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David M Berman

Publications and source records attributed to David M Berman.

At least 19 recordsLinked to original sources
PubMed2007

A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing.

Adult cancers may derive from stem or early progenitor cells. Epigenetic modulation of gene expression is essential for normal function of these early cells but is highly abnormal in cancers, which often show aberrant promoter CpG island hypermethylation and transcriptional silencing of tumor suppressor genes and pro-differentiation factors. We find that for such genes, both normal and malignant embryonic cells generally lack the hypermethylation of DNA found in adult cancers. In embryonic stem cells, these genes are held in a 'transcription-ready' state mediated by a 'bivalent' promoter chromatin pattern consisting of the repressive mark, histone H3 methylated at Lys27 (H3K27) by Polycomb group proteins, plus the active mark, methylated H3K4. However, embryonic carcinoma cells add two key repressive marks, dimethylated H3K9 and trimethylated H3K9, both associated with DNA hypermethylation in adult cancers. We hypothesize that cell chromatin patterns and transient silencing of these important regulatory genes in stem or progenitor cells may leave these genes vulnerable to aberrant DNA hypermethylation and heritable gene silencing during tumor initiation and progression.

Adult↗
PubMed2006

A nonsynonymous single-nucleotide polymorphism in the PDZ-Rho guanine nucleotide exchange factor (Ser1416Gly) modulates the risk of lung cancer in Mexican Americans.

BACKGROUND: Based on in vitro studies, Rho guanine nucleotide exchange factors (RhoGEFs) are key regulators of mitogenic and transforming pathways. At least 1 family member, PDZ-RhoGEF, also integrates signaling between monomeric Rho G proteins and heterotrimeric G proteins through a so-called regulator of G-protein signaling (RGS) domain. Recently, the authors reported that 3 single-nucleotide polymorphisms (SNPs) in 2 members of the RGS family were associated with significant reductions in the risk of cancer. METHODS: For the current report, the authors studied the risk of lung cancer associated with a nonsynonymous SNP (rs868188; Ser1416Gly) in PDZ-RhoGEF in a large lung cancer case-control study of 2260 Caucasians and 369 Mexican Americans. RESULTS: Compared with individuals who had the wild-type genotype (AA), Mexican Americans with the variant genotypes (AG and GG) had a significantly reduced risk for lung cancer (odds ratio [OR], 0.57; 95% confidence interval [95%CI], 0.34-0.94). The protective effect appeared to be more evident in younger individuals (OR, 0.42; 95%CI, 0.20-0.91), men (OR, 0.36; 95%CI, 0.18-0.71), and ever smokers (OR, 0.50; 95%CI, 0.29-0.88). A joint effect was observed between Ser1416Gly and polymorphisms in 2 cell-cycle control genes: p53 (intron 3) and cyclin D1 (CCND1). Tallying the variant alleles of the 4 RGS gene SNPs, a gene-dosage effect was apparent. Compared with individuals who had < 3 variant alleles, patients with > or = 3 variant alleles had a 51% reduction in lung cancer risk (OR, 0.49; 95%CI, 0.28-0.88). CONCLUSIONS: To the authors' knowledge, this is the first epidemiological study to link PDZ-RhoGEF polymorphisms with cancer risk. The results suggest that there are interactions between RGS2, RGS6, and PDZ-RhoGEF and validate this family of proteins as key regulators of tumorigenesis.

Aged↗
PubMed2006

Measuring tissue-based biomarkers by immunochromatography coupled with reverse-phase lysate microarray.

PURPOSE: There is a need for new technologies to study tissue-based biomarkers. The current gold standard, immunohistochemistry, is compromised by variability in tissue processing and observer bias. Reverse transcription-PCR (RT-PCR), immunocytochemistry, and reverse-phase lysate microarrays (RPM) are promising alternative technologies but have not yet been validated, or correlated, on the same patient-derived tissues. Furthermore, RPM is currently limited by time-consuming microdissection and low amounts of evaluable protein lysates. EXPERIMENTAL DESIGN: Metastatic melanoma was surgically excised from 30 patients and macroscopically dissected from surrounding stroma. Each specimen was processed by formalin-fixation (immunohistochemistry), cytospin (immunocytochemistry), or disaggreagation and enrichment (RT-PCR and RPM). The latter protocol uses immunochromatography to remove hematopoetic-derived cells, thus enriching for melanoma cells. Each sample was measured for the expression of gp100 or MART-1 normalized to actin. RESULTS: Immunochromatography coupled with RPM (I-RPM) is reproducible (r >/= 0.70) and, for gp100, correlates strongly with immunohistochemistry and immunocytochemistry (r = 0.78 and 0.76, respectively) and moderately with transcript levels, measured by RT-PCR (r = 0.61). In contrast, for MART-1, I-RPM correlates strongly with transcript level (r = 0.78) but only moderately strong correlations are noted with immunohistochemistry and immunocytochemistry (r = 0.64 and 0.59, respectively). In general, transcript levels show only moderately strong correlations with immunohistochemistry and immunocytochemistry (r = 0.41-0.64). CONCLUSION: I-RPM is a promising technology for quantitative grading of tissue biomarkers; however, antigen-dependent correlations are noted.

Antigens, Neoplasm↗
PubMed2006

Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibody as a single agent.

OBJECTIVE: To describe the clinical and histologic manifestations of skin reactions incidentally noted in patients with stage IV melanoma who were treated with up to 9 mg/kg of a humanized monoclonal antibody reactive against human cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) as a single agent every 3 weeks. SETTING: Single-institution prospective study. DESIGN: Patients treated with anti-CTLA-4 as a sole agent were prospectively referred for clinicopathologic characterization of skin reactions occurring during treatment. MAIN OUTCOME MEASURES: Specific clinicopathologic features were determined by means of a detailed history, a physical examination, conventional histologic analysis, antibody staining, and complete blood cell counts. RESULTS: Nine (14%) of 63 consecutive patients treated with anti-CTLA-4 as a sole agent developed skin eruptions that were attributed to anti-CTLA-4 in 8 of them. Skin lesions consisted primarily of discrete, pruritic, erythematous, minimally scaly papules that typically coalesced into thin plaques on the trunk and extensor surfaces of the extremities. Extensive alopecia was also noted in 1 patient. Histologically, a superficial, perivascular CD4+-predominant T-cell infiltrate with eosinophils in the dermis, rare dyskeratotic cells, and mild epidermal spongiosis were present. An increase (compared with pretreatment values) in the peripheral blood eosinophil frequency was observed in patients at the time of skin eruptions (P = .006). CONCLUSIONS: Specific features of the skin eruption dermatitis with increased tissue and peripheral blood eosinophil levels in a subset of treated patients. Specific features of skin eruption associated with anti-CTLA-4 resemble those described for maculopapular reactions to medications.

Adult↗
PubMed2006

Mollaret's meningitis due to human herpesvirus 6 in an adolescent.

We report the first pediatric case of Mollaret meningitis in an adolescent female with acute lymphoblastic leukemia in remission. This patient had signs and symptoms consistent with meningitis, with three episodes over a 3-month period. Human herpesvirus 6 (HHV-6) was identified during her last episode from polymerase chain reaction assay of a cerebrospinal fluid specimen. She was treated successfully with foscarnet, after which HHV-6 was undetectable in her cerebrospinal fluid.

Adolescent↗
PubMed2005

Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma.

The identification of many tumor-associated epitopes as nonmutated "self" Ags led to the hypothesis that the induction of large numbers of self/tumor Ag-specific T cells would be prevented because of central and peripheral tolerance. We report in this study on vaccination efforts in 95 HLA-A*0201 patients at high risk for recurrence of malignant melanoma who received prolonged immunization with the "anchor-modified" synthetic peptide, gp100209-217(210M). Vaccination using this altered peptide immunogen was highly effective at inducing large numbers of self/tumor-Ag reactive T cells in virtually every patient tested, with levels as high as 42% of all CD8+ T cells assessed by tetramer analysis. From 1 to 10% of all CD8+ cells were tumor-Ag reactive in 44% of patients and levels >10% were generated in 17% of patients. These studies were substantiated using the ELISPOT assay and a bulk cytokine release assay. Although our data regarding "tumor escape" were inconclusive, some patients had growing tumors that expressed Ag and HLA-A*0201 in the presence of high levels of antitumor T cells. There was no difference in the levels of antitumor Ag-specific T cells in patients who recurred compared with those that remained disease-free. Thus, the mere presence of profoundly expanded numbers of vaccine-induced, self/tumor Ag-specific T cells cannot by themselves be used as a "surrogate marker" for vaccine efficacy. Further, the induction of even high levels of antitumor T cells may be insufficient to alter tumor progression.

Adult↗
PubMed2005

Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma.

PURPOSE: We investigated the combination of lymphodepleting chemotherapy followed by the adoptive transfer of autologous tumor reactive lymphocytes for the treatment of patients with refractory metastatic melanoma. PATIENTS AND METHODS: Thirty-five patients with metastatic melanoma, all but one with disease refractory to treatment with high-dose interleukin (IL) -2 and many with progressive disease after chemotherapy, underwent lymphodepleting conditioning with two days of cyclophosphamide (60 mg/kg) followed by five days of fludarabine (25 mg/m(2)). On the day following the final dose of fludarabine, all patients received cell infusion with autologous tumor-reactive, rapidly expanded tumor infiltrating lymphocyte cultures and high-dose IL-2 therapy. RESULTS: Eighteen (51%) of 35 treated patients experienced objective clinical responses including three ongoing complete responses and 15 partial responses with a mean duration of 11.5 +/- 2.2 months. Sites of regression included metastases to lung, liver, lymph nodes, brain, and cutaneous and subcutaneous tissues. Toxicities of treatment included the expected hematologic toxicities of chemotherapy including neutropenia, thrombocytopenia, and lymphopenia, the transient toxicities of high-dose IL-2 therapy, two patients who developed Pneumocystis pneumonia and one patient who developed an Epstein-Barr virus-related lymphoproliferation. CONCLUSION: Lymphodepleting chemotherapy followed by the transfer of highly avid antitumor lymphocytes can mediate significant tumor regression in heavily pretreated patients with IL-2 refractory metastatic melanoma.

Adolescent↗
PubMed2005

Loss of S100 antigenicity in metastatic melanoma.

Melanoma is a highly malignant disease that may initially present as a poorly differentiated metastatic tumor. Therefore, the S100 immunostain, immunoreactive in 96% to 99% of melanoma, is used to evaluate poorly differentiated malignant tumors. To develop criteria for correctly diagnosing S100-negative melanomas, we studied the immunohistochemical profile of 1553 patients enrolled in ongoing National Cancer Institute clinical trials for melanoma. Seventeen patients (1%) had metastatic melanoma specimens that were negative for S100. Of the 17 S100-negative lesions, 10 (59%) were immunoreactive for both GP100 and MART-1. Of the 17 S100-negative cases, 13 had a documented primary melanoma. Twenty-four percent of the S100-negative cases had an ocular primary, whereas only 6% of all melanomas had an ocular origin. In 11 of the 17 cases with previous surgical specimens, a prior documented S100-immunoreactive specimen was identified in 9 cases (82%). The time interval for loss of S100 immunoreactivity ranged from 3 weeks to 3 years (average, 13.5 months). There was no association between S100-negative status and histological appearance or site of metastasis. We conclude that all S100-negative melanomas could be correctly identified by negative workup for carcinoma, lymphoma, and sarcoma plus (1) GP100/MART-1 immunoreactivity and/or (2) prior documentation of melanoma.

Biomarkers, Tumor↗
PubMed2005

Candida epiglottitis in an adolescent with acquired immunodeficiency syndrome.

We report a case of an adolescent with human immunodeficiency virus infection who presented with epiglottitis caused by Candida albicans. This patient's symptom was severe oropharyngeal thrush without the classic manifestations of epiglottitis. Atypical organisms can cause epiglottitis in immunocompromised adolescents and they can have mild symptoms.

AIDS-Related Opportunistic Infections↗
PubMed2005

Surgical pathology in the era of the Civil War: the remarkable life and accomplishments of Joseph Janvier Woodward, MD.

Joseph Janvier Woodward was an assistant surgeon in the US Army during the Civil War, coauthored the definitive works on the mortality and morbidity of that war, attended at the autopsy of President Lincoln, and attended President Garfield after he was shot. He revolutionized the field of photomicroscopy and was one of the first pathologists to use aniline dyes as tissue stains. Yet despite the occasional biographical sketch every few decades, he is largely unknown today. Herein, we review his contributions to surgical pathology and medicine and present modern-day photomicrographs of 140-year-old slides from Woodward's original collection.

American Civil War↗
PubMed2004

Tissue repair and stem cell renewal in carcinogenesis.

Cancer is increasingly being viewed as a stem cell disease, both in its propagation by a minority of cells with stem-cell-like properties and in its possible derivation from normal tissue stem cells. But stem cell activity is tightly controlled, raising the question of how normal regulation might be subverted in carcinogenesis. The long-known association between cancer and chronic tissue injury, and the more recently appreciated roles of Hedgehog and Wnt signalling pathways in tissue regeneration, stem cell renewal and cancer growth together suggest that carcinogenesis proceeds by misappropriating homeostatic mechanisms that govern tissue repair and stem cell self-renewal.

Animals↗
PubMed2004

A functional polymorphism in RGS6 modulates the risk of bladder cancer.

RGS proteins negatively regulate heterotrimeric G protein signaling. Recent reports have shown that RGS proteins modulate neuronal, cardiovascular, and lymphocytic activity, yet their role in carcinogenesis has not been explored. In an epidemiologic study of 477 bladder cancer patients and 446 matched controls, three noncoding single-nucleotide polymorphisms (SNPs) in RGS2 and RGS6 were each associated with a statistically significant reduction in bladder cancer risk. The risk of bladder cancer was reduced by 74% in those individuals with the variant genotype at all three SNPs (odds ratio, 0.26; 95% confidence interval, 0.09-0.71). When the SNPs were analyzed separately, the RGS6-rs2074647 (C-->T) polymorphism conferred the greatest overall reduction in risk of bladder cancer (odds ratio, 0.66; 95% confidence interval, 0.46-0.95). These reductions in risk were more pronounced in ever smokers, suggesting a gene-environment interaction. In transfection assays, the RGS6-rs2074647 (C-->T) polymorphism increased the activity of a luciferase-RGS fusion protein by 2.9-fold, suggesting that this SNP is functionally significant. Finally, we demonstrate that RGS2 transcripts and several splice variants of RGS6 are expressed in bladder cancer cells. These data provide the first evidence that RGS proteins may be important modulators of cancer risk and validate RGS6 as a target for further study.

Case-Control Studies↗
PubMed2004

Hedgehog signalling in prostate regeneration, neoplasia and metastasis.

Metastatic cancers adopt certain properties of normal cells in developing or regenerating organs, such as the ability to proliferate and alter tissue organization. We find here that activity of the Hedgehog (Hh) signalling pathway, which has essential roles in developmental patterning, is required for regeneration of prostate epithelium, and that continuous pathway activation transforms prostate progenitor cells and renders them tumorigenic. Elevated pathway activity furthermore distinguishes metastatic from localized prostate cancer, and pathway manipulation can modulate invasiveness and metastasis. Pathway activity is triggered in response to endogenous expression of Hh ligands, and is dependent upon the expression of Smoothened, an essential Hh response component that is not expressed in benign prostate epithelial cells. Monitoring and manipulating Hh pathway activity may thus offer significant improvements in diagnosis and treatment of prostate cancers with metastatic potential.

Animals↗
PubMed2004

Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis.

Previous studies have demonstrated that the Hedgehog (Hh) signaling pathway plays a critical role in the development and patterning of many endodermally derived tissues. We have investigated the role of Sonic hedgehog (Shh) in formation of the prostate gland by examining the urogenital phenotype of Shh mutant fetuses. Consistent with earlier work reporting an essential role for Shh in prostate induction, we have found that Shh mutant fetuses display abnormal urogenital development and fail to form prostate buds. Unexpectedly, however, we have discovered that this prostate defect could be rescued by three different methods: renal grafting, explant culture in the presence of androgens, and administration of dihydrotestosterone (DHT) to pregnant mice, indicating that the prostate defect in Shh mutants is due to insufficient levels of androgens. Furthermore, we find that the inhibition of Hh pathway signaling by treatment with cyclopamine does not block prostate formation in explant culture, but instead produces morphological defects consistent with a role for Hh signaling in ductal patterning. Taken together, our studies indicate that the initial organogenesis of the prostate proceeds independently of Shh, but that Shh or other Hh ligands may play a role in subsequent events that pattern the prostate.

Androgens↗
PubMed2004

Profiling the activity of G proteins in patient-derived tissues by rapid affinity-capture of signal transduction proteins (GRASP).

The next phase in molecular medicine will require the ability to identify signal transduction events inside a cell, in the biologic context of the disease-host interface and at a given point in time. New technologies are needed to profile the activity of these signaling pathways in patient tissue rather than cultured cell lines since the tumor-host microenvironment influences the cellular proteome. We introduce such a technology, rapid affinity capture of signaling proteins (GRASP), to investigate the activity of signaling pathways from patient-derived carcinomas and benign epithelial surfaces and apply it to studying important signaling events in ovarian carcinoma. During the progression from benign ovarian epithelium to invasive carcinoma, there is loss of repression of Rho A as evidenced by its dissociation from its inhibitor, Rho Guanine Nucleotide Dissociation Inhibitor (RhoGDI). GRASP is more informative than simply profiling transcript or protein levels. Furthermore, GRASP coupled with mass spectrometry allowed us to identify a protein-binding partner of RhoGDI, demonstrating the power of this technology in the discovery of potentially novel protein-protein interactions. GRASP represents an advance in the field of proteomics as it detects protein interactions present in cells as they exist in their native tissue microenvironment.

Carcinoma↗
PubMed2004

Borderline ovarian tumors: diverse contemporary viewpoints on terminology and diagnostic criteria with illustrative images.

The National Cancer Institute sponsored a Borderline Ovarian Tumor Workshop held in August 2003 in Bethesda, MD. This report was developed from discussions at the Workshop. The participants acknowledged several areas of disagreement on basic terminology issues and agreed that a glossary with example images would help clarify many commonly misunderstood issues. This report defines terminology used in the pathological description of borderline tumors and their variants, and illustrates examples of each of the most common entities. It also addresses controversial aspects of the definitions and issues involving specimen handling and reporting. For those issues where there is disagreement, the terminology and diagnostic approaches reflecting the differing views are presented.

Cystadenocarcinoma↗
PubMed2004

Molecular genetic analysis of ovarian serous cystadenomas.

Ovarian serous cystadenomas are common ovarian lesions that may be precursors of serous borderline tumors, which can in turn progress to low-grade serous carcinomas. It has been shown that low-grade serous carcinoma and serous borderline tumors are characterized by frequent mutations in BRAF or KRAS genes, but the mutational status of these genes in serous cystadenomas and the clonal nature of serous cystadenomas have not been fully investigated. We isolated cyst-lining epithelium from 30 consecutive serous cystadenomas, and analyzed their BRAF and KRAS mutational status. Wild-type sequences of BRAF and KRAS were detected in all specimens. Using the human androgen receptor gene as a polymorphic marker, we also examined the clonal status of epithelial cells in all of the serous cystadenomas. Four of 29 (14%) informative specimens were monoclonal based on the methylation pattern. These monoclonal cystadenomas were significantly (P<0.01) larger in size (>8 cm) than the nonclonal cystadenomas. These data indicate that serous cystadenomas do not contain mutations in either BRAF or KRAS genes and that most serous cystadenomas are polyclonal. Accordingly, it appears that serous cystadenomas develop as a hyperplastic expansion from epithelial inclusions with a clonal/neoplastic transformation occurring in a subset of them.

Apoptosis↗