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Andrew Chan

Publications and source records attributed to Andrew Chan.

17 recordsLinked to original sources
PubMed2025

CINner: Modeling and simulation of chromosomal instability in cancer at single-cell resolution.

Cancer development is characterized by chromosomal instability, manifesting in frequent occurrences of different genomic alteration mechanisms ranging in extent and impact. Mathematical modeling can help evaluate the role of each mutational process during tumor progression, however existing frameworks can only capture certain aspects of chromosomal instability (CIN). We present CINner, a mathematical framework for modeling genomic diversity and selection during tumor evolution. The main advantage of CINner is its flexibility to incorporate many genomic events that directly impact cellular fitness, from driver gene mutations to copy number alterations (CNAs), including focal amplifications and deletions, missegregations and whole-genome duplication (WGD). We apply CINner to find chromosome-arm selection parameters that drive tumorigenesis in the absence of WGD in chromosomally stable cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG, [Formula: see text]). We found that the selection parameters predict WGD prevalence among different chromosomally unstable tumors, hinting that the selective advantage of WGD cells hinges on their tolerance for aneuploidy and escape from nullisomy. Analysis of inference results using CINner across cancer types in The Cancer Genome Atlas ([Formula: see text]) further reveals that the inferred selection parameters reflect the bias between tumor suppressor genes and oncogenes on specific genomic regions. Direct application of CINner to model the WGD proportion and fraction of genome altered (FGA) in PCAWG uncovers the increase in CNA probabilities associated with WGD in each cancer type. CINner can also be utilized to study chromosomally stable cancer types, by applying a selection model based on driver gene mutations and focal amplifications or deletions (chronic lymphocytic leukemia in PCAWG, [Formula: see text]). Finally, we used CINner to analyze the impact of CNA probabilities, chromosome selection parameters, tumor growth dynamics and population size on cancer fitness and heterogeneity. We expect that CINner will provide a powerful modeling tool for the oncology community to quantify the impact of newly uncovered genomic alteration mechanisms on shaping tumor progression and adaptation.

Chromosomal Instability↗
PubMed2006

Phagocytosis of apoptotic inflammatory cells downregulates microglial chemoattractive function and migration of encephalitogenic T cells.

Apoptosis of autoaggressive T cells in the central nervous system (CNS) and subsequent phagocytosis by microglia is probably crucial in the rapid resolution of the inflammatory infiltrate in T cell mediated neuroinflammatory diseases. In addition to mere clearance, phagocytosis of apoptotic leukocytes results in the downregulation of different microglial immune functions. Chemoattractive functions of Lewis rat microglia and secretion of chemokines and matrix-metalloproteinases (MMPs) were investigated after phagocytosis of apoptotic T cells in vitro. In a modified Boyden chamber assay migration of encephalitogenic T cells toward LPS-stimulated microglial supernatants after phagocytosis of apoptotic thymocytes was reduced by 24.9% in comparison to interaction with viable target cells (P < 0.001). Phagocytosis of apoptotic cells downregulated CC-chemokine ligand (CCL)-5-secretion by LPS-stimulated microglia by 66.2% (P < 0.001), whereas there was only a trend toward decreased CCL2-secretion. As determined by gelatinase-zymography, secretion of MMP-9 by microglia was decreased after phagocytosis of apoptotic cells, whereas MMP-2 secretion was not altered. These mechanisms may reduce further recruitment of pathogenic inflammatory cells into the CNS-lesion and thus contribute to the active resolution of the inflammatory infiltrate and termination of the autoimmune attack.

Animals↗
PubMed2005

Teaching resources. Ras-MAPK pathways.

This Teaching Resource provides lecture notes and slides for a class covering three kinase-mediated signaling pathways and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The focus is three major signaling cascades that are implicated in cell proliferation, survival, and stress response. They are, respectively, the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and Jun N-terminal kinase (JNK) cascades. The aim of this lecture is to review the major players of these intracellular signaling cascades in mammalian cells. In addition, emphasis is placed on understanding the dynamic, rather than linear, nature of signal transduction in determining cellular responses to external stimuli.

Animals↗
PubMed2004

Thoracic manifestations of common nonpulmonary malignancies of women.

Metastatic, gender-related, nonpulmonary malignancy can exhibit different patterns of tumor spread and different natural histories. The pulmonologist often is involved in the diagnosis and treatment of patients with pulmonary metasteses; and a thorough understanding of the patterns of metastasis from these cancers can help to guide appropriate work-up and therapy. In the case of solitary pulmonary metastases, a surgical approach may not be unreasonable based on current clinical evidence. Knowledge of the clinical spectrum of these diseases, together with their unique molecular biology, may improve the clinical care of patients.

Breast Neoplasms↗
PubMed2004

Bronchiolitis obliterans: an update.

PURPOSE OF REVIEW: Bronchiolitis obliterans (BO) occurs in both post-lung transplant and nontransplant-related individuals, and is characterized by mainly irreversible airflow obstruction that is often ultimately progressive. RECENT FINDINGS: While post-lung transplant BO is a major cause of lung allograft dysfunction, and hence is better characterized than nontransplant-related BO, it is likely that many similarities in pathogenesis and treatment apply to both categories. SUMMARY: Optimal management for BO remains to be established, and the role of retransplantation in this disease requires further consensus. Minimization of risk factors for BO and earlier detection in the form of methacholine challenge testing and HRCT scans of the chest amongst other forms of detection, may help in the stabilization and possible resolution of early BO.

Biopsy↗
PubMed2004

Single-detector helical CT in PET-CT: assessment of image quality.

OBJECTIVE: CT in positron emission tomography (PET)-CT imaging is often performed as a single scan from the base of the skull to the groin, potentially resulting in degradation of the quality of CT scans depending on the position of the patient's arms and mode of breathing and the use and timing of IV contrast injection. The aim of our study was to assess the impact of artifacts on the diagnostic quality of CT scans using a single-detector helical CT scanner in PET-CT imaging. MATERIALS AND METHODS: Two radiologists retrospectively evaluated the diagnostic image quality of CT scans obtained with PET-CT in 81 patients with lymphoma. The severity of the artifacts related to the position of the patient's arms beside the body, the influence of breathing motion, and the presence of contrast material in the upper thoracic veins were ranked using a 4-point scale. RESULTS: Performing CT with the patient's arms positioned beside the body resulted in streak artifacts, predominantly in the upper abdomen, that were graded as mild in 22%, moderate in 40%, and severe in 38% of the scans. A patient's weight significantly correlated with the degree of severity of the artifacts (p < 0.05). Shallow breathing by the patient during scanning caused blurring and double-imaging, again predominantly in the upper abdomen, that were graded as mild in 23%, moderate in 49%, or severe in 28% of the scans. In 84% of the CT scans obtained with IV contrast material, the image quality of the upper thoracic region was moderately (27%) or severely (57%) degraded by streak artifacts from highly concentrated contrast material in the upper thoracic veins. CONCLUSION: The use of a single-detector CT scanner in whole-body PET-CT decreases the image quality of CT scans because of streak artifacts that occur predominantly in scans of the upper abdomen. Scanning with the patient's arms raised eliminates the streak artifacts in scans of the abdominal region. With the new generation of PET-CT devices equipped with MDCT scanners, breathing motion artifacts can be expected to be eliminated if protocols for breath-hold CT are applied. Reversing the direction of CT scanning allows one to avoid imaging the thoracic region at a time when undiluted IV contrast material is still present in the upper thoracic veins.

Adolescent↗
PubMed2003

Phagocytosis of apoptotic inflammatory cells by microglia and its therapeutic implications: termination of CNS autoimmune inflammation and modulation by interferon-beta.

Apoptosis of autoaggressive T-cells in the CNS is an effective, noninflammatory mechanism for the resolution of T-cell infiltrates, contributing to clinical recovery in T-cell-mediated neuroinflammatory diseases. The clearance of apoptotic leukocytes by tissue-specific phagocytes is critical in the resolution of the inflammatory infiltrate and leads to a profound downregulation of phagocyte immune functions. Adult human microglia from surgically removed normal brain tissue was used in a standardized, light-microscopic in vitro phagocytosis assay of apoptotic autologous peripheral blood-derived mononuclear cells (MNCs). Microglia from five different patients had a high capacity for the uptake of apoptotic MNCs in contrast to nonapoptotic target cells with the phagocytosis rate for nonapoptotic MNCs amounting to only 61.6% of the apoptotic MNCs. A newly described phosphatidylserine receptor, critical in the phagocytosis of apoptotic cells by macrophages, is also expressed at similar levels on human microglia. The effects of the therapeutically used immunomodulatory agent interferon-beta (IFNbeta) were investigated using Lewis rat microglia and apoptotic, encephalitogenic, myelin basic protein-specific autologous T-cells. Also, rat microglia had a high capacity to phagocytose apoptotic T-cells specifically. IFNbeta increased the phagocytosis of apoptotic T-cells to 36.8% above the untreated controls. The enhanced phagocytic activity was selective for apoptotic T-cells and was not mediated by increased IL-10 secretion. Apoptotic inflammatory cells may be efficiently and rapidly removed by microglial cells in the autoimmune-inflamed human CNS. The in vitro increase of phagocytosis by IFNbeta merits further investigations whether this mechanism could also be therapeutically exploited.

Animals↗
PubMed2003

Effects of polyclonal immunoglobulins and other immunomodulatory agents on microglial phagocytosis of apoptotic inflammatory T-cells.

T-cell apoptosis in the CNS is an effective mechanism for the noninflammatory resolution of autoimmune T-cell infiltrates. Ingestion of apoptotic leukocytes by microglia results in an efficient clearance of the inflammatory infiltrate, followed by a profound downregulation of proinflammatory phagocyte immune functions. The effects of different immunomodulatory agents on Lewis rat microglial phagocytosis of apoptotic autologous thymocytes or myelin-basic protein (MBP)-specific, encephalitogenic T-cells were investigated using a standardized, light microscopical in vitro phagocytosis assay. Pretreatment of microglia with polyclonal 7S immunoglobulins (IVIg) decreased the phagocytosis of apoptotic thymocytes by 38.2% (p<0.0001). Also, immunoglobulin F(ab')(2) fragments decreased microglial phagocytosis, suggesting an Fc receptor-independent mechanism. Similar results were obtained using MBP-specific T-cells. Pretreatment of microglia with IFN-gamma increased the phagocytosis of apoptotic cells by 65.4%, which was to a large extent counteracted by IVIg. Glatiramer acetate (GLAT) did not exert an effect on microglial phagocytosis, while methylprednisolone (MP) induced microglial apoptosis in vitro. These results indicate that IVIg has a high potential to inhibit microglial phagocytosis of apoptotic inflammatory T-cells even under proinflammatory conditions and extend our view of the complex immunomodulatory effects of IVIg.

Animals↗
PubMed2003

Positional mapping for amplified DNA sequences on 1q21-q22 in hepatocellular carcinoma indicates candidate genes over-expression.

BACKGROUND/AIMS: Comparative genomic hybridization analysis on hepatocellular carcinoma (HCC) indicated frequent gains of 1q and an amplicon at 1q21-q22. Current cytogenetic evidences confer much importance on 1q21-q22, where a role in drug resistance, tumor metastasis and shorter patient survival had been implicated. METHODS: Using positional mapping by interphase cytogenetics, we investigated the amplicon 1q21-q22 in five HCC cases. Three amplification maxima represented by yeast artificial chromosomes (YACs) 955E11, 876B11 and 945D5 that mapped to regions 1q21.1, 1q21.2 and 1q22, respectively, were indicated. We further investigated candidate genes expression in the mapped YACs by quantitative reverse-transcription-polymerase chain reaction. A panel of genes encoding protein transcripts involved in apoptosis, cell cycle progression, calcium binding and jumping translocation was studied. RESULTS: Among ten HCC cases with the amplicon 1q21-q22 examined, we found a significant gene expression level of JTB, SHC1, CCT3 and COPA in the tumors than the paired adjacent non-malignant liver tissues (P< or =0.04). CONCLUSIONS: Our interphase findings on 1q21-q22 pinpointed three affected loci between D1S305 and D1S2369. Up-regulation of candidate genes identified within these over-represented regions may represent targets in the progression of HCC and may carry prognostic significance.

Carcinoma, Hepatocellular↗
PubMed2003

Obstructive sarcoidosis.

Sarcoidosis is a systemic granulomatous disease that frequently involves the lung. Although classically thought of as a restrictive lung disease, airway obstruction has become a recognized feature of the disease in the past years. Sarcoidosis can affect the airway at any level and when the involvement includes small airways, it can resemble more common obstructive airway diseases, such as asthma and chronic bronchitis. Pulmonary function testing and high-resolution computerized tomography of the chest are two important tools to evaluate the presence and extent of airway obstruction in sarcoidosis. Pharmacologic options for the treatment of obstructive sarcoidosis are, in large part, not supported by large, randomized clinical trials. In severe cases of bronchostenosis owing to sarcoidosis granuloma or extrinsic compression from intrathoracic lymphadenopathy, interventional bronchoscopy has successfully been performed, although repeated procedures are usually required. Lung transplantation is an ultimate option in selected patients with late-stage fibrotic disease.

Airway Obstruction↗
PubMed2003

Bronchiolitis obliterans.

Bronchiolitis obliterans (BO) is a disease of small airways that results in progressive dyspnea and airflow limitation. It is a common sequela of bone marrow, lung, and heart-lung transplantation, but can also occur as a complication of certain pulmonary infections, adverse drug reaction, toxic inhalation, and autoimmune disorders. Non-transplant-related BO is rare and can mimic asthma and chronic obstructive pulmonary disease (COPD). In transplant-related BO, the diagnosis can be suggested by obstructive changes in serial pulmonary function testings, while open lung biopsy is usually required in non-transplant cases. High-resolution computerized tomography (HRCT) is also a helpful tool to diagnose and assess the severity of BO. The treatment of BO, regarding of the cause, is usually disappointing. Systemic corticosteroid immunosuppression and retransplantation have been described with variable success.

Bronchiolitis Obliterans↗
PubMed2002

Phagocytotic removal of apoptotic, inflammatory lymphocytes in the central nervous system by microglia and its functional implications.

Apoptotic cell death of inflammatory T cells is an established mechanism to terminate an autoimmune inflammatory response in the rodent and human central nervous system (CNS). The efficient clearance of apoptotic cells protects the tissue from leakage of potentially harmful substances from secondary necrotic cells. As the resident phagocyte, the microglial cell is the primary candidate for the clearance of apoptotic lymphocytes. Furthermore, the phagocytosis of apoptotic cells is accompanied by a spectrum of anti-inflammatory effects. In this review, we focus on the mechanisms for removal of apoptotic inflammatory cells by microglia in the central nervous system and their functional consequences.

Animals↗
PubMed2002

Astrocytes are less efficient in the removal of apoptotic lymphocytes than microglia cells: implications for the role of glial cells in the inflamed central nervous system.

Apoptosis of T lymphocytes is a common pathway to terminate autoimmune inflammation in the brain as shown in experimental autoimmune encephalomyelitis (EAE) and in the autoimmune inflamed human brain. To date it is unclear to what extent different glial cells are involved in the removal of apoptotic cells. In an in vitro phagocytosis assay we compared the phagocytic capacity of rat microglia cells to remove apoptotic lymphocytes with that of astrocytes. Apoptosis was induced in autologous thymocytes and myelin basic protein (MBP)-specific T-cells by methylprednisolone (MP) or by irradiation. Apoptotic cells were then added to glial cells that were untreated or prestimulated with interferon-gamma (IFN-gamma), interleukin-4 (IL-4), transforming growth factor-beta (TGF-beta), or tumor necrosis factor-a (TNF-a). Supernatants were collected from cell cultures to measure their cytokine secretion. Surface antigen expression was analyzed by flow cytometry. Both cell types significantly increased their phagocytic activity in response to the addition of apoptotic lymphocytes when compared to non-apoptotic cells (p < 0.0001). Astrocytes removed only up to one third of the number of apoptotic lymphocytes ingested by microglia cells (p < 0.0001). Microglia cells significantly increased their phagocytosis rate after IFN-gamma stimulation and decreased it in response to IL-4. In contrast, astrocyte phagocytosis was almost unresponsive to cytokine stimulation. After interaction with apoptotic cells, microglia secreted significantly less TNF-alpha. Astrocytic TNF-alpha production was also decreased but not to a statistically significant extent. MHC-class II expression after phagocytosis was increased on microglia cells but not on astrocytes. Both microglia cells and astrocytes are capable of ingesting apoptotic cells, but microglia cells are much more efficient phagocytes. Their phagocytic capacity is modulated by the local microenvironment and microglial immune function is downregulated after phagocytosis. We suggest that in vivo astrocytes might be activated as phagocytes once the limit of microglial phagocytic capacity has been reached.

Animals↗
PubMed2002

Identification of four distinct regions of allelic imbalances on chromosome 1 by the combined comparative genomic hybridization and microsatellite analysis on hepatocellular carcinoma.

Frequent chromosome 1 abnormalities detected in human hepatocellular carcinoma have been implicated in early genetic events of liver carcinogenesis. Recurrent loss of 1p with a common deleted region 1p36-p34 has been reported from microsatellite analysis, whereas common gain of the whole chromosome q-arm was described from several comparative genomic hybridization studies. The relationships between copy number changes and allelic status however remains unclear. In this study, we have conducted a simultaneous comparative genomic hybridization and microsatellite analysis study on chromosome 1 in 31 hepatocellular carcinoma cases. Microsatellite analysis revealed frequent loss of heterozygosity on 1p at loci D1S468 (74%), D1S450 (67%), D1S2667 (65%), D1S2697 (75%), D1S199 (52%), and D1S234 (67%) corresponded to the distal 1p36 region and coincided with 12 cases (86%) that presented losses on 1p by comparative genomic hybridization analysis. Although comparative genomic hybridization indicated a common deleted region of 1p36-p35 in the current series, microsatellite analysis has refined the smallest overlapping region (SOR) to 1p36.13-p36.22. Gain of 1q as revealed by comparative genomic hybridization suggested low and high-level gains, and cases that displayed an amplicon below the heterochromatic region 1q21-q25. Common allelic imbalances of polymorphic markers D1S2635 (64%), D1S484 (67%), D1S2878 (65%), D1S196 (70%), D1S249 (64%) D1S2785 (75%), D1S2842 (73%) and D1S2836 (74%) that corresponded to the regions 1q23.1-q24.2, 1q32.1 and 1q43-q44 were detected. Three distinct regions of allelic imbalances were thus suggested on recurring 1q gain found in hepatocellular carcinoma. Furthermore, microsatellite analysis has enabled a mapping of common overrepresented regions and suggested SOR on 1q23.1-q23.3 (D1S2635-D1S2878), 1q25.1-q31.1 (D1S452-D1S238), and 1q43 (D1S2785-D1S2842). Our current study has refined chromosome 1 aberrations in hepatocellular carcinoma to four regions of allelic imbalances. The SORs delineated should provide basis for further molecular investigation in hepatocarcinogenesis on genes residing on these chromosomal regions.

Adult↗