Pediatric High Risk Leukemia — Molecular Insights

Acute leukemia comprises of 31% of all cancers in children making it the most common childhood malignancy. Significant strides have been made in treatment, partly through risk stratification and intensified therapy. A number of subtypes remain at high risk for relapse and poor outcome, despite current therapies. Here we describe risk stratification and molecular diagnosis used to identify high risk leukemias and guide treatment. Specific cytogenetic alterations that contribute to high risk B and T cell acute lymphoblastic leukemia (ALL), as well as infant leukemia are discussed. Particular attention is given to genetic alterations in IKZF1, CRLF2, and JAK, that have been identified by whole genome sequencing and recently associated with Ph-like ALL. Ongoing studies of disease mechanisms and challenges in developing pre-clinical patient-derived xenograft models to evaluate therapies are discussed

Purdue Improved Crop Storage (PICS) bags for safe storage of groundnuts

Groundnut seeds are prone to quality deterioration and damage due to improper storage. Hermetic storage of pods offers a novel, sustainable and ecologically safe alternative over traditional methods. In this paper, we demonstrate the efficacy of triple-layer “Purdue Improved Crop Storage (PICS)” bags, (that comprises of two inner high density polyethylene bags and one outer woven polypropylene bag), for protecting pods from quality deterioration, damage by bruchids (Caryedon serratus) and aflatoxin contamination (Aspergillus flavus). Custom made triple-layer bags were used and pods (of cv ICGV 91114) were placed @ 2 kg/bag. Over four months of storage under ambient conditions, triple-layer bags supported retention of seed weight, germinability and oil content significantly better than cloth bags. Further, under both natural and artificial infestations with A. flavus, seed aflatoxins levels were lower in PICS bags compared to cloth bags. Toxin accumulation in PICS bags deliberately infested with bruchids and A. flavus was less compared to cloth bags under similar conditions. Bruchid damage to pods was less in PICS bags versus cloth bags in all cases. Our results suggest the superiority of triple-layer PICS bags over cloth bags in protecting seed viability, seed weight and oil content while safeguarding the groundnuts from bruchids and retarding toxin accumulation

Neuroblastoma - Current State and Recent Updates

Neuroblastoma (NBL) is the most common extracranial solid tumor of childhood, with about 700 new cases of neuroblastoma seen each year in the United States. The 5-year survival rate for children with high-risk NBL is only 50-60%, and this survival rate has not improved over the last 10 years. High-risk patients receive multimodality treatment, including chemotherapy, surgery, radiation therapy, biologic therapy and immunotherapy, all of which are associated with significant morbidity. Recent years have seen many advances in treatment of neuroblastoma, including therapeutic MIBG, immunotherapy, and personalized targeted therapy based on the genetic alterations seen in the tumor. The primary objective of this book is to provide the readers with a comprehensive review of neuroblastoma, from clinical aspects and the currently available treatment to recent advancements and future directions in the field of NBL treatment. The topics and chapters have been compiled keeping in mind a diverse group of readers in different areas of specialty such as pediatric oncology, surgery, radiation oncology, and immunology, as well as physician scientists and basic researchers working in the field of neuroblastoma

Genetic differences among teak clones of Karnataka

Many breeding strategies have been used in India to overcome constraints on teak regeneration and establish good clonal orchards (Nautlyal & Rawat 1994, Bagchi 1995). Several methods have been used to select and identify clones for further breeding programmes. These include morphometric methods (Kedarnath 1963, Bagchi 1995), isoenzyme methods (Kumaravelu 1979, Balasubramanian & Kumaravelu 1981, Ananthapadmanabha et. a/1989) and relative resistance to parasites (Bagchi & Emmanuel 1983, Mukthar Ahmed 1987, Meshram et. a/. 1994). There are many teak clones in India. Around 40 teak clones are being used in Karnataka for breeding programmes. The present study screens 23 of these clones with the following objectives: 1.) To establish differences between clones with respect to their fruit and seed traits. 2.) To examine if the differences measured by the above traits are reflected in the overall genetic make up of the clones. 3.) To indicate if the clones with similar traits have predictable banding patterns and 4.) To identify unique clones for future breeding programmes

Chronic Generalized Lymphadenopathy in a Child—Progressive Transformation of Germinal Centers (PTGC)

Background: Enlarged lymph nodes are a common complaint in a Pediatrician’s office. Diagnosis of reactive lymphadenopathy secondary to infectious, inflammatory, immune dysregulation calls for clinical investigation, including a thorough history, physical exam, imaging, and less often, a biopsy of the lymph node. Here we discuss a rare presentation of extensive generalized, chronic, waxing, and waning lymphadenopathy diagnosed as Progressive Transformation of Germinal Centers (PTGC) and the course of illness over eight years follow up period. Discussion: Progressive Transformation of Germinal Centers (PTGC) is considered a benign condition, but extensive recurrent generalized lymphadenopathy in a very young child has not been reported before. This case demonstrates the importance of long-term follow-up and tailoring the diagnostic work-up and management based on new signs and symptoms. Here we focus on the clinical considerations and management of complex presentation of a common clinical finding

Regulation of Small GTPase Rab20 by Ikaros in B-Cell Acute Lymphoblastic Leukemia

Ikaros is a DNA-binding protein that regulates gene expression and functions as a tumor suppressor in B-cell acute lymphoblastic leukemia (B-ALL). The full cohort of Ikaros target genes have yet to be identified. Here, we demonstrate that Ikaros directly regulates expression of the small GTPase, Rab20. Using ChIP-seq and qChIP we assessed Ikaros binding and the epigenetic signature at the RAB20 promoter. Expression of Ikaros, CK2, and RAB20 was determined by qRT-PCR. Overexpression of Ikaros was achieved by retroviral transduction, whereas shRNA was used to knockdown Ikaros and CK2. Regulation of transcription from the RAB20 promoter was analyzed by luciferase reporter assay. The results showed that Ikaros binds the RAB20 promoter in B-ALL. Gain-of-function and loss-of-function experiments demonstrated that Ikaros represses RAB20 transcription via chromatin remodeling. Phosphorylation by CK2 kinase reduces Ikaros’ affinity toward the RAB20 promoter and abolishes its ability to repress RAB20 transcription. Dephosphorylation by PP1 phosphatase enhances both Ikaros’ DNA-binding affinity toward the RAB20 promoter and RAB20 repression. In conclusion, the results demonstrated opposing effects of CK2 and PP1 on expression of Rab20 via control of Ikaros’ activity as a transcriptional regulator. A novel regulatory signaling network in B-cell leukemia that involves CK2, PP1, Ikaros, and Rab20 is identified

Association analysis of CAG repeats at the KCNN3 locus in Indian patients with bipolar disorder and schizophrenia

Bipolar affective disorder and schizophrenia are severe behavioral disorders with a lifetime risk of \sim 1% in the population worldwide. There is evidence that these diseases may manifest the phenomenon of anticipation similar to that seen in diseases caused by trinucleotide repeat expansions. A recent report has implicated a potassium channel-coding gene, KCNN3, which contains a polymorphic CAG repeat in its coding region, in schizophrenia and bipolar disorder. We have tried to confirm these findings in Indian patients suffering from bipolar disorder and schizophrenia. No statistically significant evidence for the presence of an excess of longer alleles in the patient population, as compared to ethnically matched controls, was found. However, an analysis of the difference of allele sizes revealed a significantly greater number of patients with schizophrenia having differences of allele sizes \geq 5 when compared to normal controls. This finding may be of functional significance as the KCNN3 protein is thought to act as a tetramer, and a large difference in allele sizes would result in an asymmetric molecule with a different number of glutamine residues in each monomer

Mechanistic Basis for In Vivo Therapeutic Efficacy of CK2 Inhibitor CX-4945 in Acute Myeloid Leukemia

Protein Kinase CK2 (Casein Kinase 2 or CK2) is a constitutively active serine-threonine kinase overactive in human malignancies. Increased expression and activity of CK2 in Acute Myeloid Leukemia (AML) is associated with a poor outcome. CK2 promotes AML cell survival by impinging on multiple oncogenic signaling pathways. The selective small-molecule CK2 inhibitor CX-4945 has shown in vitro cytotoxicity in AML. Here, we report that CX-4945 has a strong in vivo therapeutic effect in preclinical models of AML. The analysis of genome-wide DNA-binding and gene expression in CX-4945 treated AML cells shows that one mechanism, by which CK2 inhibition exerts a therapeutic effect in AML, involves the revival of IKAROS tumor suppressor function. CK2 phosphorylates IKAROS and disrupts IKAROS’ transcriptional activity by impairing DNA-binding and association with chromatin modifiers. Here, we demonstrate that CK2 inhibition decreases IKAROS phosphorylation and restores IKAROS binding to DNA. Further functional experiments show that IKAROS negatively regulates the transcription of anti-apoptotic genes, including BCL-XL (B cell Lymphoma like–2 like 1, BCL2L1). CX-4945 restitutes the IKAROS-mediated repression of BCL-XL in vivo and sensitizes AML cells to apoptosis. Using CX-4945, alongside the cytotoxic chemotherapeutic drug daunorubicin, augments BCL-XL suppression and AML cell apoptosis. Overall, these results establish the in vivo therapeutic efficacy of CX-4945 in AML preclinical models and determine the role of CK2 and IKAROS in regulating apoptosis in AML. Furthermore, our study provides functional and mechanistic bases for the addition of CK2 inhibitors to AML therapy