Summary The lactate dehydrogenase-A (LDH-A) enzyme catalyzes the inter-conversion of pyruvate and lactate, is upregulated in human cancers and is associated with aggressive tumor outcomes. Here we use a novel inducible murine model and demonstrate that inactivation of LDH-A in mouse models of NSCLC driven by oncogenic K-RAS or EGFR leads to decreased tumorigenesis and disease regression in established tumors. We also show that abrogation of LDH-A results in reprogramming of pyruvate metabolism, with decreased lactic fermentation in vitro, in vivo, and ex vivo. This was accompanied by re-activation of mitochondrial function in vitro but not in vivo or ex vivo. Finally, using a specific small molecule LDH-A inhibitor, we demonstrated that LDH-A is essential for cancer initiating cell survival and proliferation. Thus, LDH-A can be a viable therapeutic target for NSCLC including cancer stem cell-dependent drug resistant tumors.

Object. Tarlov or perineurial cysts are lesions of the nerve root most often found in the sacral region. Although there is agreement that asymptomatic Tarlov cysts should be followed, it is still debated whether patients with symptomatic Tarlov cysts should be treated surgically. The authors assessed the outcome and efficacy of cyst wall resection in 10 patients with symptomatic Tarlov cysts. The medical literature is reviewed, theories of origin are evaluated, and suggestions as to their cause and pathogenesis are offered. Methods. Ten consecutive patients harboring symptomatic Tarlov cysts were treated by the senior author between 1989 and 1999. All patients were assessed for neurological deficits and pain by neurological examination and visual analog scale, respectively. Computerized tomography myelography was performed in all patients to diagnose delayed filling of the cysts. A sacral laminectomy with resection of the sacral cyst or cysts was performed in all patients. Resected material from eight of 10 patients was submitted for histopathological evaluation. Seven (70%) of 10 patients obtained complete or substantial resolution of their symptoms, with an average follow up of 31.7 months. All of these patients had Tarlov cysts larger than 1.5 cm in diameter, producing radicular pain or bladder and bowel dysfunction. Three (30%) of 10 patients experienced no significant improvement. All three patients harbored Tarlov cysts smaller than 1.5 cm in diameter, producing nonradicular pain. Histopathological examination was performed on specimens from eight of 10 patients, which demonstrated nerve fibers in 75% of cases, ganglion cells in 25% of cases, and evidence of old hemorrhage in half. Conclusions. Large cysts (> 1.5 cm) and the presence of associated radicular symptoms strongly correlate with excellent outcome. Tarlov cysts may result from increased hydrostatic pressure and trauma.

SUMMARY Mutations in the metabolic enzymes isocitrate dehydrogenase-1 (IDH1) and IDH2 that produce the oncometabolite D-2-hydroxyglutarate (2-HG) occur frequently in human acute myeloid leukemia (AML). 2-HG modulates numerous biological pathways implicated in malignant transformation, but the contribution of mutant IDH proteins to maintenance and progression of AML in vivo is currently unknown. To answer this crucial question we have generated transgenic mice that express IDH2R140Q in an on/ off- and tissue-specific manner using a tetracycline-inducible system. We found that IDH2R140Q can cooperate with overexpression of HoxA9 and Meis1a and with mutations in FMS-like tyrosine kinase 3 (FLT3) to drive acute leukemia in vivo. Critically, we show that genetic deinduction of mutant IDH2 in leukemic cells in vivo has profound effects on their growth and/or maintenance. Our data demonstrate the proto-oncogenic role of mutant IDH2 and support its relevance as a therapeutic target for the treatment of human AML.

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Background We sought to determine the prevalence of JCV in bone marrow samples from HIV-positive and HIV-negative patients and whether the bone marrow is a site of latency and neurotropic transformation of JC virus, the agent of progressive multifocal leukoencephalopathy(PML). Methods We collected bone marrow aspirates, archival bone marrow, blood, and urine samples from 75 HIV-negative and 47 HIV-positive patients without PML, as well as bone marrow, and urine or kidney samples from 8 HIV-negative and 15 HIV-positive patients with PML. Samples were tested for JCV DNA by quantitative PCR and JCV protein expression by immunohistochemistry. JCV regulatory regions (RR) were characterized by sequencing. Results JCV DNA was detected in bone marrow specimens of 10/75(13%) of HIV-negative, and 22/47 (47%) of HIV-positive patients without PML, but in 3/8(38%) HIV-negative and 4/15(27%) HIV-positive patients with PML. JCV DNA(2-1081 cps/μg cellular DNA) was detected in multiple leukocyte subpopulations of blood and bone marrow samples. JCV large T antigen, but not VP1 capsid protein, was expressed in bone marrow plasma cells. Bone marrow JCV RR sequences were similar to those usually found in brain of PML patients. Conclusions The bone marrow is an important reservoir and possible site of neurotropic transformation for JCV.

The polyomavirus JC (JCV) is the etiologic agent of Progressive Multifocal Leukoencephalopathy (PML). JCV remains quiescent in kidneys, where it displays a stable archetypal regulatory region (RR). Conversely, rearranged JCV RR, including tandem repeat patterns found in the CNS of PML patients, have been associated with neurovirulence. The precise site and mechanism of JCV RR transformation is unknown. We present herein a patient with Rheumatoid Arthritis treated with methotrexate, who developed PML and had a rapid fatal outcome. JCV DNA PCR was positive in CSF, bone marrow, blood and urine. Double immunohistochemistry staining demonstrated that 9% of bone marrow CD138 + plasma-cells sustained productive infection by JCV, accounting for 94% of JCV-infected cells. JCV RR analysis revealed archetype and rearranged RR forms in bone marrow, while RR with tandem repeat was predominant in blood. These results suggest that the bone marrow may be a potential site of JCV pathogenic transformation. Further studies will be needed to determine the prevalence of JCV in bone marrow of immunosuppressed individuals at risk of PML and characterize the RR and phenotype of these JCV isolates.

• MUC1-C oncoprotein contributes toward maintenance of redox balance in CTCL.• Targeting the MUC1-C oncoprotein in CTCL cells induces ROS-mediated death highlighting its potential as an effective strategy.Cutaneous T-cell lymphoma (CTCL) is an aggressive neoplasm with limited treatments for patients with advanced disease. The mucin 1 C-terminal subunit (MUC1-C) oncoprotein plays a critical role in regulating cell proliferation, apoptosis, and protection from cytotoxic injury mediated by reactive oxygen species (ROS). Although CTCL cells exhibit resistance to ROS-induced apoptosis, the expression and functional significance of MUC1 in CTCL have not been previously investigated. Present studies demonstrate that MUC1-C is overexpressed in CTCL cell lines and primary CTCL cells but is absent in resting T cells from healthy donors and B-cell lymphoma cells. We have developed a cell-penetrating peptide that disrupts homodimerization of the MUC1-C subunit necessary for its nuclear translocation and downstream signaling. We show that treatment of CTCL cells with the MUC1-C inhibitor is associated with downregulation of the p53-inducible regulator of glycolysis and apoptosis and decreases in reduced NAD phosphate and glutathione levels. In concert with these results, targeting MUC1-C in CTCL cells increased ROS and, in turn, induced ROS-mediated late apoptosis/necrosis. Targeting MUC1-C in CTCL tumor xenograft models demonstrated significant decreases in disease burden. These findings indicate that MUC1-C maintains redox balance in CTCL cells and is thereby a novel target for the treatment of patients with CTCL. (Blood. 2015;126(3):354-362)

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