PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress.

The accumulation of unfolded proteins elicits a cellular response that triggers both pro-survival and pro-apoptotic signaling events. PERK-dependent activation of NF-E2-related factor-2 (Nrf2) is critical for survival signaling during this response; however, the mechanism whereby Nrf2 confers a protective advantage to stressed cells remains to be defined. We now demonstrate that Nrf2 activation contributes to the maintenance of glutathione levels, which in turn functions as a buffer for the accumulation of reactive oxygen species during the unfolded protein response.

Quantitative effects on c-Jun N-terminal protein kinase signaling determine synergistic interaction of cisplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines.

We investigated the effects of cisplatin and the hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in combination in a panel of human colon adenocarcinoma cell lines that differ in their p53 and mismatch repair status. Analysis of cytotoxicity after combined treatment revealed additive effects of cisplatin and 17-AAG in the HCT 116, DLD1, and SW480 cell lines and antagonism in HT-29 cells. Clonogenic assays demonstrated antagonism in HT-29, an additive effect in SW480, and synergism in HCT 116 and DLD1 cell lines.

Mechanisms by which IGF-I may promote cancer.

Multiple large case-control studies in the past five years have reported positive associations between high circulating levels of the insulin-like growth factor (IGF)-I and risk for different types of cancer. Correlations certainly do not prove causation, but the reproducibility of this finding implies this is a hypothesis worth further examination through more mechanistic studies. IGF-I binds to the IGF-I receptor, a tyrosine kinase receptor that transduces signals to the nucleus and mitochondrion primarily via the mitogen-activated protein kinase (MAPK) and PI3K/Akt pathways.

An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene.

Glycogen synthase kinase-3beta-dependent phosphorylation of cyclin D1 at a conserved COOH-terminal residue, Thr-286, promotes CRM1-dependent cyclin D1 nuclear export at the G(1)-S boundary. Mutations that perturb the phosphorylation of cyclin D1 at Thr-286 contribute to cell transformation, although to date, no such mutations have been found in human cancers. Cyclin D1 (CCND1) undergoes alternative splicing leading to the production of an mRNA predicted to encode a unique cyclin D1 isoform, cyclin D1b, which lacks Thr-286.

Irinotecan and fixed-dose-rate gemcitabine in advanced pancreatic and biliary cancer: phase I study.

It is a continuing challenge for oncologists to effectively treat advanced/metastatic pancreatic and biliary cancer. Both irinotecan (CPT-11, Camptosar) and gemcitabine (Gemzar) have shown activity against these diseases with different mechanisms. Preclinical and clinical data also suggest additive or synergistic effects of the combination of these two agents with few or no overlapping toxicities.

Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival.

Activation of PERK following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) promotes translation inhibition and cell cycle arrest. PERK function is essential for cell survival following exposure of cells to ER stress, but the mechanisms whereby PERK signaling promotes cell survival are not thoroughly understood. We have identified the Nrf2 transcription factor as a novel PERK substrate.

Role of Jun and Jun kinase in resistance of cancer cells to therapy.

A series of kinases, the mitogen-activated protein (MAP) kinases, serves to regulate cellular responses to various environmental influences in metazoans. Three major pathways have been described, each with some overlap in substrate specificity that causes activation of parallel pathways. The activation of one of these, the Jun kinase pathway, has been implicated in apoptotic responses to DNA damage, cell stress and cytotoxic drugs.

A translational bridge to cancer immunotherapy: exploiting costimulation and target antigens for active and passive T cell immunotherapy.

Building on significant advances in basic tumor immunology over the past decade, current translational efforts to develop novel antitumor T cell therapeutics continue to accelerate. Both passive T cell immunotherapy (e.g.

Use of ibritumomab tiuxetan anti-CD20 radioimmunotherapy in a non-Hodgkin's lymphoma patient previously treated with a yttrium-90-labeled anti-CD22 monoclonal antibody.

Ibritumomab tiuxetan is a novel radioimmunotherapeutic agent that has a high response rate in relapsed or chemotherapy-refractory CD20+ B-cell non-Hodgkin's lymphoma. Whereas chemotherapy agents can successfully be used multiple times in a given patient, there are few data on the repeated use of radioimmunotherapy in terms of efficacy or morbidity, and no reports as yet involving radioconjugates that target different antigens We report on a patient who was treated successfully with yttrium-90-labeled humanized anti-CD22 monoclonal antibody (90Y-epratuzumab). Upon relapse 3 years later, the patient was treated again with radioimmunotherapy consisting of 90Y-ibritumomab tiuxetan anti-CD20 monoclonal antibody, with a good response and acceptable bone marrow suppression.

Geldanamycin and its 17-allylamino-17-demethoxy analogue antagonize the action of Cisplatin in human colon adenocarcinoma cells: differential caspase activation as a basis for interaction.

Several chaperone-binding drugs based on geldanamycin (GA) have been synthesized, and one of them, 17-allylamino-17-demethoxygeldanamycin (17-AAG), is being developed in the clinic. Interest in the use of 17-AAG in combination with cytotoxic drugs led us to study both GA and 17-AAG with cisplatin (DDP) in the human colon adenocarcinoma cell lines HT29 and HCT116. We performed isobologram analysis of combinations of DDP with GA or 17-AAG in these cell lines using the standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay to evaluate cell survival.

Current status of oxaliplatin in colorectal cancer.

Novel platinum compounds have been sought with the goal of identifying molecules active in cisplatin-resistant cancers such as colorectal cancer. Some 30 years ago it was shown that varying the structure of the coordination complex could enhance the activity of platinum compounds against preclinical models. The diaminocyclohexane ligand, now embodied in the structure of oxaliplatin, was the most promising of a series of such analogues.

Use of cell-based therapies for modification of host immune responses.

The success of adoptive cellular therapy depends on the ability to select optimally or produce cells genetically with the desired antigenic specificity, and then induce cellular proliferation while preserving the effector function, engraftment, and homing abilities of the lymphocytes. Unfortunately, many previous clinical trials were carried out with adoptively transferred cells that were propagated in what are now understood to be sub-optimal conditions that impair the essential functions of the adoptively transferred cells. This article reviews some of the lessons and developments emerging from the past 20 years of adoptive immunotherapy trials and basic immunology regarding immunogenicity, T cell homeostasis, and the maintenance of tolerance and repertoire.

On the need for biopsy confirmation at suspected first recurrence of cancer.

At the time of suspected first recurrence of cancer, it is unclear whether biopsy confirmation is routinely performed, although this is a very common clinical situation. First, 20 oncologists were surveyed to ascertain the pattern of practice in our community. A questionnaire with hypothetical typical cases suspected of having recurrent cancer was distributed.

Post-transplant lymphoproliferative disorder: a review.

Post-transplant lymphoproliferative disorder (PTLD) represents a spectrum of Epstein-Barr virus-related (EBV) clinical diseases, from a benign mononucleosis-like illness to a fulminant non-Hodgkin's lymphoma. In the setting of hematopoietic stem cell transplantation, PTLD is an often-fatal complication occurring relatively early after transplant. Risk factors for the development of PTLD are well established, and include HLA-mismatching, T-cell depletion, and the use of antilymphocyte antibodies as conditioning or treatment of graft-versus-host disease.

Application of breast cancer risk prediction models in clinical practice.

Breast cancer risk assessment provides an estimation of disease risk that can be used to guide management for women at all levels of risk. In addition, the likelihood that breast cancer risk is due to specific genetic susceptibility (such as BRCA1 or BRCA2 mutations) can be determined. Recent developments have reinforced the clinical importance of breast cancer risk assessment.

Future directions in the treatment of pancreatic cancer.

Fewer than 20% of patients with pancreatic cancer present with disease macroscopically confined to the pancreas, and approximately 40% already have locally advanced disease. Based on data from the Gastrointestinal Tumor Study Group, adjuvant therapy with radiation and 5-fluorouracil has become standard practice in the United States; however, in other countries, adjuvant treatment has not been as widely accepted. Other issues include the potential of neoadjuvant therapy and optimal systemic management.

Use of EBV PCR for the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients.

Epstein-Barr virus (EBV) is known to be involved in the majority of patients who develop post-transplant lymphoproliferative disorder after solid organ transplant. We conducted a retrospective study to determine the utility of qualitative and quantitative Epstein-Barr virus polymerase chain reaction (PCR) for the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients. Peripheral blood leukocytes obtained from 35 adult solid organ transplant patients consecutively referred for evaluation of possible post-transplant lymphoproliferative disorder, were tested by EBV PCR at the time of initial evaluation and at time points thereafter.

BRAF and RAS mutations in human lung cancer and melanoma.

BRAF encodes a RAS-regulated kinase that mediates cell growth and malignant transformation kinase pathway activation. Recently, we have identified activating BRAF mutations in 66% of melanomas and a smaller percentage of many other human cancers. To determine whether BRAF mutations account for the MAP kinase pathway activation common in non-small cell lung carcinomas (NSCLCs) and to extend the initial findings in melanoma, we screened DNA from 179 NSCLCs and 35 melanomas for BRAF mutations (exons 11 and 15).