Αναζήτηση αυτού του ιστολογίου

Τετάρτη 4 Ιανουαρίου 2023

Integrative systems immunology uncovers molecular networks of the cell cycle that stratify COVID‐19 severity

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Abstract

Several perturbations in the number of peripheral blood leukocytes, such as neutrophilia and lymphopenia associated with Coronavirus disease 2019 (COVID-19) severity, point to systemic molecular cell cycle alterations during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, the landscape of cell cycle alterations in COVID-19 remains primarily unexplored. Here, we performed an integrative systems immunology analysis of publicly available proteome and transcriptome data to characterize global changes in the cell cycle signature of COVID-19 patients. We found significantly enriched cell cycle-associated gene co-expression modules and an interconnected network of cell cycle-associated differentially expressed proteins (DEPs) and genes (DEGs) by integrating the molecular data of 1,469 individuals (981 SARS-CoV-2 infected patients and 488 controls [either healthy controls or individuals with other respiratory illnesses]). Among these DEPs and DEGs are seve ral cyclins (CCNs), cell division cycles (CDCs), cyclin-dependent kinases (CDKs), and mini-chromosome maintenance (MCMs) proteins. COVID-19 patients partially shared the expression pattern of some cell cycle-associated genes with other respiratory illnesses but exhibited some specific differential features. Notably, the cell cycle signature predominated in the patients' blood leukocytes (B, T, and NK cells) and was associated with COVID-19 severity and disease trajectories. These results provide a unique global understanding of distinct alterations in cell cycle-associated molecules in COVID-19 patients, suggesting new putative pathways for therapeutic intervention.

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Birth weight, gestational age and risk of cardiovascular disease in early adulthood: Influence of familial factors

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Abstract
The association between intrauterine growth restriction (IUGR) and cardiovascular disease (CVD) later in life might be confounded by familial factors. We conducted a bi-national register-based cohort study to assess associations of birthweight for gestational age (GA), a proxy for IUGR, and GA with CVD risk in early adulthood, before and after addressing familial factors via sibling comparison. We included 3,410,334 live non-malformed singleton births in Sweden (1973-1996) and Denmark (1978-1998). During a median follow-up of 10 years from age 18 onwards, 29,742 individuals developed incident CVD (hypertensive, ischemic heart, and cerebrovascular diseases). Compared with individuals born with appropriate birthweight for GA (AGA, 10th-90th percentiles) or full term (39-40 gestational weeks), individuals born severely small for GA (SGA, <3rd percentile) or preterm (22-36 weeks) were at increased risk of CVD [HRs (95% CIs): 1.38 (1.32-1.45) and 1 .31 (1.25-1.38), respectively]. The association was attenuated when comparing individuals born SGA with their AGA siblings (1.11, 0.99-1.25), but remained robust when comparing individuals born preterm with their term siblings (1.21, 1.07-1.37). Our findings suggest that both SGA and preterm birth are associated with CVD risk in early adulthood, with greater familial confounding noted for SGA.
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Τρίτη 3 Ιανουαρίου 2023

Mutation-associated transcripts reconstruct the prognostic features of oral tongue squamous cell carcinoma

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International Journal of Oral Science, Published online: 03 January 2023; doi:10.1038/s41368-022-00210-3

Mutation-associated transcripts reconstruct the prognostic features of oral tongue squamous cell carcinoma
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Automating the treatment planning process for 3D‐conformal pediatric craniospinal irradiation therapy

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Abstract

Purpose

Pediatric patients with medulloblastoma in low- and middle-income countries (LMICs) are most treated with 3D-conformal photon craniospinal irradiation (CSI), a time-consuming, complex treatment to plan, especially in resource-constrained settings. Therefore, we developed and tested a 3D-conformal CSI autoplanning tool for varying patient lengths.

Methods and materials

Autocontours were generated with a deep learning model trained:tested (80:20 ratio) on 143 pediatric medulloblastoma CT scans (patient ages: 2–19 years, median = 7 years). Using the verified autocontours, the autoplanning tool generated two lateral brain fields matched to a single spine field, an extended single spine field, or two matched spine fields. Additional spine subfields were added to optimize the corresponding dose distribution. Feathering was implemented (yielding nine to 12 fields) to give a composite plan. Each planning approach was tested on six patients (ages 3–10 years). A pediatric radiation oncologist assessed clinical acceptability of each autoplan.

Results

The autocontoured structures' average Dice similarity coefficient ranged from .65 to .98. The average V95 for the brain/spinal canal for single, extended, and multi-field spine configurations was 99.9% ± 0.06%/99.9% ± 0.10%, 99.9% ± 0.07%/99.4% ± 0.30%, and 99.9% ± 0.06%/99.4% ± 0.40%, respectively. The average maximum dose across all field configurations to the brainstem, eyes (L/R), lenses (L/R), and spinal cord were 23.7 ± 0.08, 24.1 ± 0.28, 13.3 ± 5.27, and 25.5 ± 0.34 Gy, respectively (prescription = 23.4 Gy/13 fractions). Of the 18 plans tested, all were scored as clinically acceptable as-is or clinically acceptable with minor, time-efficient edits preferred or required. No plans were scored as clinically unacceptable.

Conclusion

The autoplanning tool successfully generated pediatric CSI plans for varying patient lengths in 3.50 ± 0.4 minutes on average, indicating potential for an efficient planning aid in a resource-constrained settings.

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Promising applications of human-derived saliva biomarker testing in clinical diagnostics

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International Journal of Oral Science, Published online: 04 January 2023; doi:10.1038/s41368-022-00209-w

Promising applications of human-derived saliva biomarker testing in clinical diagnostics
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Temporal Trends in Variability of Respirable Dust and Respirable Quartz Concentrations in the European Industrial Minerals Sector

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Abstract
While between- and within-worker variability have been studied quite extensively, hardly any research is available that examines long-term trends in the variability of occupational exposure. In this first study on trends in occupational exposure variability temporal changes in the variability of respirable dust and respirable quartz concentrations within the European industrial minerals sector were demonstrated. Since 2000 the European Industrial Minerals Association's Dust Monitoring Program (IMA-DMP) has systematically collected respirable dust and respirable quartz measurements. The resulting IMA-DMP occupational exposure database contains at present approximately 40 000 personal full-shift measurements, collected at 177 sites owned by 39 companies, located in 23 European countries. Repeated measurements of workers performing their duties within a specific site-job-campaign combination allowed estimation of within- and between-worker variabi lity in exposure concentrations. Overall day-to-day variability predominated the between-worker variability for both respirable dust concentrations and quartz concentrations. The within-worker variability in concentrations by job was two to three times higher for respirable quartz than for respirable dust. The median between-worker variability in respirable dust concentrations was low and further reduced over time. For quartz concentrations the same phenomenon albeit somewhat less strong was observed. In contrast, for the within-worker variability in concentrations downward and upward temporal trends were apparent for both respirable dust and respirable quartz. The study shows that the (relative) size of temporal variability is large and unpredictable and therefore regular measurement campaigns are needed to ascertain compliance to occupational exposure limit values.
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Δευτέρα 2 Ιανουαρίου 2023

Deferoxamine mesylate enhances mandibular advancement‐induced condylar osteogenesis by promoting H‐type angiogenesis

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Background

The effect of functional orthopedic treatment for mandibular deficiency relies on mandibular advancement (MA)-induced condylar new bone formation. However, this is not easy to achieve, especially in non-growing patients. Therefore, how to obtain reliable MA-induced condylar osteogenesis is much worthy of studying.

Objective

To investigate whether deferoxamine mesylate (DFM) enhances MA-induced condylar osteogenesis in middle-aged mice.

Methods

Forty 30-week-old male C57BL/6J mice were randomly divided into 4 groups: the control (Ctrl), DFM, MA+Ctrl, and MA+DFM groups. After a 4-week experimental period, femurs, tibias, and condyles were collected for morphological, micro-computed tomography, and histological evaluation.

Results

For long bones, DFM reversed osteoporosis in middle-aged mice by promoting H-type angiogenesis. For mandibular condyles, MA promoted condylar osteogenesis in middle-aged mice, thereby allowing the mandible to achieve a stable protruding position. In addition, DFM enhanced the volume and quality of MA-induced condylar new bone formation. Furthermore, histological analysis revealed that DFM enhanced MA-induced condylar subchondral ossification. Mechanistically, it was confirmed that DFM increased the number of H-type vessels and their coupled Osterix+ osteoprogenitors by up-regulating the hypoxia-inducible factor (HIF)-1α signaling pathway, thereby enhancing MA-induced condylar osteogenesis.

Conclusion

Applying DFM to enhance MA-induced condylar osteogenesis through H-type angiogenesis is expected to be an effective strategy to achieve favorable functional orthopedic treatment effectiveness in non-growing patients.

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Small Molecule-mediated Disruption of Ribosome Biogenesis Synergizes With FGFR Inhibitors to Suppress Glioma Cell Growth

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Abstract
Background
High-grade gliomas are malignant brain tumors characterized by aggressiveness and resistance to chemotherapy. Prognosis remains dismal, highlighting the need to identify novel molecular dependencies and targets. Ribosome biogenesis (RiBi), taking place in the nucleolus, represents a promising target as several cancer types rely on high RiBi rates to sustain proliferation. Publicly available transcriptomics data of glioma patients revealed a positive correlation between RiBi rates and histological grades. We, therefore, hypothesized that glioma cells could be susceptible to RiBi inhibition.
Methods
Transcriptomics data from glioma patients were analyzed for RiBi-related processes. BMH-21, a small molecule inhibitor of RNA polI transcription, was tested in adult and pediatric high-grade glioma cell lines and a zebrafish transplant model. Cellular phenotypes were evaluated by transcriptomics, cell cycle analysis, and vi ability assays. A chemical synergy screen was performed to identify drugs potentiating BMH-21-mediated effects.
Results
BMH-21 reduced glioma cell viability, induced apoptosis, and impaired the growth of transplanted glioma cells in zebrafish. Combining BMH-21 with TMZ potentiated cytotoxic effects. Moreover, BMH-21 synergized with FGFR inhibitor Erdafitinib, a top hit in the chemical synergy screen. RiBi inhibition using BMH-21, POLR1A siRNA, or Actinomycin D revealed engagement of the FGFR-FGF2 pathway. BMH-21 downregulated FGFR1 and SOX2 levels, whereas FGF2 was induced and released from the nucleolus.
Conclusions
This study conceptualizes the implementation of RiBi inhibition as a viable future therapeutic strategy for glioma and reveals an FGFR connection to the cellular response upon RiBi inhibition with potential translational value.
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Wnt Signaling Regulates MFSD2A-dependent Drug Delivery through Endothelial Transcytosis in Glioma

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
Systemic delivery of anti-tumor therapeutic agents to brain tumors is thwarted by the blood-brain barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). A failure of pharmacological compounds to cross BBB is one culprit for the dismal prognosis of glioblastoma (GBM) patients. Identification of novel vascular targets to overcome the challenges posed by the BBB in tumors for GBM treatment is urgently needed.
Methods
Temozolomide (TMZ) delivery was investigated in CT2A and PDGFB-driven RCAS/tv-a orthotopic glioma models. Transcriptome analysis was performed on ECs from murine gliomas. Mfsd2a deficient, Cav1 deficient and Mfsd2a EC specific inducible mice were developed to study the underlying molecular mechanisms.
Results
We demonstrated that inhibiting Wnt signaling by LGK974 could increase TMZ delivery and sensitize glioma to chemotherapy in both murine glioma models. Transcriptome analysis of ECs from murine gliomas revealed that Wnt signaling inhibition enhanced vascular transcytosis as indicated by the upregulation of PLVAP and downregulation of MSFD2A. Mfsd2a deficiency in mice enhances TMZ delivery in tumors, whereas constitutive expression of Mfsd2a in ECs suppresses the enhanced TMZ delivery induced by Wnt pathway inhibition in murine glioma. In addition, Wnt signaling inhibition enhanced caveolin-1 (Cav1)-positive caveolae-mediated transcytosis in tumor ECs. Moreover, Wnt signaling inhibitor or Mfsd2a deficiency fails to enhance TMZ penetration in tumors from Cav1-deficient mice.
Conclusions
These results demonstrated that Wnt signaling regulates MFSD2A-dependent TMZ deli very through a caveolae-mediated EC transcytosis pathway. Our findings identify Wnt signaling as a promising therapeutic target to improve drug delivery for GBM treatment.
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Κυριακή 1 Ιανουαρίου 2023

H‐Type Tracheoesophageal Fistula Cannulation for Rapid Intraoperative Localization

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H-Type Tracheoesophageal Fistula Cannulation for Rapid Intraoperative Localization

Various techniques for tracheoesophageal fistula cannulation have been reported. In this case, we created a loop using a plastic catheter. The loop allowed us to create traction for rapid intraoperative localization and to pull a difficult-to-reach fistula, superiorly into the neck, to be reached through a cervical approach. Laryngoscope, 2022


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