Chemotherapeutic Activity of Pitavastatin in Vincristine Resistant B-Cell Acute Lymphoblastic Leukemia.

B-cell acute lymphoblastic leukemia (ALL) is derived from an accumulation of malignant, immature B cells in the bone marrow and blood. Relapse due, in part, to the emergence of tumor cells that are resistant to front line standard chemotherapy is associated with poor patient outcomes. This challenge highlights the need for new treatment strategies to eliminate residual chemoresistant tumor cells.

Characterization of complex fluvial-deltaic deposits in Northeast India using Poisson impedance inversion and non-parametric statistical technique.

Characterizing complex fluvial-deltaic deposits is a challenging task for finding hydrocarbon discoveries. We described a methodology for predicting the hydrocarbon zones from complex well-log and prestack seismic data. In this current study, data analysis involves an integrated framework based on Simultaneous prestack seismic inversion (SPSI), target correlation coefficient analysis (TCCA), Poisson impedance inversion, and non-parametric statistical analysis, and Bayesian classification.

Pitavastatin Is Anti-Leukemic in a Bone Marrow Microenvironment Model of B-Lineage Acute Lymphoblastic Leukemia.

The lack of complete therapeutic success in the treatment of B-cell acute lymphoblastic leukemia (ALL) has been attributed, in part, to a subset of cells within the bone marrow microenvironment that are drug resistant. Recently, the cholesterol synthesis inhibitor, pitavastatin (PIT), was shown to be active in acute myeloid leukemia, prompting us to evaluate it in our in vitro co-culture model, which supports a chemo-resistant ALL population. We used phospho-protein profiling to evaluate the use of lipid metabolic active compounds in these chemo-resistant cells, due to the up-regulation of multiple active survival signals.

Co-culture model of B-cell acute lymphoblastic leukemia recapitulates a transcription signature of chemotherapy-refractory minimal residual disease.

B-cell acute lymphoblastic leukemia (ALL) is characterized by accumulation of immature hematopoietic cells in the bone marrow, a well-established sanctuary site for leukemic cell survival during treatment. While standard of care treatment results in remission in most patients, a small population of patients will relapse, due to the presence of minimal residual disease (MRD) consisting of dormant, chemotherapy-resistant tumor cells. To interrogate this clinically relevant population of treatment refractory cells, we developed an in vitro cell model in which human ALL cells are grown in co-culture with human derived bone marrow stromal cells or osteoblasts.

Recurrent DHA nephropathy in renal allograft-revisiting clinicopathological aspects of a rare entity.

Background: Adenine phosphoribosyltransferase (APRT) enzyme deficiency is a rare autosomal recessive disorder of purine metabolism affecting mainly the kidneys. It can present at any age with varying degrees of acute and chronic renal damage. Though xanthine dehydrogenase inhibitors offer effective control over the disease process, delay in diagnosis and treatment often lead to compromised function of native and even graft kidneys.

Misleading Focal Clinical, Neurophysiologic, and Imaging Features in 2 Children With Generalized Epilepsy Who Underwent Invasive Electroencephalographic (EEG) Monitoring.

Children and adults with genetic generalized epilepsy may have focal clinical seizure symptoms as well as electroencephalographic (EEG) findings. This may pose a diagnostic challenge to clinicians, especially when concomitant focal neuroimaging findings exist and the epilepsy is medically refractory. We sought to highlight the challenges that clinicians may face through the description of 2 children with suspected genetic generalized epilepsy who had both focal seizure symptoms and EEG/neuroimaging findings and underwent invasive EEG monitoring.

Pyrvinium Pamoate Use in a B cell Acute Lymphoblastic Leukemia Model of the Bone Tumor Microenvironment.

Purpose: Pyrvinium pamoate (PP) is an anthelmintic drug that has been found to have anti-cancer activity in several cancer types. In the present study, we evaluated PP for potential anti-leukemic activity in B cell acute lymphoblastic leukemia (ALL) cell lines, in an effort to evaluate the repurposing potential of this drug in leukemia.

Methods: ALL cells were treated with PP at various concentrations to determine its effect on cell proliferation.

The MitoNEET Ligand NL-1 Mediates Antileukemic Activity in Drug-Resistant B-Cell Acute Lymphoblastic Leukemia.

Disease relapse in B-cell acute lymphoblastic leukemia (ALL), either due to development of acquired resistance after therapy or because of de novo resistance, remains a therapeutic challenge. In the present study, we have developed a cytarabine (Ara-C)-resistant REH cell line (REH/Ara-C) as a chemoresistance model. REH/Ara-C 1) was not crossresistant to vincristine or methotrexate; 2) showed a similar proliferation rate and cell surface marker expression as parental REH; 3) demonstrated decreased chemotaxis toward bone marrow stromal cells; and 4) expressed higher transcript levels of cytidine deaminase () and mitoNEET () than the parental REH cell line.

Crystal structure of the mitochondrial protein mitoNEET bound to a benze-sulfonide ligand.

MitoNEET (gene ) is a mitochondrial outer membrane [2Fe-2S] protein and is a potential drug target in several metabolic diseases. Previous studies have demonstrated that mitoNEET functions as a redox-active and pH-sensing protein that regulates mitochondrial metabolism, although the structural basis of the potential drug binding site(s) remains elusive. Here we report the crystal structure of the soluble domain of human mitoNEET with a sulfonamide ligand, furosemide.

Single-fraction radiation: A promising adjuvant therapy to prevent keloid recurrence.

Introduction: Keloids are characterized by collection of atypical fibroblasts with excessive deposition of extracellular matrix components. Keloids are prone to high recurrence (50%-80%) with unimodality treatment. Radiation is a promising approach among the adjuvant modalities in vogue though consensus is lacking on dose-fractionation schedule.

Combination of cabazitaxel and plicamycin induces cell death in drug resistant B-cell acute lymphoblastic leukemia.

Bone marrow microenvironment mediated downregulation of BCL6 is critical for maintaining cell quiescence and modulating therapeutic response in B-cell acute lymphoblastic leukemia (ALL). In the present study, we have performed a high throughput cell death assay using BCL6 knockdown REH ALL cell line to screen a library of FDA-approved oncology drugs. In the process, we have identified a microtubule inhibitor, cabazitaxel (CAB), and a RNA synthesis inhibitor, plicamycin (PLI) as potential anti-leukemic agents.

Novel compounds that target lipoprotein lipase and mediate growth arrest in acute lymphoblastic leukemia.

Over the past decade, the therapeutic strategies employed to treat B-precursor acute lymphoblastic leukemia (ALL) have been progressively successful in treating the disease. Unfortunately, the treatment associated dyslipidemia, either acute or chronic, is very prevalent and a cause for decreased quality of life in the surviving patients. To overcome this hurdle, we tested a series of cylopropanecarboxamides, a family demonstrated to target lipid metabolism, for their anti-leukemic activity in ALL.

Actinomycin D Down-regulates SOX2 Expression and Induces Death in Breast Cancer Stem Cells.

Background/aim: One of the major hurdles in the treatment of breast cancers is the inability of anti-cancer drugs to eliminate the breast cancer stem cells (BCSCs) population, which leads to disease relapse. The dearth in anti-cancer drugs that target BCSCs can be attributed to the absence of in vitro screening models that can not only recapitulate the tumor microenvironment consisting of BCSCs but also preserve the 3-dimensional (3D) architecture of in vivo tumors.

Materials And Methods: In our present study, we have developed a 3D cell culture system that shows: (i) enrichment of BCSCs, (ii) increased drug resistance, and (iii) generation of hypoxic conditions similar to tumors.

Stable and Potent Selenomab-Drug Conjugates.

Selenomabs are engineered monoclonal antibodies with one or more translationally incorporated selenocysteine residues. The unique reactivity of the selenol group of selenocysteine permits site-specific conjugation of drugs. Compared with other natural and unnatural amino acid and carbohydrate residues that have been used for the generation of site-specific antibody-drug conjugates, selenocysteine is particularly reactive, permitting fast, single-step, and efficient reactions under near physiological conditions.

Surface Acoustic Waves (SAW)-Based Biosensing for Quantification of Cell Growth in 2D and 3D Cultures.

Detection and quantification of cell viability and growth in two-dimensional (2D) and three-dimensional (3D) cell cultures commonly involve harvesting of cells and therefore requires a parallel set-up of several replicates for time-lapse or dose-response studies. Thus, developing a non-invasive and touch-free detection of cell growth in longitudinal studies of 3D tumor spheroid cultures or of stem cell regeneration remains a major unmet need. Since surface acoustic waves (SAWs) permit mass loading-based biosensing and have been touted due to their many advantages including low cost, small size and ease of assembly, we examined the potential of SAW-biosensing to detect and quantify cell growth.

MTI-101 (cyclized HYD1) binds a CD44 containing complex and induces necrotic cell death in multiple myeloma.

Our laboratory recently reported that treatment with the d-amino acid containing peptide HYD1 induces necrotic cell death in multiple myeloma cell lines. Because of the intriguing biological activity and promising in vivo activity of HYD1, we pursued strategies for increasing the therapeutic efficacy of the linear peptide. These efforts led to a cyclized peptidomimetic, MTI-101, with increased in vitro activity and robust in vivo activity as a single agent using two myeloma models that consider the bone marrow microenvironment.

Nail-patella syndrome-a novel mutation in the LMX1B gene.

Nail-patella syndrome (NPS) is an autosomal-dominant pleiotropic disorder characterized by dyplasia of finger nails, skeletal anomalies and frequently renal disease. In the reported case, genetic analysis revealed a new missense mutation in the homeodomain of LMX1B, presumed to abolish DNA binding (c.725T>C, p.

Emerging strategies for targeting cell adhesion in multiple myeloma.

Multiple myeloma (MM) is an incurable hematological cancer involving proliferation of abnormal plasma cells that infiltrate the bone marrow (BM) and secrete monoclonal antibodies. The disease is clinically characterized by bone lesions, anemia, hypercalcemia, and renal failure. MM is presently treated with conventional therapies like melphalan, doxorubicin, and prednisone; or novel therapies like thalidomide, lenalidomide, and bortezomib; or with procedures like autologous stem cell transplantation.

Role of STAT3 in Transformation and Drug Resistance in CML.

Chronic myeloid leukemia (CML) is initially driven by the bcr-abl fusion oncoprotein. The identification of bcr-abl led to the discovery and rapid translation into the clinic of bcr-abl kinase inhibitors. Although, bcr-abl inhibitors are efficacious, experimental evidence indicates that targeting bcr-abl is not sufficient for elimination of minimal residual disease found within the bone marrow (BM).

Potentiation of Nilotinib-mediated cell death in the context of the bone marrow microenvironment requires a promiscuous JAK inhibitor in CML.

In this study, we show that conditioned media (CM) generated from bone marrow (BM)-derived mesenchymal stromal cells lead to BCR-ABL independent STAT3 activation. Activation of STAT3 is important not only for survival of CML cells but also for its protection against Nilotinib (NI), within the BM microenvironment. Reducing the expression of both JAK2 and TYK2 or utilizing a pan-JAK inhibitor blocked CM-mediated STAT3 activation and sensitized CML cells to NI-mediated cell death.

Acquisition of resistance toward HYD1 correlates with a reduction in cleaved α4 integrin expression and a compromised CAM-DR phenotype.

We recently reported that the β1 integrin antagonist, referred to as HYD1, induces necrotic cell death in myeloma cell lines as a single agent using in vitro and in vivo models. In this article, we sought to delineate the determinants of sensitivity and resistance toward HYD1-induced cell death. To this end, we developed an HYD1 isogenic resistant myeloma cell line by chronically exposing H929 myeloma cells to increasing concentrations of HYD1.

Influence of the anion on the electrical conductivity and glass formation of 1-butyl-3-methylimidazolium ionic liquids.

Six ionic liquids based on the 1-butyl-3-methylimidazolium cation have been studied. As anions Cl(-), Br(-), I(-), [NCS](-), [N(CN)(2)](-), and [BF(4)](-) were selected. The electrical conductivities were determined between 173 and 393 K based on impedance measurements in the frequency range from 0.

The bone marrow microenvironment as a sanctuary for minimal residual disease in CML.

Bcr-abl kinase inhibitors have provided proof of principal that targeted therapy holds great promise for the treatment of cancer. However, despite the success of these agents in treating chronic myelogenous leukemia (CML), the majority of patients continue to present with minimal residual disease contained within the bone marrow microenvironment. These clinical observations suggest that the bone marrow microenvironment may provide survival signals that contribute to the failure to eliminate minimal residual disease.