The need for a systematic approach to complex pathways in molecular epidemiology.
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DNA Damage↗
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Homing and trafficking of hemopoietic progenitor cells.
Investigations of the homing of transplanted hemopoietic cells into preconditioned recipients have in most studies been referable to parameters that determine engraftment. The principles, however, that govern their early traffic into the host's blood and tissues have remained much less explored. Early studies and experiments from our own laboratory suggest that intravenously administered hemopoietic cells, including progenitors, are not selectively taken up by bone marrow, as they are distributed widely in several tissues (liver, lung, kidney, spleen, bone marrow). As the hemopoietic cells are later on found almost exclusively in the bone marrow (and spleen in the mouse), the data argue for either preferential retention in these tissues or just only preferential survival and proliferation. Our recent studies showing modulation of cells lodged to the bone marrow, before proliferation ensues (i.e. 3 h after infusion), would favor preferential retainment and/or survival of these cells within the bone marrow. Furthermore we established that the VLA4/VCAM-1 adhesion pathway plays a significant role in this process, thus defining VCAM-1 as the dominant bone marrow endothelial addressin in hemopoietic cell homing. Since homing likely represents a cascade of adhesive interactions between hemopoietic cells and bone marrow stroma and/or its extracellular matrix, other adhesion pathways are likely to be involved and remain to be defined. Finally, our data on mobilization of hemopoietic progenitors from normal individuals, induced by blocking the VLA4/VCAM-1 adhesion pathway, suggest that the molecular pathways involved in homing are also of importance in governing hemopoietic progenitor cell trafficking in and out of the bone marrow.
Animals↗
Acute promyelocytic leukemia as a model for cross-talk between interferon and retinoic acid pathways: from molecular biology to clinical applications.
Acute promyelocytic leukemia (APL) has been regarded as the paradigm for therapeutic approaches utilizing differentiating agents, due to the fact that almost 95% of patients undergo complete remission when treated with all-trans retinoic acid (ATRA). However, complete clinical remission with ATRA alone is always transient, and relapse in APL is almost invariably associated with the acquisition of resistance to ATRA. Acquired resistance to ATRA in APL cell lines and in some APL clinical cases can be partially overcome by interferons (IFNs), cytokines which have well established tumor-growth suppressive activities. APL is associated in 99% of cases with a 15;17 translocation that fuses the PML and Retinoic Acid Receptor alpha (RARalpha) genes. RARalpha is one of the Retinoic Acid (RA) nuclear receptors which mediates, at the transcriptional level, ATRA differentiating and growth suppressive activity. PML is a tumor-growth suppressor whose expression is directly regulated by IFNs. Here we review the molecular mechanisms by which IFNs and RA can cooperate in controlling cell growth and differentiation of normal hemopoietic cells and leukemic cells, focusing on APL as a model system.
Drug Synergism↗
[Studying the SUMO modification pathway: from molecular structure to regulation of epigenome].
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Animals↗
Studies on the biosynthetic pathways of molecular species of lecithin by rat lung slices.
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Animals↗
Ab initio genotype-phenotype association reveals intrinsic modularity in genetic networks.
Microbial species express an astonishing diversity of phenotypic traits, behaviors, and metabolic capacities. However, our molecular understanding of these phenotypes is based almost entirely on studies in a handful of model organisms that together represent only a small fraction of this phenotypic diversity. Furthermore, many microbial species are not amenable to traditional laboratory analysis because of their exotic lifestyles and/or lack of suitable molecular genetic techniques. As an adjunct to experimental analysis, we have developed a computational information-theoretic framework that produces high-confidence gene-phenotype predictions using cross-species distributions of genes and phenotypes across 202 fully sequenced archaea and eubacteria. In addition to identifying the genetic basis of complex traits, our approach reveals the organization of these genes into generic preferentially co-inherited modules, many of which correspond directly to known enzymatic pathways, molecular complexes, signaling pathways, and molecular machines.
Bacteria↗
RNA-seq Analysis of Peri-Implant Tissue Shows Differences in Immune, Notch, Wnt, and Angiogenesis Pathways in Aged Versus Young Mice.
The number of total joint replacements (TJRs) in the United States is increasing annually. Cementless implants are intended to improve upon traditional cemented implants by allowing bone growth directly on the surface to improve implant longevity. One major complication of TJR is implant loosening, which is related to deficient osseointegration in cementless TJRs. Although poor osseointegration in aged patients is typically attributed to decreased basal bone mass, little is known about the molecular pathways that compromise the growth of bone onto porous titanium implants. To identify the pathways important for osseointegration that are compromised by aging, we developed an approach for transcriptomic profiling of peri-implant tissue in young and aged mice using our murine model of osseointegration. Based on previous findings of changes of bone quality associated with aging, we hypothesized that aged mice have impaired activation of bone anabolic pathways at the bone-implant interface. We found that pathways most significantly downregulated in aged mice relative to young mice are related to angiogenic, Notch, and Wnt signaling. Downregulation of these pathways is associated with markedly increased expression of inflammatory and immune genes at the bone-implant interface in aged mice. These results identify osseointegration pathways affected by aging and suggest that an increased inflammatory response in aged mice may compromise peri-implant bone healing. Targeting the Notch and Wnt pathways, promoting angiogenesis, or modulating the immune response at the peri-implant site may enhance osseointegration and improve the outcome of joint replacement in older patients. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
AGING↗
Concurrent EGFr and Cox-2 expression in colorectal cancer: proliferation impact and tumour spreading.
BACKGROUND: Many reports were produced on single epidermal growth factor receptor (EGFr) and cyclo-oxygenase-2 (Cox-2) evaluation using immunohistochemical techniques (IHC), but very few works considered concurrent expression of these two proteins in the light of their impact on proliferation and tumour spreading. At least three molecular pathways (EGFr, Cox-2, and APC/beta-catenin molecular cascade) may interact in this malignancy giving rise to cross talking effects on proliferation and cancer spreading. PATIENTS AND METHODS: To better detail these two latter aggressive features, we studied 205 sporadic colorectal cancer patients, comparing concurrent expression of EGFr, Cox-2, Ki-67, Cyclins D1-A, and E, with tumour spreading (budding) (BUD) and pN status. RESULTS: Our results point to a different aggressive molecular profile due to Cox-2 expression. Cox-2 High expressing cases showed a clear EGFr proliferation-promoting role. On the contrary, EGFr seems directly involved in cancer cells spreading rather than in promoting cancer proliferation in Cox-2 Low/Negative cases. CONCLUSIONS: Immunohistochemical profiling of colorectal cancer seems to be a promising approach, not only to define prognostic impact, but also to detail proliferation-related molecular interplays between EGFr and Cox-2 pathways, with these two latter proteins, at present, being the hottest pharmacological targets for colorectal cancer (CRC) chemoprevention and therapy.
Adult↗
Local recurrence of myxofibrosarcoma is associated with increase in tumour grade and cytogenetic aberrations, suggesting a multistep tumour progression model.
Myxofibrosarcoma is one of the most frequent soft tissue tumours in elderly patients, mostly arising in the extremities. Grade I lesions are only locally aggressive whereas grade II and grade III lesions have metastatic potential. The differential diagnosis contains several other (benign) myxoid soft tissue tumours. A number of sarcomas are characterised by specific cytogenetic aberrations, giving not only insight in their biological pathways; they also serve as molecular markers in difficult diagnoses. Cytogenetic data on myxofibrosarcoma are scarce with only few isolated cases described in the literature. No specific chromosomal aberrations have been detected so far. Moreover, molecular pathways in tumorigenesis and progression of myxofibrosarcoma are barely understood. We studied the clinicopathologic data and karyotypes of 32 myxofibrosarcomas using conventional banding and multicolour COmbined Binary RAtio labelling fluorescence in situ hybridisation technique. We included eight grade I, eight grade II and 16 grade III lesions. In all, 22 were primary tumours, nine were local recurrences and one a lymph node metastasis. The myxofibrosarcomas showed equal sex distribution, were mostly located at the extremities with two thirds deep-seated and had an average age of occurrence of 66 years. We found normal karyotypes in eight cases and clonal beside nonclonal aberrations in 22 cases. Complex cytogenetic anomalies were found in all grades. However, no tumour-specific chromosomal abnormalities could be withdrawn. Local recurrences showed increase in grade compared to their primary lesions. Interestingly, these recurrences showed more complex cytogenetic aberrations. Increase in grade seems to parallel increase in cytogenetic aberrations and malignant potential. Since the chromosomal aberrations found were not tumour type specific, they seem to be rather the result of secondary events in tumour progression and tumour genetic instability. Based on these findings, we suggest that tumorigenesis of myxofibrosarcoma is mainly a multistep genetic process, probably ruled by genetic instability caused by targeted checkpoint genes.
Adult↗
Probing the molecular program of apoptosis by cancer chemopreventive agents.
This paper provides a rational molecular basis for studies intended to clarify the interactions between cancer chemopreventive agents and apoptosis, one of the natural forms of cell death that overlaps molecular mechanisms with other forms such as programmed cell death and specialized forms of physiological cell death. Molecular details of the process show the existence of distinct molecular pathways leading to the activation of critical effector elements (apoptosis gene products) functioning under the control of a network of negative regulatory elements. Dysregulation of either apoptosis or anti-apoptosis genes has a significant role in multistage carcinogenesis. Inhibition of apoptosis is one of the underlying mechanisms of the action of tumor promoters. The network of apoptosis and anti-apoptosis gene products provides multiple targets for compounds with cancer chemopreventive potential. Many data in the literature show initiating, potentiating or inhibitory effects of such compounds on apoptosis. However, the molecular mechanism of these effects is largely unknown. We initiated a series of studies using mouse thymocytes which undergo apoptosis through distinct molecular mechanisms after T-cell receptor activation (TCR pathway), following the addition of glucocorticoids (DEX pathway) or DNA damaging agents (p53 pathway). All trans-and 9-cis-retinoic acid induced apoptosis, elicited through the DEX pathway, inhibited the TCR pathway, and did not affect p53- initiated apoptosis. N-acetylcysteine can inhibit all forms. Sodium salicylate enhanced spontaneous cell death, decreased p53-dependent apoptosis, and did not affect the DEX and TCR pathways. These preliminary results, which show differential effects of the studied compounds on distinct molecular pathways of apoptosis, warrant further investigations in the effort to utilize the molecular elements of apoptosis in proper cancer chemoprevention, and find biochemical targets for apoptosis-related surrogate endpoint biomarker assays of chemoprevention.
Acetylcysteine↗
Understanding the molecular causes of Parkinson's disease.
Parkinson's disease (PD) is a neurodegenerative disease that is both common and incurable. The majority of cases are sporadic and of unknown origin but several genes have been identified that, when mutated, give rise to rare, familial forms of the disease. The principal genes that have been shown to cause PD are alpha-synuclein (SNCA), parkin, leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1) and DJ-1. Here, we discuss what has been learnt from the study of these genes and what has been elucidated of the molecular pathways that lead to cell degeneration. Of importance is what these molecular events and pathways tell scientists of the common sporadic form of PD. Although complete knowledge of these genes' functions remains elusive, recent work implicates abnormal protein accumulation, protein phosphorylation, mitochondrial dysfunction and oxidative stress as common pathways to PD pathogenesis.
Adult↗
Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation.
The limited number of genome-wide transcriptome analyses using the postmortem brains of bipolar disorder sufferers has not produced a clear consensus on the molecular pathways affected by the disorder. To expand the knowledge in this area, we examined the expression levels of more than 12 000 genes in Brodmann's Area (BA), 46 (dorsolateral prefrontal cortex) from bipolar I disorder and control samples using Affymetrix GeneChips. This analysis detected 108 differentially expressed genes in bipolar brains. Validation studies using quantitative RT-PCR on the two original diagnostic cohorts plus tissue from schizophrenic subjects, confirmed the differential expressions of eight genes (RAP1GA1, SST, HLA-DRA, KATNB1, PURA, NDUFV2, STAR and PAFAH1B3) in a bipolar-specific manner and one gene (CCL3) which was downregulated in both bipolar and schizophrenic brains. Of these, protein levels of RAP1GA1 (RAP1 GTPase activating protein 1) showed a trend of increase in BA46 from bipolar brains, in keeping with mRNA transcript levels. Transmission disequilibrium analysis of the nine genes using 43 single nucleotide polymorphisms (SNPs) in 229 National Institute of Mental Health bipolar trios exposed nominal SNP association and modest empirical haplotypic association (P=0.033) between SST (somatostatin) and disease. Finally, gene network analysis using the currently obtained expression data highlighted cellular growth and nervous system development pathways as potential targets in the molecular pathophysiology of bipolar disorder.
1-Alkyl-2-acetylglycerophosphocholine Esterase↗
Revealing and utilizing receptor recognition mechanisms in a high-throughput world.
Recent genomic mapping promises to identify essentially all of the proteins that underpin normal and aberrant biology in humans. What genomics leaves undone is to determine how these proteins interact and integrate into molecular pathways in health and disease. Specific molecular interactions provide the fundamental mechanism for selectivity in virtually every aspect of biological structure and function. The convergence of structural and mutational studies makes it possible to define what parts of a protein are important for recognition. Still, knowing what is important does not necessarily foretell how binding epitopes actually function. We have applied the approach of epitope randomization on phage to explore how structural elements in such receptor recruitment systems as interleukin-5 (IL-5) and HIV-1 function in receptor recognition. This work has led in the IL-5 case to differentiation of recognition and activation epitopes, and this in turn has potential to help in the design of non-activating mimetics that could stimulate development of therapeutic antagonists for allergic inflammations such as asthma. Whether it is possible to differentiate recognition and activation in designing inhibitors in cases such as HIV-1 cell attachment and infection remains a tantalizing, but unsolved goal at present. Overall, these studies portray advances as well as limitations in the effort to decipher protein recognition mechanisms and utilize the wisdom gained for mechanism-based antagonist design in an increasingly high throughput world stimulated by the advent of genomics and proteomics.
Binding Sites↗
Cocaine induced inflammatory response in human neuronal progenitor cells.
We have employed a genomic approach in homogenous cell culture to investigate the fundamental transcriptional responses which occur in neurons over time as a consequence of a single 30-min exposure to cocaine. Data from 24 Affymetrix microarrays, representing eight treatment groups, were analyzed by GeneChip Operating Software and then further mined by hierarchical clustering, anova, and Ingenuity Pathway Analysis software to examine known molecular pathways impacted by the observed transcriptional changes. For each time point under investigation, the data sets of genes exhibiting altered expression in treated cells compared with control were interrogated with a specific focus on differential expression of genes involved in immunomodulation and inflammation. The existing literature on the effects of cocaine in a diverse array of experimental paradigms demonstrates a significant modulation of inflammation and immune mechanisms, but these have typically been studies of chronic exposure in immune-competent cells. Our data show a time-dependent up-regulation of genes associated with pro-inflammatory and immune responses, peaking at 24 h as confirmed by all methods of analysis, suggesting a specific neuronal immunomodulatory response to acute cocaine exposure.
Analysis of Variance↗
Mechanisms of ventral patterning in the vertebrate nervous system.
Dorsoventral patterning of the neural tube has a crucial role in shaping the functional organization of the CNS. It is well established that hedgehog signalling plays a key role in specifying ventral cell types throughout the neuroectoderm, and major progress has been made in elucidating how hedgehog signalling works in this ventral specification. In addition, other molecular pathways, including nodal, retinoic acid and fibroblast growth factor signalling, have been identified as important molecular cues for ventral patterning of the spinal cord, telencephalon and eye. Here, we discuss recent advances in this field, highlighting the emerging interplay of these signalling pathways in the molecular specification of ventral patterning at different rostrocaudal levels of the CNS.
Animals↗
B-lymphocyte quiescence, tolerance and activation as viewed by global gene expression profiling on microarrays.
Self-tolerance is achieved by deleting or regulating self-reactive lymphocytes at a series of cellular checkpoints placed at many points along the developmental pathways to plasma cells and effector T cells. At each checkpoint, what are the molecular pathways that determine whether a lymphocyte remains quiescent, begins dividing, differentiates or dies? In splenic B cells, the decision between quiescence, tolerance by anergy, and activation provides a tractable setting to explore these issues by global gene expression profiling on DNA microarrays. Here we discuss the application of microarrays to illuminate a set of cell fate decisions that appear to be determined by summation of numerous small changes in expression of stimulatory and inhibitory genes. Many genes with known or predicted inhibitory functions are highly expressed in naive, quiescent B cells, notably the signal inhibitor SLAP and DNA-binding proteins of the Kruppel family (LKLF, BKLF, GKLF), Tsc-22, GILZ, Id-3, and GADD45. Activation of naive B cells, triggered by acute binding of antigen to the B-cell receptor, involves a rapid decrease in expression of these inhibitory genes. Promitotic genes are induced in parallel, including c myc, LSIRF/IRF4, cyclin D2, Egr-1 and Egr-2, as are the anti-apoptotic gene A1 and genes for the T-cell-attracting chemokines MIP-1alpha and beta. B-cell tolerance through the process of anergy, induced by chronic binding of self antigen, maintains expression of the inhibitory genes found in quiescent B cells and induces an additional set of inhibitory genes. The latter include inhibitors of signaling - CD72, neurogranin, pcp4 - and additional inhibitors of gene expression such as SATB1, MEF2C, TGIF and Nab-2. The effects of tolerance, the immunosuppressive drug FK506 and other modulators of calcium or MAPK signaling allow individual gene responses to be linked to different signal transduction pathways. The global molecular profiles obtained illustrate how quiescence and anergy are actively maintained in circulating B cells, how these states are switched to clonal expansion and how they could be better emulated by pro-tolerogenic drugs.
Animals↗
From genes to systems: new global strategies for the characterization of NCL biology.
Neuronal ceroid lipofuscinoses (NCL) are rare neurological disorders with a uniform phenotype, caused by mutations in seven known genes. NCL provide a unique model to characterize molecular pathways critical for normal neuronal development and pathological neuronal degeneration. Systems biology based approach utilizes the rapidly developing tools of genomics, proteomics, lipidomics and metabolomics and aims at thorough understanding of the functions of cells, tissues and whole organisms by molecular analysis and biocomputing-assisted modeling. The systems level understanding of NCL is now possible by utilizing different model organisms. Initial work has revealed disturbed metabolic pathways in several NCL disorders and most analyses have utilized the infantile (INCL/CLN1) and juvenile (JNCL/CLN3) disease modeling and utilized mainly human and mouse samples. To date, the data obtained from transcript and lipidomic profiling has pinpointed the role of lipid metabolism and synaptic function in the infantile NCL. Changes in glutamate utilization and amino acid metabolism have been a common theme emerging from the transcript and metabolite profiling of the juvenile NCL. Further experimental models are being developed and systematic sample collection as well as data integration projects are needed. The combined analyses of the global information should provide means to expose all the NCL-associated molecular pathways.
Animals↗
Cytokine therapy for craniosynostosis.
The birth prevalence of craniosynostosis (premature suture fusion) is 300-500 per 1,000,000 live births. Surgical management involves the release of the synostosed suture. In many cases, however, the suturectomy site rapidly reossifies, further restricts the growing brain and alters craniofacial growth. This resynostosis requires additional surgery, which increases patient morbidity and mortality. New findings in bone biology and molecular pathways involved with suture fusion, combined with novel tissue engineering techniques, may allow the design of targeted and complementary therapies to decrease complications inherent in high-risk surgical procedures. This paper selectively reviews recent advances in i) identifying genetic mutations and the aetiopathogenesis of a number of craniosynostotic conditions; ii) cranial suture biology and molecular biochemical pathways involved in suture fusion; and iii) the design, development and application of various vehicles and tissue engineered constructs to deliver cytokines and genes to cranial sutures. Such biologically based therapies may be used as surgical adjuncts to rescue fusing sutures or help manage postoperative resynostosis.
Child↗