genes using ordinal logistic, conditional logistic, and Cox regression models, respectively. Results: Median age at cancer diagnosis for discovery cases and control subjects was 6 years and 8 years, respectively. Gene-level association for P2RX7 (OR: 0.10; 95% CI: 0.04-0.27; P = 2.19 × 10-6) was successfully replicated (HR: 0.65; 95% CI: 0.47-0.90; P = 0.009) in the CCSS cohort. Additional signals were identified on TNIK, LRRK2, MEFV, NOBOX, and FBN3. Individual SNPs across all discovery genes, except FBN3, were replicated. Conclusions: In our study, SNP sets having 1 or no copies of P2RX7 variant alleles were associated with reduced risk of cardiomyopathy, presenting a potential therapeutic target to mitigate cardiac outcomes in cancer survivors.

Potential Action Mechanism and Inhibition Efficacy of Morinda citrifolia Essential Oil and Octanoic Acid against Stagonosporopsis cucurbitacearum Infestations.

The use of plant-based products has been shown to efficiently inhibit fungi-mediated diseases in agricultural crops. Here, we extracted and evaluated the composition of noni, Morinda citrifolia L., essential oil and assessed its activities against Stagonosporopsis cucurbitacearum in Cucumis melo L. Using in silico molecular approaches, potential interactions between the essential oil major components and S. cucurbitacearum tyrosine-tRNA ligase were predicted. Finally, we also measured the potential interference of plant physiology (the stomatal conductance and net photosynthesis) mediated by the application of the M. citrifolia essential oil. Chromatographic analysis revealed that octanoic acid (75.8%), hexanoic acid (12.8%), and isobutyl pent-4-enyl carbonate (3.1%) were the major essential oil compounds. Octanoic acid and noni essential oil, when used as preventive measures, reduce fungal mycelial growth at a concentration of 5 mg/mL without causing significant damage to the treated leaves, which reinforces their efficacies as preventive tools against S. cucurbitacearum. Molecular docking analyses predicted very stable interactions between the major essential oil constituents and S. cucurbitacearum tyrosine-tRNA ligase, suggesting the interference of these plant-based molecules upon enzyme activation. Octanoic acid and M. citrifolia essential oil at concentrations of 20 mg/mL decreased the stomatal conductance and net photosynthesis rate of melon plants, resulting in robust phytotoxicity. Collectively, our findings indicated that despite the phytotoxicity risks at higher concentrations, M. citrifolia essential oil and octanoic acid, have potential as alternative tools for the integrative management of S. cucurbitacearum.

The reverse question mark and L.G. Kempe incisions for decompressive craniectomy: A case series and narrative review of the literature.

Background: Decompressive craniectomy (DC) is a lifesaving procedure, relieving intracranial hypertension. Conventionally, DCs are performed by a reverse question mark (RQM) incision. However, the use of the L. G. Kempe's (LGK) incision has increased in the last decade. We aim to describe the surgical nuances of the LGK and the standard RQM incisions to treat patients with severe traumatic brain injury (TBI), intracranial hemorrhage (ICH), empyema, and malignant ischemic stroke. Furthermore, to describe, surgical limitations, wound healing, and neurological outcomes related to each technique. Methods: To describe a prospective acquired, case series including patients who underwent a DC using either an RQM or an LGK incision in our institution between 2019 and 2020. Results: A total of 27 patients underwent DC. Of those, ten patients were enrolled. The mean age was 42.1 years (26-71), and 60% were male. Five patients underwent DC using a large RQM incision; three had severe TBI, one ICH, and one ischemic stroke. The other five patients underwent DC using an LGK incision (one ICH, one subdural empyema, and one ischemic stroke). About 50% of patients presented severe headaches associated with vomiting, and six presented altered mental status (drowsy or stuporous). Motor deficits were present in four cases. In patients with ischemic or hemorrhagic stroke, symptoms were directly related to the stroke location. Hospital stays varied between 13 and 22 days. No readmissions were recorded, and no fatal outcome was documented during the follow-up. Conclusion: The utility of the LGK incision is comparable with the classic RQM incision to treat acute brain injuries, where an urgent decompression must be performed. Some of these cases include malignant ischemic strokes, ICH, and empyema. No differences were observed between both techniques in terms of prevention of scalp necrosis and general cosmetic outcomes.

Biomaterials for Mimicking and Modelling Tumor Microenvironment.

This chapter summarizes the current biomaterials and associated technologies used to mimic and characterize the tumor microenvironment (TME) for developing preclinical therapeutics. Research in conventional 2D cancer models systematically fails to provide physiological significance due to their discrepancy with diseased tissue's native complexity and dynamic nature. The recent developments in biomaterials and microfabrication have enabled the popularization of 3D models, displacing the traditional use of Petri dishes and microscope slides to bioprinters or microfluidic devices. These technologies allow us to gather large amounts of time-dependent information on tissue-tissue, tissue-cell, and cell-cell interactions, fluid flows, and biomechanical cues at the cellular level that were inaccessible by traditional methods. In addition, the wave of new tools producing unprecedented amounts of data is also triggering a new revolution in the development and use of new tools for analysis, interpretation, and prediction, fueled by the concurrent development of artificial intelligence. Together, all these advances are crystalizing a new era for biomedical engineering characterized by high-throughput experiments and high-quality data.Furthermore, this new detailed understanding of disease and its multifaceted characteristics is enabling the long searched transition to personalized medicine.Here we outline the various biomaterials used to mimic the extracellular matrix (ECM) and redesign the tumor microenvironment, providing a comprehensive overview of cancer research's state of the art and future.

Epidemiological and genetic features of anti-3­hydroxy-3-methylglutaryl-CoA reductase necrotizing myopathy: Single-center experience and literature review.

OBJECTIVE: To characterize the demographic, genetic, clinical, and serological features of patients with anti-3­hydroxy-3-methylglutaryl-CoA reductase (HMGCR) immune-mediated necrotizing myopathy (IMNM) in a region of northern Spain. METHODS: Study of all patients diagnosed with anti-HMGCR IMNM during a 5-year period at a reference hospital in northern Spain. Besides clinical and laboratory data, we analyzed the genetic influence of HLA genes and the rs4149056 (c.521T>C) single nucleotide polymorphism (SNP) in the SLCO1B1 gene. RESULTS: 8 patients (5 women, 3 men) with a mean ± SD age of 64.9 ± 7.3 years, fulfilled the criteria for anti-HMGCR IMNM. The incidence rate was 0.6 per 100.000 person-years and the prevalence 3 per 100.000 population. All patients had been exposed to statins. All of them had predominant lower limb proximal and symmetric muscle weakness that was severe in 2 and had elevated serum CK levels with a median [IQR] of 4488 [2538-9194] IU/L. Serum 25­hydroxy vitamin D levels were decreased in all patients in whom it was determined. The 3 patients with a previous diagnosis of hypothyroidism had abnormal levels of TSH at the time of diagnosis. All patients experienced improvement with different schemes of immunosuppressive therapy. Noteworthy, 7 of 8 patients carried the HLA-DRB1*11 allele. The frequency of the rs4149056 C allele in the SLCO1B1 gene (12.5%) was similar to that of the general population. CONCLUSION: In northern Spain, anti-HMGCR IMNM preferentially affects people over 50 years of age who are carriers of the HLA-DRB1*11 allele and take statins. Both low vitamin D levels and hypothyroidism may play a potential predisposing role in the development of this disease.

Nesting substrates and nest density of stingless bees in the Petenes Biosphere Reserve, Mexico / Sustratos de nidificación y densidad de nidos de abejas sin aguijón en la reserva de la biósfera de los petenes, méxico

RESUMEN Las abejas sin aguijón (ASA) son organismos relevantes en los ecosistemas por su desempeño como polinizadores. En México, la mayor diversidad de ASA se encuentra en el sureste. En este estudio se determinaron las especies de ASA y densidad de nidos en dos sitios con diferente perturbación dentro de la Reserva de la Biósfera de los Petenes (RBLP) Campeche (México). Asimismo, se identificaron los sustratos y las especies arbóreas de nidificación. En total se realizaron diez muestreos en transectos entre los meses de enero a mayo de 2018. Se registraron 56 nidos pertenecientes a ocho especies diferentes de ASA (Cephalotrigona zexmeniae, Frieseomelitta nigra, Lestrimellita niitkib, Nannotrigona perilampoides, Partamona bilineata, Plebeia frontalis, Scaptotrigona pectoralis y Trígona fulviventris). Las especies con mayor número de nidos correspondieron a F. nigra (41,07 %) y S. pectoralis (28,57 %). No se encontraron diferencias significativas en la densidad de nidos entre los sitios Hecelchakán (2,15 nidos/ha) y Calkiní (0,19 nidos/ha). El sustrato preferido para anidación son las cavidades en árboles vivos (78,57 %). En total 15 especies arbóreas fueron identificadas como sustrato de nidificación y la especie más abundante correspondió a Crescentia cujete (n = 18, 40,9 %). El grado de perturbación tuvo poco efecto en el número y densidad de nidos de ASA, sin embargo, en general, la RBLP presentó una composición de especies y densidad de nidos reducida. Por lo tanto, este estudio permitió establecer las bases para futuros estudios sobre estrategias de manejo y conservación de estas especies para evitar su desaparición en la RBLP.

ABSTRACT Stingless bees (ASA) are relevant organisms in ecosystems because of their performance as pollinators. In Mexico, the higher diversity of ASA is found in the southeast. In this study, the ASA species and nest density of nests were identified at two sites with different disturbances (Hecelchakán and Calkiní) within the Petenes Biosphere Reserve (RBLP), Campeche (Mexico). Also, the substrates and the nesting tree species were identified. In total, ten sampling transects were performed between January and May 2018. In total 56 nests belonging to eight different species of ASA (Cephalotrigonazexmeniae, Frieseomelitta nigra, Lestrimellita niitkib, Nanotrigonaperilampoides, Partamona bilineata, Plebeia frontalis, Scaptotrigona pectoralis and Trigona fulviventris) were found. The species with the highest number of nests corresponded to F. nigra (41.07 %) and S. pectoralis (28.57 %). No significant differences were found in nest density between the Hecelchakán (2.15 nests/ha) and Calkiní (0.19 nests/ha) site. The preferred substrate for nesting is cavities in living trees (78.57 %). In total 15 tree species were identified as nesting substrate and the most abundant species corresponded to Crescentia cujete (n = 8, 40.90 %). The degree of disturbance had little effect on the number and density of ASA nest, however, in general, the RBLP presented low species composition and nest density. Therefore, this study allowed to establish the bases for future studies on management and conservation strategies of these species to avoid their loss in the RBLP.