Δευτέρα 2 Ιανουαρίου 2023

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

Neurotization of the radial forearm free flap improves swallowing outcomes in hemiglossectomy defects

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Abstract

Background

We examined the effect of free tissue neurotization on speech and swallowing outcomes for patients undergoing reconstruction of hemiglossectomy defects with a radial forearm free flap (RFFF).

Methods

A retrospective study was performed in patients with oral cavity squamous cell carcinoma undergoing a hemiglossectomy and reconstruction with a RFFF. Functional outcomes including nutritional mode, range of liquids and solids, and speech understandability were analyzed 1-year post-treatment.

Results

Eighty-four patients were included in this analysis, 41 of whom had neurotized flaps (49%). No significant differences in demographic or clinical variables were seen between the neurotized and non-neurotized groups. On multivariate analysis controlling for BMI, flap area, and N-classification, patients with neurotized flaps were significantly more likely to have normal range of liquids and solids and less likely to have a G-tube.

Conclusions

Neurotization of RFFF reconstructing hemiglossectomy defects results in decreased G-tube dependence and improved range of liquids and solids.

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Managing Oromandibular Hardware Failure after Free Flap Surgery

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Semin Plast Surg
DOI: 10.1055/s-0042-1760289

Hardware failure after oromandibular reconstruction using free tissue transfer can delay additional therapies directed at cancer treatment and prevent patients from returning to normal oral function. Understanding and strict adherence to principles of rigid fixation is critical in preventing complications. Early surgical intervention for hardware exposure as well as utilization of locoregional flaps may prevent the need for more ex tensive revision surgery.
[...]

Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Stereotactic Partial Breast Irradiation: What Does the Future Hold?

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imageBreast irradiation has evolved significantly over the last several decades. Accelerated partial breast and stereotactic breast irradiation have evolved as strategies to reduce irradiated volumes, preserve appropriate oncologic control, and improve cosmetic outcome. The sequencing and/or combination of stereotactic partial breast irradiation with novel systemic agents is of great interest to the oncologic community. Here we explore the landscape of modern trials and opine on the future of partial breast irradiation.
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Disparities in Survival Outcomes Among Black Patients with HPV‐Associated Oropharyngeal Cancer

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Purpose/Objective

Patients with Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) have been shown to have a favorable prognosis and excellent overall survival, and studies have demonstrated these findings in predominantly White cohorts. Racial/ethnic (R/E) minorities, particularly Black patients, with head and neck squamous cell carcinoma (HNSCC) have worse survival outcomes compared to White patients. In this study, we aimed to determine if Black patients with HPV-OPSCC have a similar favorable prognosis to the White population.

Methods

his was a population based retrospective cohort study that analyzed HNSCC patients using the National Cancer Database from 2010-2016. We identified patients with Stage I-IV HPV-associated OPSCC who were treated with radiation, surgery, chemotherapy, or a combination of modalities. Patient outcomes were stratified by R/E groups including White Versus Black patients. The main outcome in this study was overall survival (OS). Analyses for proportions of categorical variables were performed using a Chi-Square or Fisher's Exact test. Univariate and multivariate time-to-event survival analyses were performed using Kaplan Meier product limit estimates and log-rank test to test the differences between strata. A Cox proportional hazards regression model was used to assess the association between covariates and risk of death (OS).

Results

We identified 9,256 OPSCC patients who met inclusion criteria and were treated between 2010-2016, of which 7,912 were white (85.5%) and 1,344 were Black (14.5%). 1,727 were HPV-OPSCC, of which 1598 were White (92.5%) and 129 (7.5%) were Black. By race, the 5-year OS for White Vs Black OPSCC patients was 42% versus 23%, respectively (log-rank, p<0.0001). Among HPV-Positive OPSCC patients, the 5-year OS for White vs Black patients was 65% versus 39% (log-rank, p<0.0001). Among HPV negative patients the 5-year OS for White vs Black patients was 36% versus 13% (log-rank, p<0.0001). On multivariate analysis, after accounting for age, sex, insurance status, income, Charlson-Deyo score, receipt of surgery, distance from facility, and total treatment time, Black race trended towards, but was not associated with worse survival. (HR:1.24, 95% CI 0.85-1.81, p=0.255)

Conclusions

This national cohort study of OPSCC patients demonstrates that Black patients with HPV-OPSCC have a poor prognosis and overall survival similar to HPV-negative White patients. This may be partly due to socioeconomic barriers such as insurance and income. Further work is needed to better understand the specific drivers of inferior survival outcomes in this specific patient population.

This article is protected by copyright. All rights reserved.

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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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