Bcl2 suppresses DNA repair by enhancing c-Myc transcriptional activity.

Bcl2 and c-Myc are two major oncogenic proteins that can functionally promote DNA damage, genetic instability, and tumorigenesis. However, the mechanism(s) remains unclear. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the most potent carcinogen contained in cigarette smoke that induces cellular DNA damage.

Rationale and appropriate use of chemotherapy and radiotherapy for pancreatic ductal adenocarcinoma.

The emergence of effective systemic chemotherapy, along with the parallel development of new targeted cell signal inhibitors for pancreatic cancer treatment, has provided impetus for a re-examination of the appropriate use of chemotherapy and radiation therapy in this malignancy. In addition to exciting developments in the treatment of locally advanced and metastatic disease, new data have emerged regarding the efficacy of adjuvant and neoadjuvant therapy when combined with traditional surgical approaches such as a Whipple procedure. This review summarizes the sentinel clinical trials and discoveries that have influenced the development and deployment of scientifically based multidisciplinary care for today's patients, with a particular focus on modern radiation and chemotherapy.

Protein kinase Ciota promotes nicotine-induced migration and invasion of cancer cells via phosphorylation of micro- and m-calpains.

Nicotine is a major component in cigarette smoke that activates the growth-promoting pathways to facilitate the development of lung cancer. However, it is not clear whether nicotine affects cell motility to facilitate tumor metastasis. Here we discovered that nicotine potently induces phosphorylation of both mu- and m-calpains via activation of protein kinase Ciota (PKCiota), which is associated with accelerated migration and invasion of human lung cancer cells.

ABCB1 over-expression and drug-efflux in acute lymphoblastic leukemia cell lines with t(17;19) and E2A-HLF expression.

Background: The t(17;19)(q21;p13), which occurs in a small subset of acute lymphoblastic leukemias (ALLs) and is associated with a dismal prognosis, creates a chimeric E2A-HLF transcription factor with transforming properties.

Procedure: We used representational difference analysis to identify candidate E2A-HLF target genes. Transient transfection assays and an inducible expression model system were then used to evaluate the ability of E2A-HLF to modulate target gene expression.

The vascular disrupting agent ZD6126 shows increased antitumor efficacy and enhanced radiation response in large, advanced tumors.

Purpose: ZD6126 is a vascular-targeting agent that induces selective effects on the morphology of proliferating and immature endothelial cells by disrupting the tubulin cytoskeleton. The efficacy of ZD6126 was investigated in large vs. small tumors in a variety of animal models.

Post-transcriptional gene regulation by gamma herpesviruses.

The Epstein-Barr virus (EBV) SM protein is a member of a highly conserved family of proteins present in most mammalian herpes viruses. There is a significant amount of functional and sequence divergence among the homologs encoded by the human herpes viruses, including differences in mechanism of action and varying effects on splicing and transcription. Nevertheless, in those cases where it has been studied, these proteins are essential for lytic replication of the virus.

Cloning and functional characterization of MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins created by a variant t(1;19)(q23;p13.3) in acute lymphoblastic leukemia.

We analyzed the TS-2 acute lymphoblastic leukemia (ALL) cell line that contains a t(1;19)(q23;p13.3) but lacks E2A-PBX1 fusion typically present in leukemias with this translocation. We found that the t(1;19) in TS-2 fuses the 19p13 gene DAZAP1 (Deleted in Azoospermia-Associated Protein 1) to the 1q23 gene MEF2D (Myocyte Enhancer Factor 2D), leading to expression of reciprocal in-frame DAZAP1/MEF2D and MEF2D/DAZAP1 transcripts.

The changing face of invasive fungal infections in hematopoietic cell transplant recipients.

Purpose Of Review: To review recent observations that describe changes in the likelihood of invasive fungal infections, shifts in types of fungal pathogens, and altered manifestations of fungal syndromes after hematopoietic cell transplantation and explore how changes in transplant practices are influencing these epidemiologic shifts.

Recent Findings: Shifts in invasive fungal infections are occurring as a consequence of changes in transplant practices, including the intensity of conditioning regimens, new immunosuppressive therapies, new antineoplastic therapies administered before hematopoietic cell transplantation, and possibly use of mold-active agents as prophylaxis. Non-fumigatus Aspergillus species and other mold pathogens, such as Fusarium and zygomycosis, are assuming greater prominence and may be increasing.

Survival function of protein kinase C{iota} as a novel nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-activated bad kinase.

Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is formed by nitrosation of nicotine and has been identified as the most potent carcinogen in cigarette smoke. NNK cannot only induce DNA damage but also promotes the survival of human lung cancer cells. Protein kinase C (PKC)iota is an atypical PKC isoform and plays an important role in cell survival, but the downstream survival substrate(s) is not yet identified.

Nicotine inactivation of the proapoptotic function of Bax through phosphorylation.

Nicotine-induced cell survival is associated with chemoresistance of human lung cancer cells, but our understanding of the intracellular mechanism(s) is fragmentary. Bax is a major proapoptotic member of the Bcl2 family and a molecule required for apoptotic cell death. Growth factor (i.

SDF-1 is both necessary and sufficient to promote proliferative retinopathy.

Diabetic retinopathy is the leading cause of blindness in working-age adults. It is caused by oxygen starvation in the retina inducing aberrant formation of blood vessels that destroy retinal architecture. In humans, vitreal stromal cell-derived factor-1 (SDF-1) concentration increases as proliferative diabetic retinopathy progresses.

The nitric oxide pathway modulates hemangioblast activity of adult hematopoietic stem cells.

We have previously established a model inducing hematopoietic stem cell (HSC) production of circulating endothelial progenitor cells (EPCs) to revascularize ischemic injury in adult mouse retina. The unique vascular environment of the retina results in new blood vessel formation primarily from HSC-derived EPCs. Using mice deficient (-/-) in inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS), we show that vessel phenotype resulting from hemangioblast activity can be altered by modulation of the NO/NOS pathway.

Design issues in a prospective randomized double-blinded trial of prophylaxis with fluconazole versus voriconazole after allogeneic hematopoietic cell transplantation.

Background: Aspergillus infections pose the toughest infectious challenges to the clinician caring for hematopoietic cell transplant recipients. About 15% of patients become infected, with a case fatality rate of approximately 65%. To date, no effective prophylactic strategies have been developed.

The hemangioblast: cradle to clinic.

In the embryo, the mesodermal precursor cell, the hemangioblast, gives rise to blood and blood vessels. During adult life, the hematopoietic stem cell (HSC) also exhibits this bipotential hemangioblast activity, serving as a rich source for circulating endothelial progenitor cells (EPCs). As a result of this finding, many questions have arisen as to whether the adult HSC is involved in the day-to-day maintenance of tissues, what mechanisms influence this adult hemangioblast activity, and whether blood vessels harbor hematopoietic capability.

Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induces phosphorylation of mu- and m-calpain in association with increased secretion, cell migration, and invasion.

Mounting evidence indicates that cigarette smoking not only promotes tumorigenesis but also may increase the spread of cancer cells in the body. However, the intracellular mechanism(s) by which cigarette smoking promotes metastasis of human lung cancer remains enigmatic. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is an important component in cigarette smoke and is formed by nitrosation of nicotine.

Postoperative irradiation for squamous cell carcinoma of the oral cavity: 35-year experience.

Background: The purpose of this study was to analyze factors influencing outcome in patients who received postoperative irradiation for advanced squamous cell carcinoma of the oral cavity.

Methods: Between October 1964 and November 2000, 226 patients with 230 previously untreated primary invasive squamous cell carcinomas of the oral cavity were treated postoperatively with continuous-course external beam irradiation. All patients had a minimum follow-up of 2 years (analysis, November 2002).

Empirical antifungal therapy in treating febrile neutropenic patients.

Persistent or recurrent unexplained fever in neutropenic patients receiving antibiotics can be caused by invasive fungal infections, which are often difficult to diagnose. Early trials of empirical antifungal therapy with amphotericin B deoxycholate (AmB) documented reductions in the frequency of and the morbidity and mortality associated with invasive fungal infections. Because of AmB's infusional and renal toxicities, subsequent trials used newer, less toxic agents, such as the lipid formulations of AmB, the extended-spectrum azoles, and, more recently, the echinocandins.

Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone promotes functional cooperation of Bcl2 and c-Myc through phosphorylation in regulating cell survival and proliferation.

Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is formed by nitrosation of nicotine and has been identified as the most potent carcinogen contained in cigarette smoke. NNK significantly contributes to smoking-related lung cancer, but the molecular mechanism remains enigmatic. Bcl2 and c-Myc are two major oncogenic proteins that cooperatively promote tumor development.

Bone marrow transdifferentiation in brain after transplantation: a retrospective study.

Background: End-organ repair by adult haemopoietic stem cells is under great scrutiny with investigators challenging the notion of these cells' plasticity. Some investigations of animals and short-term human bone marrow transplants suggest that bone marrow can repair brain. We looked for evidence of clinically relevant marrow-derived restorative neurogenesis: long-term, multilineage, neural engraftment that is not the result of cell-fusion events.

Stem cell plasticity or fusion: two approaches to targeted cell therapy.

The possibility the adult stem cells may be able to differentiate along atypical developmental pathways has garnered widespread attention. Recent papers have demonstrated that some "plasticity" arises as a result of cellular fusion events. This review attempts to highlight and reconcile the current data on both sides of the plasticity debate.

A new era of antifungal therapy.

Invasive fungal infections pose major management problems for clinicians caring for hematopoietic cell transplant patients. Two major fungal genera, Candida and Aspergillus, account for most fungal infections. Rates of systemic Candida infection range from 15% to 25%, mostly in the pre-engraftment period.

Cooperation between PKC-alpha and PKC-epsilon in the regulation of JNK activation in human lung cancer cells.

Phorbol esters can induce activation of two mitogen-activated protein kinase (MAPK) pathways, the extracellular signal-regulated kinase (ERK) pathway and the c-Jun N-terminal kinase (JNK) pathway. Unlike ERK activation, JNK activation by phorbol esters is somehow cell-specific. However, the mechanism(s) that contribute to the cell-specific JNK activation remain elusive.