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Aberrant metabolism is a hallmark of malignancies including gliomas. Intracranial microdialysis enables the longitudinal collection of extracellular metabolites within CNS tissues including gliomas and can be leveraged to evaluate changes in the CNS microenvironment over a period of days. However, delayed metabolic impacts of CNS injury from catheter placement could represent an important covariate for interpreting the pharmacodynamic impacts of candidate therapies. Intracranial microdialysis was performed in patient-derived glioma xenografts of glioma before and 72 h after systemic treatment with either temozolomide (TMZ) or a vehicle. Microdialysate from GBM164, an IDH-mutant glioma patient-derived xenograft, revealed a distinct metabolic signature relative to the brain that recapitulated the metabolic features observed in human glioma microdialysate. Unexpectedly, catheter insertion into the brains of non-tumor-bearing animals triggered metabolic changes that were significantly enriched for the extracellular metabolome of glioma itself. TMZ administration attenuated this resemblance. The human glioma microdialysate was significantly enriched for both the PDX versus brain signature in mice and the induced metabolome of catheter placement within the murine control brain. These data illustrate the feasibility of microdialysis to identify and monitor the extracellular metabolome of diseased versus relatively normal brains while highlighting the similarity between the extracellular metabolome of human gliomas and that of CNS injury.
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BACKGROUND AND AIMS: Mother-to-child-transmission (MTCT) of hepatitis B virus (HBV) may still occur despite birth-dose HBV vaccinations when pregnant women are positive for hepatitis B surface antigen (HBsAg) with high viral loads (HBV DNA ≥ 200 000 IU/mL). A pilot integrated model nurse clinic (IMNC) was started in 2020 to implement the pre-emptive antiviral therapy with tenofovir disoproxil fumarate (TDF). We aimed to evaluate the performance of IMNC on uptake of TDF. METHODS: This was a territory-wide retrospective cohort of all consecutive HBsAg-positive women of child-bearing age with pregnancy records in public hospitals 2019-2022. Demographic characteristics, liver biochemistries and virologic parameters, and TDF use were collected. Concurrently, data from a prospective audit in Union Hospital, the private hospital with the highest number of deliveries in Hong Kong, from June 2022 to May 2023 were compared. RESULTS: The prevalence rate of HBV DNA ≥ 200 000 IU/mL in pregnant women with available HBV DNA records was 29.2% (66/226) in 2019, 27.3% (99/363) in 2020, 15.9% (125/784) in 2021 and 17.2% (117/679) in 2022 (p < .001), out of 2052 pregnant women who had their HBV DNA checked within 1 year prior to delivery. An increasing uptake rate of TDF by highly viraemic pregnant women (i.e. ≥ 200 000 IU/mL) was noted after the commencement of IMNC in public hospitals, with 67% (45/67) in 2019, 83% (88/106) in 2020, 91% (117/128) in 2021 and 89% (149/167) in 2022. Moreover, all highly viraemic pregnant women from Union Hospital received TDF. Continuous use of TDF was associated with a reduced risk of postpartum biochemical flare. CONCLUSIONS: IMNC increases the uptake of antiviral treatment in pregnant women at risk of MTCT of HBV. IMNC contributes to hepatitis elimination through a structured care plan to prevent MTCT of HBV.
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Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) has developed substantial antigenic variability. As the majority of the population now has pre-existing immunity due to infection or vaccination, the use of experimentally generated animal immune sera can be valuable for measuring antigenic differences between virus variants. Here, we immunized Syrian hamsters by two successive infections with one of nine SARS-CoV-2 variants. Their sera were titrated against 16 SARS-CoV-2 variants, and the resulting titers were visualized using antigenic cartography. The antigenic map shows a condensed cluster containing all pre-Omicron variants (D614G, Alpha, Delta, Beta, Mu, and an engineered B.1+E484K variant) and considerably more diversity among a selected panel of Omicron subvariants (BA.1, BA.2, BA.4/BA.5, the BA.5 descendants BF.7 and BQ.1.18, the BA.2.75 descendant BN.1.3.1, the BA.2-derived recombinants XBB.2 and EG.5.1, and the BA.2.86 descendant JN.1). Some Omicron subvariants were as antigenically distinct from each other as the wildtype is from the Omicron BA.1 variant. Compared to titers measured in human sera, titers in hamster sera are of higher magnitude, show less fold change, and result in a more compact antigenic map topology. The results highlight the potential of sera from hamsters for the continued antigenic characterization of SARS-CoV-2.
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Variación Antigénica , COVID-19 , Mesocricetus , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Animales , SARS-CoV-2/inmunología , SARS-CoV-2/genética , COVID-19/inmunología , COVID-19/virología , Cricetinae , Variación Antigénica/inmunología , Variación Antigénica/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Antígenos Virales/inmunología , Antígenos Virales/genética , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Humanos , Sueros Inmunes/inmunologíaRESUMEN
Our knowledge of alphavirus genetic diversity is mainly based on viruses isolated from anthropophilic mosquito species, humans, and livestock during outbreaks. Studies on alphaviruses from sylvatic amplification cycles in sub-Saharan Africa have been conducted less often than from epizootic environments. To gain insight into alphavirus diversity in enzootic transmission cycles, we collected over 23,000 mosquitoes in lowland rainforest and savannah gallery forest in southwestern Uganda and tested them for alphavirus infections. We detected Sindbis virus (SINV) in a Culex Culex sp. mosquito and Middelburg virus (MIDV) in Eretmapodites intermedius and Mansonia africana. MIDV is a mosquito-borne alphavirus that causes febrile illness in sheep, goats, and horses and was previously not known to occur in Uganda. SINV, also a mosquito-borne alphavirus, causes mild infections in humans. Full genomes of SINV and MIDV were sequenced, showing a nucleotide identity of 99% to related strains. Both isolates replicated to high titres in a wide variety of vertebrate cells. Our data suggest endemic circulation of SINV and MIDV in Uganda.
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Mobile genetic elements (MGEs) like plasmids, viruses, and transposable elements can provide fitness benefits to their hosts for survival in the presence of environmental stressors. Heavy metal resistance genes (HMRGs) are frequently observed on MGEs, suggesting that MGEs may be an important driver of adaptive evolution in environments contaminated with heavy metals. Here, we report the meta-mobilome of the heavy metal-contaminated regions of the Oak Ridge Reservation subsurface. This meta-mobilome was compared with one derived from samples collected from unimpacted regions of the Oak Ridge Reservation subsurface. We assembled 1615 unique circularized DNA elements that we propose to be MGEs. The circular elements from the highly contaminated subsurface were enriched in HMRG clusters relative to those from the nearby unimpacted regions. Additionally, we found that these HMRGs were associated with Gamma and Betaproteobacteria hosts in the contaminated subsurface and potentially facilitate the persistence and dominance of these taxa in this region. Finally, the HMRGs were associated with conjugative elements, suggesting their potential for future lateral transfer. We demonstrate how our understanding of MGE ecology, evolution, and function can be enhanced through the genomic context provided by completed MGE assemblies.
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The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires ongoing monitoring to judge the ability of newly arising variants to escape the immune response. A surveillance system necessitates an understanding of differences in neutralization titers measured in different assays and using human and animal serum samples. We compared 18 datasets generated using human, hamster, and mouse serum and six different neutralization assays. Datasets using animal model serum samples showed higher titer magnitudes than datasets using human serum samples in this comparison. Fold change in neutralization of variants compared to ancestral SARS-CoV-2, immunodominance patterns, and antigenic maps were similar among serum samples and assays. Most assays yielded consistent results, except for differences in fold change in cytopathic effect assays. Hamster serum samples were a consistent surrogate for human first-infection serum samples. These results inform the transition of surveillance of SARS-CoV-2 antigenic variation from dependence on human first-infection serum samples to the utilization of serum samples from animal models.
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , Pruebas de Neutralización , SARS-CoV-2 , Animales , Humanos , SARS-CoV-2/inmunología , COVID-19/inmunología , COVID-19/sangre , COVID-19/virología , Ratones , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Cricetinae , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Modelos Animales de EnfermedadRESUMEN
This case report presents a rare complication of hepatic cystic echinococcosis in a 12-year-old Latino male, residing in a nonendemic region, who developed long-term sequelae of portal vein thrombosis accompanied by the emergence of a hyper-vascular sigmoid colon mass. Portal vein involvement in hepatic cystic echinococcosis is exceedingly uncommon, with limited documented cases. The presentation of the patient included intermittent hematochezia, abdominal pain, and fatigue. Imaging revealed liver cysts and chronic portal vein thrombosis with cavernous transformation, resulting in portal hypertension. Notably, the patient also exhibited mesenteric venous thrombosis, further complicating the clinical picture. The diagnosis was confirmed through echinococcus serology testing. Treatment involved a six month course of Albendazole, puncture-aspiration-injection-reaspiration procedure, splenectomy, and splenorenal shunt to alleviate portal hypertension. This case underscores the significance of considering portal hypertension secondary to hepatic cystic echinococcosis, even in nonendemic regions, particularly in pediatric patients with unique clinical presentations.
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BACKGROUND: Evolving SARS-CoV-2 variants and changing levels of pre-existing immunity require re-evaluation of antigen-detecting rapid diagnostic test (Ag-RDT) performance. We investigated possible associations between Ag-RDT sensitivity and various potential influencing factors, such as immunisation status and viral variant, in symptomatic hospital employees. METHODS: In this observational study, RT-PCR, Ag-RDT, and symptom-specific data were collected at three SARS-CoV-2 test centres for employees of the Charité-Universitätsmedizin Berlin hospital (Berlin, Germany). Employees reporting SARS-CoV-2-like symptoms, those at an increased risk of infection (eg, due to contact with an infected person), those testing positive in a previous self-administered Ag-RDT, or those seeking release-testing to return to work at least 7 days after a positive RT-PCR test were eligible for combined testing by RT-PCR and Ag-RDT. Only data from individuals with an ongoing SARS-CoV-2 infection as assessed by RT-PCR were used for further analysis. Bayesian regression analyses were done to evaluate possible differences in viral load and Ag-RDT sensitivity according to viral variant and immunisation status (previous vaccination or recovery from infection), using data from first RT-PCR positive samples in an infection. A comprehensive logistic regression analysis was used to investigate potential concomitant associations between Ag-RDT sensitivity and level of pre-existing immunity, time post symptom onset, viral load, gender, age, and Ag-RDT device. Ag-RDT performance was also compared between supernatants from cell cultures infected with the omicron variant of concern (VOC) or the wild-type strain (pre-VOC). FINDINGS: Between Nov 30, 2020 and Feb 11, 2022, a total of 14 773 samples from 7675 employees were tested for SARS-CoV-2 by both RT-PCR and Ag-RDT. We found a negative association between immunisation status and Ag-RDT sensitivity in symptomatic employees, with an observed sensitivity of 82% (94% highest posterior density interval [HPDI] 78-86) in immunologically naive participants compared with 73% (68-78) in multiply immunised individuals (ie, those with at least two vaccinations or recoveries from infection) and median log10 viral loads of 7·02 (IQR 5·83-8·07) and 8·08 (6·80-8·89), respectively. The dominant viral variant changed several times during the study period, from the pre-VOC period (sensitivity 80% [94% HPDI 75-85] in symptomatic participants) through the alpha variant (82% [70-94]), delta variant (75% [69-82]), and omicron variant (72% [65-79]) waves, concomitantly with a steep increase in vaccination coverage in our dataset. In a comparison of Ag-RDT performance on cell culture supernatants, we found no difference between the wild-type and omicron viral variants. INTERPRETATION: On the basis of our findings and data from other studies, we hypothesise that the observed reduction in clinical Ag-RDT sensitivity, despite higher SARS-CoV-2 RNA loads, is due to shorter incubation times later in our study period resulting from increased population immunity or changes in immune response dynamics caused by later SARS-CoV-2 VOCs. FUNDING: Berlin University Alliance, German Ministry of Education and Research, the EU (Projects EU4Health and ReCoVer), and the Berlin Institute of Health.
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COVID-19 , SARS-CoV-2 , Carga Viral , Humanos , COVID-19/inmunología , COVID-19/diagnóstico , COVID-19/virología , COVID-19/epidemiología , Masculino , Femenino , Persona de Mediana Edad , SARS-CoV-2/inmunología , Adulto , Sensibilidad y Especificidad , Prueba Serológica para COVID-19/métodos , Berlin/epidemiología , Alemania/epidemiología , Antígenos Virales/inmunologíaRESUMEN
While serial sampling of glioma tissue is rarely performed prior to recurrence, cerebrospinal fluid (CSF) is an underutilized longitudinal source of candidate glioma biomarkers for understanding therapeutic impacts. However, the impact of key variables to consider in longitudinal CSF samples, including anatomical location and post-surgical changes, remains unknown. To that end, pre- versus post-resection intracranial CSF samples were obtained at early (1-16 days; n=20) or delayed (86-153 days; n=11) timepoints for patients with glioma. Paired lumbar-versus-intracranial glioma CSF samples were also obtained (n=14). Using aptamer-based proteomics, we identify significant differences in the CSF proteome between lumbar, subarachnoid, and ventricular CSF. Our analysis of serial intracranial CSF samples suggests the early potential for disease monitoring and evaluation of pharmacodynamic impact of targeted therapies. Importantly, we found that resection had a significant, evolving longitudinal impact on the CSF proteome. Proteomic data are provided with individual clinical annotations as a resource for the field. One Sentence Summary: Glioma cerebrospinal fluid (CSF) accessed intra-operatively and longitudinally via devices can reveal impacts of treatment and anatomical location.
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The sources and sinks of nitrous oxide, as control emissions to the atmosphere, are generally poorly constrained for most environmental systems. Initial depth-resolved analysis of nitrous oxide flux from observation wells and the proximal surface within a nitrate contaminated aquifer system revealed high subsurface production but little escape from the surface. To better understand the environmental controls of production and emission at this site, we used a combination of isotopic, geochemical, and molecular analyses to show that chemodenitrification and bacterial denitrification are major sources of nitrous oxide in this subsurface, where low DO, low pH, and high nitrate are correlated with significant nitrous oxide production. Depth-resolved metagenomes showed that consumption of nitrous oxide near the surface was correlated with an enrichment of Clade II nitrous oxide reducers, consistent with a growing appreciation of their importance in controlling release of nitrous oxide to the atmosphere. Our work also provides evidence for the reduction of nitrous oxide at a pH of 4, well below the generally accepted limit of pH 5.
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Óxido Nitroso , Óxido Nitroso/metabolismo , Bacterias/metabolismo , Oxidorreductasas/metabolismo , DesnitrificaciónRESUMEN
Genomic profiling has identified therapeutic targets for precision treatment of certain cancers, but many patients lack actionable mutations. Additional omics approaches, like proteomics and phosphoproteomics, are essential for comprehensive mapping of cancer-associated molecular phenotypes. In vivo models, such as cell line and patient-derived xenografts (PDX), offer valuable insights into cancer biology and treatment strategies.This chapter presents a semiautomated high-throughput workflow for integrated proteomics and phosphoproteomics analysis on the Kingfish platform coupled with MagReSyn® Zr-IMAC HP. It enhances protein extraction from in vivo xenograft samples and provides better insights into cancers with poor prognosis. The approach successfully identified over 11,000 unique phosphosites and ~6000 proteins in SJSA-1 pediatric osteosarcoma xenografts, demonstrating its efficacy. This workflow is a valuable tool for studying tumor biology and developing precision oncology strategies.
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Biomarcadores de Tumor , Fosfoproteínas , Proteómica , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Proteómica/métodos , Biomarcadores de Tumor/metabolismo , Ratones , Fosfoproteínas/metabolismo , Línea Celular Tumoral , Neoplasias/metabolismo , Neoplasias/patología , Osteosarcoma/metabolismo , Osteosarcoma/patología , NiñoRESUMEN
Objective: Closed-suction drains are commonly placed after thoracolumbar surgery to reduce the risk of post-operative hematoma and neurologic deterioration, and may stay in place for a longer period of time if output remains high. Prolonged maintenance of surgical site drains, however, is associated with an increased risk of surgical site infection (SSI). The present study aims to examine the literature regarding extended duration (≥24 h) prophylactic antibiotic use in patients undergoing posterior thoracolumbar surgery with closed-suction drainage. Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Relevant studies reporting the use of 24-h post-operative antibiotics compared with extended duration post-operative antibiotics in patients undergoing posterior thoracolumbar surgery with closed-suction drainage were identified from a PubMed database query. Results: Six studies were included for statistical analysis, encompassing 1003 patients that received 24 h of post-operative antibiotics and 984 patients that received ≥24 h of post-operative antibiotics. The SSI rate was 5.16 % for the shorter duration group (24 h) and 4.44 % (p = 0.7865) for the longer duration group (≥24 h). Conclusions: There is no significant difference in rates of SSI in patients receiving 24 h of post-operative antibiotics compared with patients receiving ≥24 h of post-operative antibiotics. Shorter durations of post-operative antibiotics in patients with thoracolumbar drains have similar outcomes compared to patients receiving longer courses of antibiotics. Shorter durations of antibiotics could potentially help lead to lower overall cost and length of stay for these patients.
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Wastewater-based epidemiology (WBE) has become a valuable tool for monitoring the prevalence of SARS-CoV-2 on university campuses. However, concerns about effectiveness of raw sewage as a COVID-19 early warning system still exist, and it's not clear how useful normalization by simultaneous comparison of Pepper Mild Mottle Virus (PMMoV) is in addressing variations resulting from fecal discharge dilution. This study aims to contribute insights into these aspects by conducting an academic-year field trial at the student residences on the University of Tennessee, Knoxville campus, raw sewage. This was done to investigate the correlations between SARS-CoV-2 RNA load, both with and without PMMoV normalization, and various parameters, including active COVID-19 cases, self-isolations, and their combination among all student residents. Significant positive correlations between SARS-CoV-2 RNA load a week prior, during the monitoring week, and the subsequent week with active cases. Despite these correlations, normalization by PMMoV does not enhance these associations. These findings suggest the potential utility of SARS-CoV-2 RNA load as an early warning indicator and provide valuable insights into the application and limitations of WBE for COVID-19 surveillance specifically within the context of raw sewage on university campuses.
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Acute allograft rejection is a well-known complication of liver transplantation (LT). The incidence, epidemiology, and outcomes of acute rejection have not been well described in Australia. We retrospectively studied consecutive adults who underwent deceased donor LT at a single center between 2010 and 2020. Donor and recipient data at the time of LT and recipient outcomes were collected from a prospective LT database. Liver biopsy reports were reviewed, and only a graft's first instance of biopsy-proven acute rejection was analyzed. During the study period, 796 liver transplants were performed in 770 patients. Biopsy-proven rejection occurred in 34.9% of transplants. There were no significant changes in the incidence of rejection over time (linear trend p =0.11). The median time to the first episode of rejection was 71 days after LT: 2.2% hyperacute, 50.4% early (≤90 d), and 47.5% late rejection (>90 d). Independent risk factors for rejection were younger recipient age at transplant (aHR 0.98 per year increase, 95% CI: 0.97-1.00, p =0.01), and ABO-incompatible grafts (aHR 2.55 vs. ABO-compatible, 95% CI: 1.27-5.09, p <0.01) while simultaneous multiorgan transplants were protective (aHR 0.21 vs. LT only, 95% CI: 0.08-0.58, p <0.01). Development of acute rejection (both early and late) was independently associated with significantly reduced graft (aHR 3.13, 95% CI: 2.21-4.42, p <0.001) and patient survival (aHR 3.42, 95% CI: 2.35-4.98, p <0.001). In this 11-year Australian study, acute LT rejection occurred in 35%, with independent risk factors of younger recipient age and ABO-incompatible transplant, while having a simultaneous multiorgan transplant was protective. Acute rejection was independently associated with reduced graft and patient survival after adjustment for other factors.
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Carbon amendments designed to remediate environmental contamination lead to substantial perturbations when injected into the subsurface. For the remediation of uranium contamination, carbon amendments promote reducing conditions to allow microorganisms to reduce uranium to an insoluble, less mobile state. However, the reproducibility of these amendments and underlying microbial community assembly mechanisms have rarely been investigated in the field. In this study, two injections of emulsified vegetable oil were performed in 2009 and 2017 to immobilize uranium in the groundwater at Oak Ridge, TN, USA. Our objectives were to determine whether and how the injections resulted in similar abiotic and biotic responses and their underlying community assembly mechanisms. Both injections caused similar geochemical and microbial succession. Uranium, nitrate, and sulfate concentrations in the groundwater dropped following the injection, and specific microbial taxa responded at roughly the same time points in both injections, including Geobacter, Desulfovibrio, and members of the phylum Comamonadaceae, all of which are well established in uranium, nitrate, and sulfate reduction. Both injections induced a transition from relatively stochastic to more deterministic assembly of microbial taxonomic and phylogenetic community structures based on 16S rRNA gene analysis. We conclude that geochemical and microbial successions after biostimulation are reproducible, likely owing to the selection of similar phylogenetic groups in response to EVO injection.
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Background: This study aimed to determine whether proton craniospinal irradiation (CSI) decreased the dose to normal tissue and resulted in less toxicity than photon CSI for adult patients. Methods: This single-institution retrospective analyzed differences in radiation doses, acute toxicity, and cost between proton and CSI for adult medulloblastoma patients. Results: Of 39 total patients, 20 were treated with photon CSI prior to 2015, and 19 were treated with proton CSI thereafter. Median age was 28 years (range 18-66). The molecular subtype was most commonly sonic hedgehog (68%). Patients most commonly received 36 Gy CSI in 20 fractions with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to cochleae, lacrimal glands, lens, parotid glands, pharyngeal constrictors, esophagus, lungs, liver, and skin (all Pâ <â .001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% versus 35%, Pâ =â .044) and decreased median weight loss during radiation (+1.0 versus -2.8 kg, Pâ =â .011). Weight loss was associated with acute hospitalization (Pâ =â .009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At the last follow-up, 5 photon patients had died (2 of progressive disease, 3 without recurrence ages 41-63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. Conclusions: This study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.
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BACKGROUND AND OBJECTIVES: Almost one third of cancer patients in the United States will develop brain metastases on an annual basis. Surgical resection is indicated in the setting of brain metastases for reasons, such as maximizing local control in select patients, decompression of mass effect, and/or tissue diagnosis. The current standard of care following resection of a brain metastasis has shifted from whole brain radiation therapy to post-operative stereotactic radiosurgery (SRS). However, there is a significant rate of local recurrence within one year of postoperative SRS. Emerging retrospective and prospective data suggest pre-operative SRS is a safe and potentially effective treatment paradigm for surgical brain metastases. This trial intends to determine, for patients with an indication for resection of a brain metastasis, whether there is an increase in the time to a composite endpoint of adverse outcomes; including the first occurrence of either: local recurrence, leptomeningeal disease, or symptomatic radiation brain necrosis - in patients who receive pre-operative SRS as compared to patients who receive post-operative SRS. METHODS: This randomized phase III clinical trial compares pre-operative with post-operative SRS for brain metastases. A dynamic random allocation procedure will allocate an equal number of patients to each arm: pre-operative SRS followed by surgery or surgery followed by post-operative SRS. EXPECTED OUTCOMES: If pre-operative SRS improves outcomes relative to post-operative SRS, this will establish pre-operative SRS as superior. If post-operative SRS proves superior to pre-operative SRS, it will remain a standard of care and halt the increasing utilization of pre-operative SRS. If there is no difference in pre- versus post-operative SRS, then pre-operative SRS may still be preferred, given patient convenience and the potential for a condensed timeline. DISCUSSION: Emerging retrospective and prospective data have demonstrated some benefits of pre-op SRS vs. post-op SRS. This study will show whether there is an increase in the time to the composite endpoint. Additionally, the study will compare overall survival; patient-reported outcomes; morbidity; completion of planned therapies; time to systemic therapy; time to regional progression; time to CNS progression; time to subsequent treatment; rate of radiation necrosis; rate of local recurrence; and rate of leptomeningeal disease. TRIAL REGISTRATION NUMBER: NCT03750227 (Registration date: 21/11/2018).
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Neoplasias Encefálicas , Radiocirugia , Humanos , Estudios Retrospectivos , Radiocirugia/métodos , Estudios Prospectivos , Resultado del Tratamiento , Neoplasias Encefálicas/secundario , Necrosis/etiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Fase III como AsuntoRESUMEN
The PEAK family of pseudokinases, comprising PEAK1-3, are signalling scaffolds that play oncogenic roles in several poor prognosis human cancers, including triple negative breast cancer (TNBC). However, therapeutic targeting of pseudokinases is challenging due to their lack of catalytic activity. To address this, we screened for PEAK1 effectors by affinity purification and mass spectrometry, identifying calcium/calmodulin-dependent protein kinase 2 (CAMK2)D and CAMK2G. PEAK1 promoted CAMK2D/G activation in TNBC cells via a novel feed-forward mechanism involving PEAK1/PLCγ1/Ca 2+ signalling and direct binding via a consensus CAMK2 interaction motif in the PEAK1 N-terminus. In turn, CAMK2 phosphorylated PEAK1 to enhance association with PEAK2, which is critical for PEAK1 oncogenic signalling. To achieve pharmacologic targeting of PEAK1/CAMK2, we repurposed RA306, a second generation CAMK2 inhibitor under pre-clinical development for treatment of cardiovascular disease. RA306 demonstrated on-target activity against CAMK2 in TNBC cells and inhibited PEAK1-enhanced migration and invasion in vitro . Moreover, RA306 significantly attenuated TNBC xenograft growth and blocked metastasis in a manner mirrored by CRISPR-mediated PEAK1 ablation. Overall, these studies establish PEAK1 as a critical cell signalling nexus, identify a novel mechanism for regulation of Ca 2+ signalling and its integration with tyrosine kinase signals, and identify CAMK2 as a therapeutically 'actionable' target downstream of PEAK1.
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Chronic and elevated levels of the antiviral cytokine IFN-α in the brain are neurotoxic. This is best observed in patients with genetic cerebral interferonopathies such as Aicardi-Goutières syndrome. Cerebral interferonopathies typically manifest in early childhood and lead to debilitating disease and premature death. There is no cure for these diseases with existing treatments largely aimed at managing symptoms. Thus, an effective therapeutic strategy is urgently needed. Here, we investigated the effect of antisense oligonucleotides targeting the murine IFN-α receptor (Ifnar1 ASOs) in a transgenic mouse model of cerebral interferonopathy. Intracerebroventricular injection of Ifnar1 ASOs into transgenic mice with brain-targeted chronic IFN-α production resulted in a blunted cerebral interferon signature, reduced neuroinflammation, restoration of blood-brain barrier integrity, absence of tissue destruction, and lessened neuronal damage. Remarkably, Ifnar1 ASO treatment was also effective when given after the onset of neuropathological changes, as it reversed such disease-related features. We conclude that ASOs targeting the IFN-α receptor halt and reverse progression of IFN-α-mediated neuroinflammation and neurotoxicity, opening what we believe to be a new and promising approach for the treatment of patients with cerebral interferonopathies.
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Interferón Tipo I , Enfermedades del Sistema Nervioso , Preescolar , Humanos , Ratones , Animales , Enfermedades Neuroinflamatorias , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/farmacología , Interferón-alfa/genética , Ratones TransgénicosRESUMEN
BACKGROUND & AIMS: FibroScan® Expert 630 and FibroScan® Mini+430 are novel vibration-controlled transient elastography devices equipped with the same SmartExam software, which allows continuous measurement of controlled attenuation parameter (CAP) during the entire examination. This study aims to compare the CAP variabilities and the quantification for liver fibrosis and steatosis between the conventional FibroScan and the SmartExam-equipped machines in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: This retrospective study included 118 patients with biopsy-proven MASLD who underwent liver biopsy at two tertiary centres between 2021 and 2023. Liver stiffness and steatosis measurements were performed using both FibroScan machines and M and XL probes for each individual. Liver histology was used as the reference standard for liver fibrosis and steatosis staging. RESULTS: Standard deviations of continuous CAP (cCAP) were significantly lower than those of CAP for all probes (p < .0001). CAP variability was significantly associated with body mass index (p < .01), probe selection (p < .001) as well as the random effect of centre. Only the effect of probe selection (p < .001) was significantly associated with cCAP variability. No significant difference was found in the performance of staging liver fibrosis and steatosis between two types of machines at the same cut-offs. CONCLUSIONS: The SmartExam-based VCTE reduces the variability of CAP measurement and achieves a similar accuracy as the FibroScan 502 device for the estimation of both hepatic steatosis and fibrosis. Future studies should determine if cCAP is a better tool to monitor changes in steatosis than the original CAP.