Oncotarget

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A subset of thyroid cancers present at advanced stage or with dedifferentiated histology and have limited response to standard therapy. Tumors harboring the BRAF V600E mutation may be treated with BRAF inhibitors; however, tumor response is often short lived due to multiple compensatory resistance mechanisms. One mode of resistance is the transition to an alternative cell state, which on rare occasions can correspond to tumor dedifferentiation. DNA sequencing and RNA expression profiling show that thyroid tumors that dedifferentiate after BRAF inhibition are enriched in known genetic alterations that mediate resistance to BRAF blockade, and may also drive tumor dedifferentiation, including mutations in the PI3K/AKT/MTOR ( PIK3CA , MTOR ), MAP/ERK ( MET , NF2 , NRAS , RASA1 ), SWI/SNF chromatin remodeling complex ( ARID2 , PBRM1 ), and JAK/STAT pathways ( JAK1 )...

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Oligodendrocyte precursor markers have become of great interest to identify new diagnostic and therapeutic targets for diffuse gliomas, since state-of-the-art studies point towards immature oligodendrocytes as a possible source of gliomagenesis. Brain enriched myelin associated protein 1 (BCAS1) is a novel marker of immature oligodendrocytes and was proposed to contribute to tumorigenesis in non-central nervous system tumors. However, BCAS1 role in diffuse glioma is still underexplored. This study analyzes the expression of BCAS1 in different tumor samples from patients with diffuse gliomas (17 oligodendrogliomas; 8 astrocytomas; 60 glioblastomas) and uncovers the molecular and ultrastructural features of BCAS1+ cells by immunostaining and electron microscopy...

Glioblastoma cells can restrict the DNA-damaging effects of temozolomide (TMZ) and radiation therapy (RT) using the DNA damage response (DDR) mechanism which activates cell cycle arrest and DNA repair pathways. Ataxia-telangiectasia and Rad3-Related protein (ATR) plays a pivotal role in the recognition of DNA damage induced by chemotherapy and radiation causing downstream DDR activation. Here, we investigated the activity of gartisertib, a potent ATR inhibitor, alone and in combination with TMZ and/or RT in 12 patient-derived glioblastoma cell lines...

Multiple Myeloma (MM) is the second most common hematological malignancy and is characterized by clonal expansion of malignant plasma cells in the bone marrow. In spite of recent advances in the field of MM, the disease has remained incurable. MM is preceded by a premalignant state known as monoclonal gammopathy of undetermined significance (MGUS), with a risk of progression to MM of 1% per year. Establishing a scalable approach that refines the identification of MGUS patients at high risk of progression to MM can transform the clinical management of the disease, improve the patient's quality of life, and will have significant socioeconomic implications...

Osimertinib has been shown to be effective for patients with non-small cell lung cancer (NSCLC) with activating EGFR mutations, and these patients are at risk for leptomeningeal disease. In this report, we present a patient of East Asian descent whose initial presentation included severe, progressive leptomeningeal carcinomatosis and a small lung mass, with limited tissue available for molecular testing. She responded to empiric, urgent initiation of osimertinib, repeat tissue sampling revealed an EGFR L858R mutation, and she has experienced durable disease improvement for 18 months on osimertinib monotherapy...

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No abstract text is available yet for this article.

Transformation-associated recombination (TAR) cloning represents a unique tool to selectively and efficiently recover a given chromosomal segment up to several hundred kb in length from complex genomes (such as animals and plants) and simple genomes (such as bacteria and viruses). The technique exploits a high level of homologous recombination in the yeast Sacharomyces cerevisiae . In this review, we summarize multiple applications of the pioneering TAR cloning technique, developed previously for complex genomes, for functional, evolutionary, and structural studies, and extended the modified TAR versions to isolate biosynthetic gene clusters (BGCs) from microbes, which are the major source of pharmacological agents and industrial compounds, and to engineer synthetic viruses with novel properties to design a new generation of vaccines...

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To evade cell cycle controls, malignant cells rely upon rapid expression of select proteins to mitigate proapoptotic signals resulting from damage caused by both cancer treatments and unchecked over-proliferation. Cyclin-dependent kinase 9 (CDK9)-dependent signaling induces transcription of downstream oncogenes promoting tumor growth, especially in hyperproliferative 'oncogene-addicted' cancers, such as human hematological malignancies (HHMs). GFH009, a potent, highly selective CDK9 small molecule inhibitor, demonstrated antiproliferative activity in assorted HHM-derived cell lines, inducing apoptosis at IC50 values below 0...

The history of studies of melatonin effects on cancer in mice is outlined, the main lesson being that the systemic in vivo effects of melatonin on animals may overwhelm the in vitro effects found using tissue explants or cell cultures. In particular, the timing of melatonin administration is of crucial importance for using the drug, which is freely available over counter and thus needs no licensing for its applications in oncology.

Classic Hodgkin lymphoma (CHL), which accounts for 90-95% of all cases of Hodgkin lymphoma, is the most frequent cancer in adolescents and the most frequent lymphoma in adolescents and young adults. Despite progressive improvements over past decades and the general sensitivity of CHL to frontline chemotherapy, approximately 10-15% of patients have refractory disease that either does not respond to such therapy or progresses after an initial partial response. In patients with refractory or relapsed disease, standard treatment until recently consisted mainly of salvage chemotherapy, in many cases followed by high-dose chemotherapy and autologous stem-cell transplantation...

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No abstract text is available yet for this article.

In myeloma patients, high levels of soluble BCMA (sBCMA) can limit the efficacy of BCMA-directed therapies. Belantamab-mafodotin is a BCMA antibody-drug conjugate and shows good overall response rates in heavily pretreated patients but progression-free survival data are poor. As the drug induces apoptosis, we hypothesized that sBCMA includes extracellular vesicles (EV) and thus evaluated numbers of BCMA-EV before and during belantamab therapy in 10 myeloma patients. BCMA-EV were significantly higher in patients prior to Belantamab (median: 3227/μl; p = ...

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No abstract text is available yet for this article.

Metastasizing cells display a unique metabolism, which is very different from the Warburg effect that arises in primary tumors. Over short time frames, oxidative phosphorylation and ATP generation are prominent. Over longer time frames, mitochondrial biogenesis becomes a pronounced feature and aids metastatic success. It has not been known whether or how these two phenomena are connected. We hypothesized that Osteopontin splice variants, which synergize to increase ATP levels in deadherent cells, also increase the mitochondrial mass via the same signaling mechanisms...