Distinct IDH1/2-associated Methylation Profile and Enrichment of and Mutations Distinguish Dedifferentiated Chondrosarcoma from Conventional Chondrosarcoma.

Unlabelled: Dedifferentiated chondrosarcoma (DDCS) is a rare high-grade chondrosarcoma characterized by a well-differentiated chondrosarcoma (WDCS) component that abruptly transitions to a high-grade, noncartilaginous sarcomatous component. To date, the molecular pathogenesis of DDCS and its distinction from conventional chondrosarcoma remain poorly understood. By targeted sequencing, we examined the mutational and copy-number profiles of 18 DDCS, including macrodissected WDCS components, compared with 55 clinically sequenced conventional chondrosarcomas.

Malignancies in Pleural, Peritoneal, and Pericardial Effusions.

Context.—: The incidence and types of malignancies in effusion cytology are largely limited to studies performed in the 1970s through the 1990s.

Objective.

Ovarian Torsion in an Adolescent with Beckwith-Wiedemann Syndrome and Unilateral Tubo-ovarian Hyperplasia.

Background: Beckwith-Wiedemann syndrome (BWS) is the most common pediatric overgrowth syndrome. BWS has a broad phenotypic presentation along with an increased propensity to develop various embryonal tumors. There are very few reported cases of gonadal hyperplasia in BWS patients in the existing literature.

Utility of Sry-Related HMG-Box Gene 10 (SOX10) as a marker of melanoma in effusion cytology.

Background: The cytodiagnosis of melanoma in effusions can be challenging. Although immunohistochemical (IHC) stains such as HMB45, Melan A, and S-100 are often utilized; the role of Sry-related HMG-box gene 10 (SOX10) in the diagnosis of melanoma in effusions has not been previously reported.

Methods: A total of 14 confirmed melanoma cases diagnosed on effusion cytology (nine pleural and five peritoneal) were collected from 2000 to 2016.

Candida pneumonia with severe clinical course, recovery with antifungal therapy and unusual pathologic findings: A case report.

Background: Candida is frequently isolated from the respiratory tract and usually reflects airway colonization. True Candida pneumonia is rare. Our aim is to document a case of Candida pneumonia confirmed by cultures, molecular techniques, and surgical lung biopsy, and to highlight a previously unreported pathologic manifestation of this infection.

Hypoxia sensing through -adrenergic receptors.

Life-sustaining responses to low oxygen, or hypoxia, depend on signal transduction by HIFs, but the underlying mechanisms by which cells sense hypoxia are not completely understood. Based on prior studies suggesting a link between the β-adrenergic receptor (β-AR) and hypoxia responses, we hypothesized that the β-AR mediates hypoxia sensing and is necessary for HIF-1α accumulation. Beta blocker treatment of mice suppressed hypoxia induction of renal HIF-1α accumulation, erythropoietin production, and erythropoiesis in vivo.

Pharmacological Targeting of the Histone Chaperone Complex FACT Preferentially Eliminates Glioblastoma Stem Cells and Prolongs Survival in Preclinical Models.

The nearly universal recurrence of glioblastoma (GBM) is driven in part by a treatment-resistant subpopulation of GBM stem cells (GSC). To identify improved therapeutic possibilities, we combined the EGFR/HER2 inhibitor lapatinib with a novel small molecule, CBL0137, which inhibits FACT (facilitates chromatin transcription), a histone chaperone complex predominantly expressed in undifferentiated cells. Lapatinib and CBL0137 synergistically inhibited the proliferation of patient-derived GBM cells.

STAT3-driven transcription depends upon the dimethylation of K49 by EZH2.

Several transcription factors, including p53, NF-κB, and STAT3, are modified by the same enzymes that also modify histones, with important functional consequences. We have identified a previously unrecognized dimethylation of K49 of STAT3 that is crucial for the expression of many IL-6-dependent genes, catalyzed by the histone-modifying enzyme enhancer of zeste homolog 2 (EZH2). Loss of EZH2 is protumorigenic in leukemias, but its overexpression is protumorigenic in solid cancers.

EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells.

Activation of nuclear factor κB (NFκB) is a central event in the responses of normal cells to inflammatory signals, and the abnormal constitutive activation of NFκB is important for the survival of most cancer cells. In nonmalignant human cells, EGF stimulates robust activation of NFκB. The kinase activity of the EGF receptor (EGFR) is required, because the potent and specific inhibitor erlotinib blocks the response.

Quinacrine overcomes resistance to erlotinib by inhibiting FACT, NF-κB, and cell-cycle progression in non-small cell lung cancer.

Erlotinib is a tyrosine kinase inhibitor approved for the treatment of patients with advanced non-small cell lung cancer (NSCLC). In these patients, erlotinib prolongs survival but its benefit remains modest because many tumors express wild-type (wt) EGFR or develop a second-site EGFR mutation. To test drug combinations that could improve the efficacy of erlotinib, we combined erlotinib with quinacrine, which inhibits the FACT (facilitates chromatin transcription) complex that is required for NF-κB transcriptional activity.