TERT and BRAF V600E mutations in thyroid cancer of World Trade Center Responders.

The 2-fold excess thyroid cancer risk reported in multiple World Trade Center (WTC) disaster exposed cohorts cannot entirely be explained by surveillance and physician bias thus highlighting the need to investigate the potential consequences of the dust exposure, containing carcinogenic and endocrine disruptive elements, on the thyroid. This study investigated the presence of TERT promoter and BRAF V600E mutations in 20 WTC-exposed versus 23 matched non-exposed thyroid cancers as potential mechanism explaining the excess risk. Although no significant difference in BRAF V600E mutation was found, TERT promoter mutations were significantly more prevalent in WTC thyroid cancer versus non-exposed thyroid cancers (P = 0.

Mebendazole Treatment Disrupts the Transcriptional Activity of Hypoxia-Inducible Factors 1 and 2 in Breast Cancer Cells.

Breast cancer is the most diagnosed cancer in women in the world. Mebendazole (MBZ) has been demonstrated to have preclinical efficacy across multiple cancers, including glioblastoma multiforme, medulloblastoma, colon, breast, pancreatic, and thyroid cancers. MBZ was also well tolerated in a recent phase I clinical trial of adults diagnosed with glioma.

Mebendazole prevents distant organ metastases in part by decreasing ITGβ4 expression and cancer stemness.

Breast cancer is the most diagnosed cancer among women. Approximately 15-20% of all breast cancers are highly invasive triple-negative breast cancer (TNBC) and lack estrogen, progesterone, and ERBB2 receptors. TNBC is challenging to treat due to its aggressive nature with far fewer targeted therapies than other breast cancer subtypes.

Neutrophil depletion enhanced the -NT therapy in mouse and rabbit tumor models.

Background: Hypoxia is a prominent feature of solid tumors and can function as fertile environment for oncolytic anaerobic bacteria such as -NT (-NT) where it can induce tumor destruction in mice and patients. However, two major obstacles have limited its use, namely the host inflammatory response and the incomplete clearance of normoxic tumor areas.

Methods: In this study, we first used a subcutaneous tumor model of a glioblastoma (GBM) cell line in immunocompetent mice to investigate the local distribution of tumor hypoxia, kinetics of -NT germination and spread, and the local host immune response.

Evaluation of a DNA demethylating agent in combination with all-trans retinoic acid for IDH1-mutant gliomas.

Background: Isocitrate Dehydrogenase 1/2 (IDH1/2) mutations are diagnostic for Astrocytoma or Oligodendroglioma, IDH-mutant. In these IDH-mutant gliomas, retinoic acid-related gene expression is commonly silenced by DNA hypermethylation. DNA demethylating agents can epigenetically reprogram IDH-mutant cells and reduce proliferation, likely by re-expression of silenced tumor suppressor pathways.

Impact of international research fellows in neurosurgery: results from a single academic center.

Objective: International research fellows have been historically involved in academic neurosurgery in the United States (US). To date, the contribution of international research fellows has been underreported. Herein, the authors aimed to quantify the academic output of international research fellows in the Department of Neurosurgery at The Johns Hopkins University School of Medicine.

Mebendazole disrupts stromal desmoplasia and tumorigenesis in two models of pancreatic cancer.

The five-year survival rate for metastatic pancreatic cancer is currently only 3%, which increases to 13% with local invasion only and to 39% with localized disease at diagnosis. Here we evaluated repurposed mebendazole, an approved anthelminthic drug, to determine how mebendazole might work at the different stages of pancreatic cancer formation and progression. We asked if mebendazole could prevent initiation of pancreatic intraepithelial neoplasia precursor lesions, interfere with stromal desmoplasia, or suppress tumor growth and liver metastasis.

Evaluation of a procaspase-3 activator with hydroxyurea or temozolomide against high-grade meningioma in cell culture and canine cancer patients.

Background: High-grade meningioma is an aggressive type of brain cancer that is often recalcitrant to surgery and radiotherapy, leading to poor overall survival. Currently, there are no FDA-approved drugs for meningioma, highlighting the need for new therapeutic options, but development is challenging due to the lack of predictive preclinical models.

Methods: To leverage the known overexpression of procaspase-3 in meningioma, PAC-1, a blood-brain barrier penetrant procaspase-3 activator, was evaluated for its ability to induce apoptosis in meningioma cells.

Post-9/11 excess risk of thyroid cancer: Surveillance or exposure?

An excess risk of thyroid cancer has been reported in different World Trade Center (WTC)-dust exposed cohorts. Increased surveillance of these cohorts has been suggested as a potential explanation of this reported excess thyroid cancer risk leading to an increased diagnosis of earlier-stage thyroid cancers. However, the uncertainty to what extent surveillance or physician bias may be contributing to the reported incidence of thyroid cancer in WTC-dust exposed populations remains, highlighting the need to investigate a potential causal link between WTC dust exposure and thyroid cancer.

The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling.

Background: Metabolic reprogramming is a common feature in cancer, and it is critical to facilitate cancer cell growth. and mutations (mut) are the most common genetic alteration in glioma grade II and III and secondary glioblastoma and these mutations increase reliance on glutamine metabolism, suggesting a potential vulnerability. In this study, we tested the hypothesis that the brain penetrant glutamine antagonist prodrug JHU-083 reduces glioma cell growth.

Mebendazole and temozolomide in patients with newly diagnosed high-grade gliomas: results of a phase 1 clinical trial.

Background: Mebendazole is an anthelmintic drug introduced for human use in 1971 that extends survival in preclinical models of glioblastoma and other brain cancers.

Methods: A single-center dose-escalation and safety study of mebendazole in 24 patients with newly diagnosed high-grade gliomas in combination with temozolomide was conducted. Patients received mebendazole in combination with adjuvant temozolomide after completing concurrent radiation plus temozolomide.

Preventative Effect of Mebendazole against Malignancies in Neurofibromatosis 1.

Patients with RASopathy Neurofibromatosis 1 (NF1) are at a markedly increased risk of the development of benign and malignant tumors. Malignant tumors are often recalcitrant to treatments and associated with poor survival; however, no chemopreventative strategies currently exist. We thus evaluated the effect of mebendazole, alone or in combination with cyclooxygenase-2 (COX-2) inhibitors, on the prevention of NF1-related malignancies in a (NPcis) mouse model of NF1.

A role for caveola-forming proteins caveolin-1 and CAVIN1 in the pro-invasive response of glioblastoma to osmotic and hydrostatic pressure.

In solid tumours, elevated interstitial fluid pressure (osmotic and hydrostatic pressure) is a barrier to drug delivery and correlates with poor prognosis. Glioblastoma (GBM) further experience compressive force when growing within a space limited by the skull. Caveolae are proposed to play mechanosensing roles, and caveola-forming proteins are overexpressed in GBM.

Matrix protease production, epithelial-to-mesenchymal transition marker expression and invasion of glioblastoma cells in response to osmotic or hydrostatic pressure.

Both hydrostatic and osmotic pressures are altered in the tumour microenvironment. Glioblastoma (GBM) is a brain tumour with high invasiveness and poor prognosis. We hypothesized that physical and osmotic forces regulate glioblastoma (GBM) invasiveness.

Mebendazole inhibits tumor growth and prevents lung metastasis in models of advanced thyroid cancer.

The most common thyroid malignancy is papillary thyroid cancer. While a majority respond to therapy and have a favorable prognosis, some papillary thyroid cancers persist. This subset may dedifferentiate to anaplastic thyroid cancer, an aggressive, highly invasive and rapidly fatal cancer.

Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors.

Neurofibromatosis type 1, including the highly aggressive malignant peripheral nerve sheath tumors (MPNSTs), is featured by the loss of functional neurofibromin 1 (NF1) protein resulting from genetic alterations. A major function of NF1 is suppressing Ras activities, which is conveyed by an intrinsic GTPase-activating protein-related domain (GRD). In this study, we explored the feasibility of restoring Ras GTPase via exogenous expression of various GRD constructs, via gene delivery using a panel of adeno-associated virus (AAV) vectors in MPNST and human Schwann cells (HSCs).

Molecular Study of Thyroid Cancer in World Trade Center Responders.

Thyroid cancer incidence is higher in World Trade Center (WTC) responders compared with the general population. It is unclear whether this excess in thyroid cancer is associated with WTC-related exposures or if instead there is an over-diagnosis of malignant thyroid cancer among WTC first responders due to enhanced surveillance and physician bias. To maximize diagnostic yield and determine the false positive rate for malignancy, the histological diagnoses of thyroid cancer tumors from WTC responders and age, gender, and histology matched non-WTC thyroid cancer cases were evaluated using biomarkers of malignancy.

Correlation of the invasive potential of glioblastoma and expression of caveola-forming proteins caveolin-1 and CAVIN1.

Introduction: Glioblastoma (GBM) is the most common primary brain cancer. The average survival time for the majority of patients is approximately 15 months after diagnosis. A major feature of GBM that contributes to its poor prognosis is its high invasiveness.

G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma.

Mutational inactivation of ATRX (α-thalassemia mental retardation X-linked) represents a defining molecular alteration in large subsets of malignant glioma. Yet the pathogenic consequences of ATRX deficiency remain unclear, as do tractable mechanisms for its therapeutic targeting. Here we report that ATRX loss in isogenic glioma model systems induces replication stress and DNA damage by way of G-quadruplex (G4) DNA secondary structure.

Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome.

Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases. Here we report that atrial natriuretic peptide can protect mice from CRS induced by such agents by reducing the levels of circulating catecholamines. Catecholamines were found to orchestrate an immunodysregulation resulting from oncolytic bacteria and lipopolysaccharide through a self-amplifying loop in macrophages.

Traps and trumps from adjacent-to-tumor samples in gastric cancer research.

The search for cancer biomarkers is frequently based on comparisons between tumors and adjacent-to-tumor samples. However, even after histological confirmation of been free of cancer cells, these adjacent-to-tumor samples might harbor molecular alterations which are not sufficient to cause them to look like cancer, but can differentiate these cells from normal cells. When comparing them, potential biomarkers are missed, and mainly the opportunity of finding initial aberrations presents in both tumors and adjacent samples, but not in true normal samples from non-cancer patients, resulting in misinterpretations about the carcinogenic process.

Mebendazole and radiation in combination increase survival through anticancer mechanisms in an intracranial rodent model of malignant meningioma.

Purpose: Meningiomas are a frequent tumor of the central nervous system. Although mostly benign, approximately 5% present as atypical or malignant tumors. Treatments for atypical meningiomas include gross total resection and radiotherapy, but about 33% of patients have recurrent tumors, sometimes as a higher grade.

Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma.

Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), a small molecule DNA alkylating agent, remains the standard-of-care for glioblastoma (GBM). TMZ has an unusual mode-of-action, spontaneously converting to its active component via hydrolysis in vivo. While TMZ has been FDA approved for two decades, it provides little benefit to patients whose tumors express the resistance enzyme MGMT and gives rise to systemic toxicity through myelosuppression.