HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma.

Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2's transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity.

Surface bioactivation of Polyetheretherketone (PEEK) by magnesium chondroitin sulfate (MgCS) as orthopedic implants for reconstruction of skeletal defects.

Polyether-ether-ketone (PEEK) is clinically used as a bio-implant for the healing of skeletal defects. However, the osseointegration of clinical-sized bone grafts remains limited. In this study, surface-porous PEEK was created by using a sulfonation method and a metal-polysaccharide complex MgCS was introduced on the surface of sulfonated PEEK to form MgCS@SPEEK. The as-prepared MgCS@SPEEK was found to have a porous surface with good hydrophilicity and bioactivity. This was followed by an investigation into whether MgCS loaded onto sulfonated PEEK surfaces could promote osseointegration and angiogenesis. The in vitro results showed that MgCS@SPEEK had a positive effect on reducing the expression levels of inflammatory genes and promoting osteogenesis and angiogenesis-related genes expression levels. Furthermore, porous MgCS@SPEEK was implanted in critical-sized rat tibial defects for in vivo evaluation of osseointegration. The micro-computed tomography evaluation results revealed substantial bone formation at 4 and 8 weeks. Collectively, these findings indicate that MgCS@SPEEK could provide improved osseointegration and an attractive strategy for orthopaedic applications.

Medial tab-type fasciocutaneous flap as an alternative for the management of soft tissue defects of the leg. / Colgajo fasciocutáneo tipo lengüeta medial como alternativa para el manejo de defectos de tejidos blandos en la pierna.

BACKGROUND: Selecting the right technique for lower limb soft tissue reconstruction is a therapeutic challenge. Despite having several reconstruction options, it's important to choose a technique that is effective and with the least possible donor site morbidity. OBJECTIVE: Demonstrate the therapeutic efficacy of the medial tab flap in soft tissue reconstruction on the leg, compared to conventional flaps. MATERIALS AND METHODS: Cohort study matched by age. 64 patients with soft tissue defects were selected and according to the intervention divided in: group 1)medial tab flap, and group 2)conventional flaps (sural, soleus, gastrocnemius) followed up to one year postoperatively. OUTCOME VARIABLES: surgical time in minutes, healing, healing time in days, complications. RESULTS: The patients who underwent surgery with medial tab flap and with conventional flaps healed completely. The healing time was 16.2±11.2 days in the tab flap and 16.1±11.2 days in conventional flaps, no statistically significant differences were found between the groups (P=.89). The surgical time for tab flaps was 225.2±117.8minutes, and 191.3±117.2minutes for the comparison flaps (P=.65), there were no statistically significant differences. There were no complications in the medial tab flaps. CONCLUSION: The findings suggest that the medial tab flap technique is as effective as the conventional flap technique, with complete flap survival and healing, and without any major complications in this studied group.

Charge density waves tuned by biaxial tensile stress.

The precise arrangement and nature of atoms drive electronic phase transitions in condensed matter. To explore this tenuous link, we developed a true biaxial mechanical deformation device working at cryogenic temperatures, compatible with x-ray diffraction and transport measurements, well adapted to layered samples. Here we show that a slight deformation of TbTe3 can have a dramatic influence on its Charge Density Wave (CDW), with an orientational transition from c to a driven by the a/c parameter, a tiny coexistence region near a = c, and without space group change. The CDW transition temperature Tc displays a linear dependence with a / c - 1 while the gap saturates out of the coexistence region. This behaviour is well accounted for within a tight-binding model. Our results question the relationship between gap and Tc in RTe3 systems. This method opens a new route towards the study of coexisting or competing electronic orders in condensed matter.

Cerebral venous thrombosis.

Cerebral venous thrombosis is part of the so-called thrombosis in unusual sites. It is defined as an occlusion in the cerebral venous territory. Its incidence is progressively increasing, especially in developing countries. It is more frequently observed in young women, with hormonal factors such as pregnancy or hormonal contraception being significant risk factors in the development of this condition. The clinical presentation will depend fundamentally on the topography of the thrombosis, with a confirmatory diagnosis based mainly on imaging tests. The treatment generally consists of anticoagulation, and other options may be considered depending on the severity of the case. Overall, the prognosis is better than that of other intracranial vascular disorders. This review describes the current evidence available regarding cerebral venous thrombosis.

Osteogenic-angiogenic coupled response of cobalt-containing mesoporous bioactive glasses in vivo.

The incorporation of cobalt ions into the composition of bioactive glasses has emerged as a strategy of interest for bone regeneration purposes. In the present work, we have designed a set of bioactive mesoporous glasses SiO2-CaO-P2O5-CoO (Co-MBGs) with different amounts of cobalt. The physicochemical changes introduced by the Co2+ ion, the in vitro effects of Co-MBGs on preosteoblasts and endothelial cells and their in vivo behaviour using them as bone grafts in a sheep model were studied. The results show that Co2+ ions neither destroy mesoporous ordering nor inhibit in vitro bioactive behaviour, exerting a dual role as network former and modifier for CoO concentrations above 3 % mol. On the other hand, the activity of Co-MBGs on MC3T3-E1 preosteoblasts and HUVEC vascular endothelial cells is dependent on the concentration of CoO present in the glass. For low Co-MBGs concentrations (1mg/ml) cell viability is not affected, while the expression of osteogenic (ALP, RUNX2 and OC) and angiogenic (VEGF) genes is stimulated. For Co-MBGs concentration of 5 mg/ml, cell viability decreases as a function of the CoO content. In vivo studies show that the incorporation of Co2+ ions to the MBGs improves the bone regeneration activity of these materials, despite the deleterious effect that this ion has on bone-forming cells for any of the Co-MBG compositions studied. This contradictory effect is explained by the marked increase in angiogenesis that takes place inside the bone defect, leading to an angiogenesis-osteogenesis coupling that compensates for the partial decrease in osteoblast cells. STATEMENT OF SIGNIFICANCE: The development of new bone grafts implies to address the need for osteogenesis-angiogenesis coupling that allows bone regeneration with viable tissue in the long term. In this sense the incorporation of cobalt ions into the composition of bioactive glasses has emerged as a strategy of great interest in this field. Due to the potential cytotoxic effect of cobalt ions, there is an important controversy regarding the suitability of their incorporation in bone grafts. In this work, we address this controversy after the implantation of cobalt-doped mesoporous bioactive glasses in a sheep model. The incorporation of cobalt ions in bioactive glasses improves the bone regeneration ability of these bone grafts, due to enhancement of the angiogenesis-osteogenesis coupling.

HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma.

Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2's transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity.

Correlation between contrast sensitivity and morphological features obtained by OCT in patients with age-related macular degeneration treated with a loading dose of vascular endothelial growth factor inhibitors.

OBJECTIVE: To determine the correlation between contrast sensitivity and morphological characteristics obtained by Optical Coherence Tomography (OCT) in patients with Age-Related Macular Degeneration treated with a loading dose of vascular endothelial growth factor inhibitors (anti-VEGF). DESIGN: This is an ambispective (prospective + retrospective) observational, cross-sectional, and analytical study. PARTICIPANTS: All patients over 55 years of age with Age-Related Macular Degeneration who attended the Retina service of the Ophthalmology department and met the inclusion criteria between March-May 2022. METHODS: Data collection was carried out by reviewing the records of patients diagnosed with Age-Related Macular Degeneration of the neovascular variety treated with the loading dose of anti-VEGF. OCT studies obtained by Optovue® iVue80 prior to the application of intravitreal injections of patients who met the inclusion criteria and were currently in the first month after the last dose of anti-VEGF were analyzed. A total of 33 subjects were included, of which 30 continued follow-ups. The subjects underwent a new ophthalmological evaluation and new retinal measurements of the affected eye. Normality tests (Shapiro‒Wilk) were performed where a nonparametric data distribution was demonstrated. RESULTS: A linear regression analysis was performed comparing the logarithmic values of both visual acuity and contrast sensitivity, obtaining a significant relationship between both values after the application of treatment (P = <.0001***). Likewise, correlation was demonstrated between the decrease in contrast sensitivity values and all the characteristics evaluated in the patients' OCT. CONCLUSIONS: Antiangiogenesis strategies can lead to better results in global visual function, positively impacting contrast sensitivity.

Is off-label thrombolysis safe and effective in a real-life primary stroke center? A retrospective analysis of data from a 5-year prospective database.

BACKGROUND: Intravenous thrombolysis (IVT) use for acute ischemic stroke (AIS) varies among countries, partly due to guidelines and product labeling changes. The study aim was to identify the characteristics of patients with AIS treated with off-label IVT and to determine its safety when performed in a primary stroke center (PSC). METHODS: This observational, single-center study included all consecutive patients admitted to Perpignan PSC for AIS and treated with IVT and patients transferred for EVT, between January 1, 2015 and December 31, 2019. Data of patients treated with IVT according to ("in-label group") or outside ("off-label") the initial guidelines and manufacturer's product specification were compared. Safety was assessed using symptomatic intracerebral hemorrhage (SIH) as the main adverse event. RESULTS: Among the 892 patients in the database (834 screened by MRI, 93.5%), 746 were treated by IVT: 185 (24.8%) "in-label" and 561 (75.2%) "off-label". In the "off-label" group, 316 (42.4% of the cohort) had a single criterion for "off-label" use, 197 (26.4%) had two, and 48 (6.4%) had three or more criteria, without any difference in IVT safety pattern among them. SIH rates were comparable between the "off-label" and "in-label" groups (2.7% vs. 1.1%, P=0.21); early neurological deterioration and systematic adverse event due to IVT treatment were similar in the 2 groups. "Off-label" patients had higher in-hospital (8.7% vs. 3.8%, P=0.05) and 3-month mortality rates (12.1% vs 5.4%, P<0.01), but this is explained by confounding factors as they were older (76 vs 67 years, P<0.0001) and more dependent (median modified Rankin scale score 0.4 vs 0.1, P<0.0001) at admission. CONCLUSIONS: "Off-label" thrombolysis for AIS seems to be safe and effective in the routine setting of a primary stroke center.

Injectable mesoporous bioactive nanoparticles regenerate bone tissue under osteoporosis conditions.

The osteogenic capability of mesoporous bioactive nanoparticles (MBNPs) in the SiO2CaO system has been assessed in vivo using an osteoporotic rabbit model. MBNPs have been prepared using a double template method, resulting in spherical nanoparticles with a porous core-shell structure that has a high surface area and the ability to incorporate the anti-osteoporotic drug ipriflavone. In vitro expression of the pro-inflammatory genes NF-κB1, IL-6, TNF-α, P38 and NOS2 in RAW-264.7 macrophages, indicates that these nanoparticles do not show adverse inflammatory effects. An injectable system has been prepared by suspending MBNPs in a hyaluronic acid-based hydrogel, which has been injected intraosseously into cavitary bone defects in osteoporotic rabbits. The histological analyses evidenced that MBNPs promote bone regeneration with a moderate inflammatory response. The incorporation of ipriflavone into these nanoparticles resulted in a higher presence of osteoblasts and enhanced angiogenesis at the defect site, but without showing significant differences in terms of new bone formation. STATEMENT OF SIGNIFICANCE: Mesoporous bioactive glass nanoparticles have emerged as one of the most interesting materials in the field of bone regeneration therapies. For the first time, injectable mesoporous bioactive nanoparticles have been tested in vivo using an osteoporotic animal model. Our findings evidence that MBG nanoparticles can be loaded with an antiosteoporotic drug, ipriflavone, and incorporated in hyaluronic acid to make up an injectable hydrogel. The incorporation of MBG nanoparticles promotes bone regeneration even under osteoporotic conditions, whereas the presence of IP enhances angiogenesis as well as the presence of osteoblast cells lining in the newly formed bone. The injectable device presented in this work opens new possibilities for the intraosseous treatment of osteoporotic bone using minimally invasive surgery.

Unravelling groundwater and surface water sources in the Esteros del Iberá Wetland Area: An isotopic approach.

In the Esteros del Iberá Wetland Area (EIWA, NE Argentina), the southern sector of the transboundary Guarani Aquifer System (SAG) is overlain by the Ramsar listed Iberá Wetlands and several rivers, that combined extend across 37,930 km2 and represent one of the largest freshwater systems on the South American continent. Previous hydrogeological studies encompassing the entire SAG proposed preferential discharge of groundwater of various origins and ages to the EIWA. In this study, a multi-tracer study using major ionic species, δ18O, δ2H and 222Rn was conducted in lagoons, rivers, wells, and boreholes in the EIWA to confirm if discharge from the transboundary SAG is contributing to the surface water system. End-member Mixing Analysis (EMMA) determined the existence of four main end-members: groundwater from the SAG, more saline groundwater from the deeper Pre-SAG, and two poorly mineralised end-members from shallow, Post-SAG. EMMA calculations clearly illustrated complex binary and ternary mixing patterns involving the four end-members and highlighted the role of geological structures, specifically regional steep faults, in controlling the mixing patterns. 222Rn activities allowed in-situ identification of preferential deep groundwater discharge into both surface waters and shallow groundwaters. These findings provide strong evidence for the widespread existence of upward flows along major faults in this sector of the SAG, inducing complex mixing flow patterns and explaining the presence of old groundwater in shallow aquifers. Mapping the sources of water and the hydrological interactions are relevant for improving water balance estimates and develop management policies towards the preservation of these wetlands.

Water stable isotopes reveal a complex rainfall to groundwater connectivity in central Honduras.

The inter-mountainous region of central Honduras has been experiencing abrupt urban drinking water shortages during the last decade. Land use fragmentation and rainfall deficits have rapidly reduced surface water quality and quantity in this region. Here we present a 3-yr (2018-2020) tracer study within the headwaters of the Choluteca River basin (2949 km2). We sampled rainfall (weekly N = 156; daily N = 270), drilled wells (N = 166; up to ~300 m depth), boreholes (N = 70; ~4-12 m depth), and springs (N = 128) to assess the spatiotemporal connectivity between rainfall and mean groundwater recharge elevations (MREs). Clear W-shaped incursions characterized rainfall isotopic seasonality from the dry to the wet season. Air mass back trajectory analysis revealed three primary moisture sources: 73 % (east, Caribbean Sea), 17 % (southwest, Pacific Ocean), and 10 % (north; Gulf of Mexico). Groundwater sources exhibited a strong meteoric origin with evidence of secondary evaporation evolution, characterized by low d-excess values. MREs for the drilled wells ranged from 821 to 2018 m asl with a mean value of 1570 ± 150 m asl. Seasonal isotopic variability during dry-wet transitions and the influence of rapid infiltration limited the performance of the MRE method in springs and boreholes. MREs coincided primarily with coniferous forests, pasture, and crop areas, within regions of moderate to high transmissivity. These results are intended to guide the mapping and delineation of critical recharge areas in central Honduras to enhance municipal water regulations, effective environmental protection, and long-term conservation practices.

Activating stress memory: eustressors as potential tools for plant breeding.

Plants are continuously exposed to stress conditions, such that they have developed sophisticated and elegant survival strategies, which are reflected in their phenotypic plasticity, priming capacity, and memory acquisition. Epigenetic mechanisms play a critical role in modulating gene expression and stress responses, allowing malleability, reversibility, stability, and heritability of favourable phenotypes to enhance plant performance. Considering the urgency to improve our agricultural system because of going impacting climate change, potential and sustainable strategies rely on the controlled use of eustressors, enhancing desired characteristics and yield and shaping stress tolerance in crops. However, for plant breeding purposes is necessary to focus on the use of eustressors capable of establishing stable epigenetic marks to generate a transgenerational memory to stimulate a priming state in plants to face the changing environment.

Delivery of Anti-IFNAR1 shRNA to Hepatic Cells Decreases IFNAR1 Gene Expression and Improves Adenoviral Transduction and Transgene Expression.

Chronic liver injury leads to advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Genetical cell treatment related to the use of adenovirus (Ads) has proven to be beneficial and efficient in the recovery of hepatic diseases. Nevertheless, they are highly immunogenic and trigger an immune response where interferons type 1 (IFN-I) play a very important role. Three shRNAs against the Interferon-1 receptor (IFNAR1) were designed and cloned in pENTR/U6 plasmid and amplified in DH5α cells. Huh7 cells were transfected with these plasmids in the presence or absence of 1 × 109 viral particles/ml of adenovirus containing the green fluorescent protein gene used as a reporter. Transfection with the shRNA plasmids partially inhibited the IFNAR1 expression. This inhibition substantially decreased antiviral response, demonstrated by the decrease of IFNAR1, IFN-α, and TNF-α gene expression, and the decrease at protein levels of IFNAR1, Protein kinase RNA-activated (PKR), and phosphorylated STAT1, allowing higher adenoviral transduction and transgene expression. Interestingly it was seen shRNA inhibited macrophage activation. These results suggest that the inhibition of the IFN-I pathway could be a strategy to minimize the immune response against Adenoviral vectors allowing higher Adenovirus transduction extending the transgene expression.

Venous thromboembolism incidence in cancer patients with germline BRCA mutations.

BACKGROUND: Germline BRCA (gBRCA) mutations predispose to an increased risk of breast and ovarian cancer among other neoplasms. Recently, several genomic alterations such as ALK and ROS-1 rearrangements have been described as molecular drivers of venous thromboembolism (VTE). The association of gBRCA mutations and VTE is unknown. MATERIALS AND METHODS: We performed an observational, retrospective, single-center study to determine the VTE incidence in consecutive patients with gBRCA mutations and cancer diagnosis attended in the multidisciplinary heredofamiliar cancer unit (HFCU) of Hospital General Universitario Gregorio Marañón, Spain, from 2010 to 2019. RESULTS: One-hundred and forty-one patients were included in the analysis. The overall VTE incidence was 12.8%. The highest incidence was reported in ovarian cancer patients (20.0%), followed by patients with both ovarian and breast cancers (16.6%) and the lowest was found in breast cancer (4.9%). No difference in the type of gBRCA mutation (1 or 2) in terms of VTE rate was observed. Sixty one percent of the patients were receiving anti-cancer therapy at the time of VTE diagnosis and the majority of the events (83.3%) were diagnosed in ambulatory setting. Khorana score was of limited value to detect high-risk patients. CONCLUSIONS: The VTE incidence observed in our study is consistent with prior data described in general population of breast and ovarian cancer. The risk of VTE in these patients seems to be driven by the type of cancer. We have not observed any significant interaction of gBRCA mutation status and cancer-associated thrombosis.

Strontium and oxygen isotopes to trace mobility routes during the Bell Beaker period in the north of Spain.

Strontium and oxygen isotopes of individuals from El Hundido and Valdescusa (north of Spain) sites, corresponding to the Bell Beaker culture, were analysed in order to determine mobility patterns and provenance areas. Strontium and oxygen isotope ratios in three teeth from two individuals at El Hundido and two teeth from the five individuals at Valdescusa were studied. The analyses were performed in both dentine and enamel fractions. 87Sr/86Sr ratios of El Hundido individuals indicate one was of foreign origin and the other was local whereas at Valdescusa were all of foreign provenance. Calculated δ18Ow values of El Hundido suggest a provenance from the geographical area close to the site while the Valdescusa would come from a warmer region. The comparison of oxygen and strontium isotope signatures indicate the west of the Iberian Peninsula (Zamora or the east of Leon regions) as the provenance area for the foreign individual at El Hundido and southwest France (Garonne basin) as the region of provenance for the Valdescusa.

Research opportunities: Traditional fermented beverages in Mexico. Cultural, microbiological, chemical, and functional aspects.

In Mexico, close to 200 fermented products have been described, of which, approximately 20 are beverages. They were obtained through rustic and ancestral fermentation methods by different indigenous Mexican communities; most of them were used in ceremonies, agricultural work, and other occasions. For their elaboration, different substrates obtained from plants are used, where uncontrolled and low-scale spontaneous anaerobic fermentation occurs. In Mexico, some of these products are considered as nutritional sources and functional beverages; the study of those products has revealed the presence of multiple compounds of biological importance. Additionally, elder generations attribute healing properties against diverse illnesses to these beverages. The aim of this review is to highlight the available information on twelve traditional Mexican fermented beverages, their traditional uses, and their fermentation processes along with toxicological, chemical, nutritional, and functional studies as seen from different areas of investigation. In the literature, pulque, cocoa, and pozol were the beverages with the greatest amount of described health properties; sendechó and guarapo were less characterized. Polyphenols, gallic and ferulic acid, anthocyanins and saponins were the most abundant molecules in all beverages. Finally, it is important to continue this research in order to determine the microorganisms that are involved in the fermentation process, as well as the organoleptic and beneficial properties they lend to the traditional Mexican fermented beverages.