Childhood myelodysplastic syndrome: focus on the approach to diagnosis and treatment of juvenile myelomonocytic leukemia.

Expansion of myeloid blasts with suppression of normal hematopoiesis is a hallmark of acute myeloid leukemia (AML). In contrast, myeloproliferative neoplasms (MPNs) are clonal disorders characterized by overproliferation of one or more lineages that retain the ability to differentiate. Juvenile myelomonocytic leukemia (JMML) is an aggressive MPN of childhood that is clinically characterized by the overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung.

Community involvement in the development and feedback about a colorectal cancer screening media campaign in Ohio Appalachia.

A community needs assessment focused on colorectal cancer (CRC) screening knowledge, behaviors, and barriers was completed in one Ohio Appalachia county. A CRC screening media campaign was developed based on the findings from the needs assessment and feedback was obtained about the media campaign. The survey was completed by 170 self-reported average-risk adults.

Environmental enrichment exerts sex-specific effects on emotionality in C57BL/6J mice.

Environmental enrichment (EE) has been shown to exert various behavioral and mood effects in rodents including emotionality, which has a high propensity to be influenced by sex. However, there are only a few comparative studies evaluating the effect of EE and their results are both inconsistent and inconclusive. In the present study, male and female C57BL/6J adolescent mice were housed in either physical enrichment or standard conditions for four weeks with analysis of affective behaviors in the open field, elevated T-maze and forced swim tests.

Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.

CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life.

Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition.

Cancer is influenced by its microenvironment, yet broader, environmental effects also play a role but remain poorly defined. We report here that mice living in an enriched housing environment show reduced tumor growth and increased remission. We found this effect in melanoma and colon cancer models, and that it was not caused by physical activity alone.

Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias.

Background: A pharmacokinetically derived schedule of flavopiridol administered as a 30 min intravenous bolus followed by 4-hour continuous intravenous infusion (IVB/CIVI) is active in fludarabine-refractory chronic lymphocytic leukemia, but no studies examining the feasibility and maximum tolerated dose of this schedule have been reported in acute leukemia.

Design And Methods: We conducted a phase I dose escalation trial of single-agent flavopiridol in adults with relapsed/refractory acute leukemias, utilizing a modification of the intravenous bolus/continuous intravenous infusion approach, intensifying treatment for administration on days 1, 2, and 3 of 21-day cycles.

Results: Twenty-four adults with relapsed/refractory acute myeloid leukemia (n=19) or acute lymphoblastic leukemia (n=5) were enrolled.

Energy restriction as an antitumor target of thiazolidinediones.

Cancer cells gain growth advantages in the microenvironment by shifting cellular metabolism to aerobic glycolysis, the so-called Warburg effect. There is a growing interest in targeting aerobic glycolysis for cancer therapy by exploiting the differential susceptibility of malignant versus normal cells to glycolytic inhibition, of which the proof-of-concept is provided by the in vivo efficacy of dietary caloric restriction and natural product-based energy restriction-mimetic agents (ERMAs) such as resveratrol and 2-deoxyglucose in suppressing carcinogenesis in animal models. Here, we identified thiazolidinediones as a novel class of ERMAs in that they elicited hallmark cellular responses characteristic of energy restriction, including transient induction of Sirt1 (silent information regulator 1) expression, activation of the intracellular fuel sensor AMP-activated protein kinase, and endoplasmic reticulum stress, the interplay among which culminated in autophagic and apoptotic death.

P2X7-mediated chemoprevention of epithelial cancers.

Background: Anti-apoptotic mechanisms contribute to the development of cancer. The purinergic ligand-gated ion channel receptor P2X(7) system is an important pro-apoptosis modulator in epithelial cells, and augmentation of P2X(7)-mediated apoptosis has been proposed as a novel pharmacological modality for chemoprevention and treatment of epithelial cancers.

Objective: This review focuses on the progress towards clinical application of therapies that directly modulate P2X(7)-mediated apoptosis.

PML: An emerging tumor suppressor and a target with therapeutic potential.

Though originally discovered as a tumor suppressor in Acute Promyelocytic Leukemia (APL), the importance of promyelocytic leukemia protein (PML) in cancers of other origins has not been widely studied. Recent studies have shown that multiple types of cancers show decreased expression of PML protein, though the mechanisms leading to this down-regulation are unknown. Decreased expression of PML can result in loss of cell cycle control and prevention of apoptosis and is likely a key event in the promotion of oncogenesis.

Mutations in CBL occur frequently in juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia is an aggressive myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Seventy-five percent of patients harbor mutations in the NF1, NRAS, KRAS, or PTPN11 genes, which encode components of Ras signaling networks. Using single nucleotide polymorphism arrays, we identified a region of 11q isodisomy that contains the CBL gene in several JMML samples, and subsequently identified CBL mutations in 27 of 159 JMML samples.

Papillary carcinoma of the breast lacks evidence of RET rearrangements despite morphological similarities to papillary thyroid carcinoma.

Rare breast neoplasms resembling the tall-cell variant of papillary thyroid carcinoma have been reported. In addition, papillary carcinoma of the breast occasionally displays nuclear features reminiscent of papillary thyroid carcinoma. In this study, we evaluated 33 intraductal/intracystic papillary carcinomas of the breast for the presence and extent of nuclear overlap, grooves, clearing, and inclusions, as well as features of the tall-cell or columnar-cell variants of papillary thyroid carcinoma.

Targeting promyelocytic leukemia protein: a means to regulating PML nuclear bodies.

The promyelocytic leukemia protein (PML) is involved in many cellular processes including cell cycle progression, DNA damage response, transcriptional regulation, viral infection, and apoptosis. These cellular activities often rely on the localization of PML to unique subnuclear structures known as PML nuclear bodies (NBs). More than 50 cellular proteins are known to traffic in and out of PML NBs, either transiently or constitutively.

Molecular therapy of obesity and diabetes by a physiological autoregulatory approach.

Hypothalamic brain-derived neurotrophic factor (BDNF) is a key element in the regulation of energy balance. Here we investigated the therapeutic efficacy of BDNF by gene transfer in mouse models of obesity and diabetes. Gene transfer of BDNF led to marked weight loss and alleviation of obesity-associated insulin resistance.

Sall2 is a novel p75NTR-interacting protein that links NGF signalling to cell cycle progression and neurite outgrowth.

By screening a fetal brain two-hybrid library with the death domain of the p75 neurotrophin receptor (NTR), we identified the Sall2 transcription factor as a novel interacting protein. Sall2 is a unique member of the Sall gene family, which is believed to be a tumour suppressor. Here, we show that Sall2 contains a p75NTR interaction domain not found in other Sall proteins and that p75NTR/Sall2 complexes co-immunoprecipitate from brain lysates.

PTPROt inactivates the oncogenic fusion protein BCR/ABL and suppresses transformation of K562 cells.

Chronic myelogenous leukemia is typified by constitutive activation of the c-abl kinase as a result of its fusion to the breakpoint cluster region (BCR). Because the truncated isoform of protein-tyrosine phosphatase receptor-type O (PTPROt) is specifically expressed in hematopoietic cells, we tested the possibility that it could potentially dephosphorylate and inactivate the fusion protein bcr/abl. Ectopic expression of PTPROt in the chronic myelogenous leukemia cell line K562 indeed resulted in hypophosphorylation of bcr/abl and reduced phosphorylation of its downstream targets CrkL and Stat5, confirming that PTPROt could inactivate the function of bcr/abl.

NOD-like receptors: role in innate immunity and inflammatory disease.

The NOD-like receptors (NLRs) are a specialized group of intracellular receptors that represent a key component of the host innate immune system. Since the discovery of the first NLR almost 10 years ago, the study of this special class of microbial sensors has burgeoned; consequently, a better understanding of the mechanism by which these receptors recognize microbes and other danger signals and of how they activate inflammatory signaling pathways has emerged. Moreover, in addition to their primary role in host defense against invading pathogens, their ability to regulate nuclear factor-kappa B (NF-kappaB) signaling, interleukin-1-beta (IL-1beta) production, and cell death indicates that they are crucial to the pathogenesis of a variety of inflammatory human diseases.

G4 resolvase 1 binds both DNA and RNA tetramolecular quadruplex with high affinity and is the major source of tetramolecular quadruplex G4-DNA and G4-RNA resolving activity in HeLa cell lysates.

Quadruplex structures that result from stacking of guanine quartets in nucleic acids possess such thermodynamic stability that their resolution in vivo is likely to require specific recognition by specialized enzymes. We previously identified the major tetramolecular quadruplex DNA resolving activity in HeLa cell lysates as the gene product of DHX36 (Vaughn, J. P.

Ovarian cancer.

Ovarian carcinomas are a heterogeneous group of neoplasms and are traditionally subclassified based on type and degree of differentiation. Although current clinical management of ovarian carcinoma largely fails to take this heterogeneity into account, it is becoming evident that each major histological type has characteristic genetic defects that deregulate specific signaling pathways in the tumor cells. Moreover, within the most common histological types, the molecular pathogenesis of low-grade versus high-grade tumors appears to be largely distinct.

Central review of cytogenetics is necessary for cooperative group correlative and clinical studies of adult acute leukemia: the Cancer and Leukemia Group B experience.

The Cancer and Leukemia Group B has performed central review of karyotypes submitted by institutional cytogenetics laboratories from patients with acute myeloid (AML) and acute lymphoblastic (ALL) leukemia since 1986. We assessed the role of central karyotype review in maintaining accurate, high quality cytogenetic data for clinical and translational studies using two criteria: the proportion of karyotypes rejected (i.e.

The inflammatory microenvironment of the aging prostate facilitates cellular proliferation and hypertrophy.

Benign Prostatic Hypertrophy (BPH, also known as benign prostatic hyperplasia or benign prostatic enlargement), is one of the most common benign proliferative conditions associated with aging in men and is pathologically characterized by the proliferation of fibroblast/myofibroblast and epithelial cell types in the prostate. Previous studies from our laboratory have shown that the CXC-type chemokines, CXCL5 and CXCL12, are secreted by aging prostate stroma and promote both proliferative and transcriptional responses from prostate epithelial cells. Using array-based gene expression profiling and quantitative reverse-transcriptase polymerase chain reaction, we now show that the transcriptome of the aging prostate stroma is characterized by the up-regulation of several genes that encode secreted inflammatory mediators, including secreted CXC-type chemokines (CXCL1, CXCL2, CXCL5, CXCL6, CXCL12), interleukins (IL11, IL33), and transcripts with cytokine homology (CYTL1).

Multiple mechanisms contribute to inhibit transcription in response to DNA damage.

Cellular DNA damage elicits the phosphorylation and ubiquitination of RNA polymerase II (RNAPII), leading to the global repression of transcription. In this report we show that there are at least two different pathways to transcriptional repression, depending on the type of DNA damage. After H2O2 treatment, transcription was rapidly inhibited and rapidly restored.

Recent developments in taxane drug delivery.

Paclitaxel (taxol, 1a) and docetaxel (taxotere, 1b) have established themselves as an important class of antitumor drugs currently available to the oncologist. While the great contribution of these drugs to the management of the disease and their effect on the improvement of the patient quality of life could not be overemphasized, a great deal of research has been ongoing to improve two key pharmacologic factors, antitumor activity and systemic toxicity. Both physical and chemical means have been employed towards the enhancement of antitumor activity and at the same time, lowering the inherent toxicity and side effects of these drugs.

In situ detection of precursor and mature microRNAs in paraffin embedded, formalin fixed tissues and cell preparations.

The in situ detection of microRNAs (miRs) expression offers several challenges. It would be advantageous to have a method which can be used in paraffin embedded, formalin fixed tissue to be able to access the large data bank of archival material. Further, it would be helpful if one could differentiate between precursor and mature, active forms of the miR.