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PubMed2026

Improving recombinant protein productivity in CHO cells via multi-omics data integration.

Chinese hamster ovary (CHO) cells represent the dominant host system for the production of recombinant therapeutic proteins. In recent decades, extensive research has focused on process/media optimization and cell line engineering to improve both the productivity and quality of biopharmaceutical proteins produced in CHO cells. Nevertheless, the inherent complexity of biological pathways and the heterogeneous cellular responses to different environmental conditions have posed substantial challenges to traditional methodologies. Recent advances in omics technologies have enabled comprehensive characterization of CHO cell physiology, providing multidimensional molecular and phenotypic insights that facilitate the enhancement of recombinant protein production. This review first summarizes the methodologies and advances in CHO omics research, including genomics, transcriptomics, proteomics, metabolomics, and epigenomics. It then examines contemporary approaches to integrate and analyze multi-omics data in CHO cells. The review further elucidates how these multi-omics datasets can be strategically applied across various developmental stages, including cell line selection, genetic engineering, expression vector design, and bioprocess optimization. Finally, we explore the transformative potential of integrating multi-omics with artificial intelligence and discuss promising future research directions in CHO cell studies. These emerging paradigms offer novel opportunities for data-driven cell engineering and bioprocess optimization in CHO-based biomanufacturing.

Bioprocessing↗
PubMed2005

CBLB variants in type 1 diabetes and their genetic interaction with CTLA4.

Type 1 diabetes (T1D) is a multifactorial disease with genetic and environmental components involved. Recent studies of an animal model of T1D, the Komeda diabetes-prone rat, have demonstrated that the Casitas-B-lineage lymphoma b (cblb) gene is a major susceptibility gene in the development of diabetes and other autoimmune features of this rat. As a result of the inhibitory role of Cbl-b in T cell costimulation, dysregulation of Cbl-b may also contribute to autoimmune diseases in man. Different isoforms of Cbl-b exist; we evaluated expression levels of two known transcript variants. Constitutive expression of both isoforms was demonstrated, as well as an increased expression, after cytokine exposure, of an isoform lacking exon 16, suggesting a possible role of this variant in the pathogenesis of autoimmunity. We screened coding regions of the human CBLB gene for mutations in a panel of individuals affected with several autoimmune diseases. Eight single nucleotide polymorphisms (SNPs) were detected. One SNP in exon 12 of the CBLB gene was significantly demonstrated to be associated to T1D in a large Danish T1D family material of 480 families. Evidence for common genetic factors underlying several autoimmune diseases has come from studies of cytotoxic T lymphocyte antigen 4 (CTLA4), which encodes another negatively regulatory molecule in the immune system. Gene-gene interactions probably play substantial roles in T1D susceptibility. We performed stratification of CBLB exon 12 SNP data, according to an established CTLA4 marker, CT60, and evidence for a genetic interaction between the CTLA4 and CBLB genes, involved in the same biological pathway of T cell receptor signaling, was observed.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Genetic determinants of obesity-related lipid traits.

In our ongoing effort to identify genes influencing the biological pathways that underlie the metabolic disturbances associated with obesity, we performed genome-wide scanning in 2,209 individuals distributed over 507 Caucasian families to localize quantitative trait loci (QTLs), which affect variation of plasma lipids. Pedigree-based analysis using a quantitative trait variance component linkage method that localized a QTL on chromosome 7q35-q36, which linked to variation in levels of plasma triglyceride [TG, logarithm of odds (LOD) score = 3.7] and was suggestive of linkage to LDL-cholesterol (LDL-C, LOD = 2.2). Covariates of the TG linkage included waist circumference, fasting insulin, and insulin:glucose, but not body mass index or hip circumference. Plasma HDL-cholesterol (HDL-C) levels were suggestively linked to a second QTL on chromosome 12p12.3 (LOD = 2.6). Five other QTLs with lower LOD scores were identified for plasma levels of LDL-C, HDL-C, and total cholesterol. These newly identified loci likely harbor genetic elements that influence traits underlying lipid adversities associated with obesity.

Blood Glucose↗
PubMed2006

Alexithymia and neuroendocrine-immune response in patients with autoimmune diseases: preliminary results on relationship between alexithymic construct and TNF-alpha levels.

Alexithymia is conceptualized as a disorder of emotion regulation mechanisms, which involves a dissociation of emotional and physical responses to life events and bodily sensations. Our results might suggest a possible relationship between the alexithymic construct and TNF levels in RA patients. These preliminary findings corroborate the integrated bidirectional interactions between neuropsychological mechanisms and the neuroendocrine-immune system in patients affected by autoimmune diseases and contribute to finding a common biological pathway linking alexithymia and autoimmune-inflammatory diseases.

Affective Symptoms↗
PubMedDate not supplied

The use of growth factors on tendon injuries.

Tendon injuries continue to be a vexing clinical problem faced by the upper extremity surgeon. These injuries often lead to disability and dissatisfaction for both the patient and treating physician. Advances throughout the century have focused largely on improvements in surgical techniques and therapy protocols. Recently, attention has been turned to the biologic pathways by which tendons heal and the growth factors involved in this process have been identified. There is great hope that these growth factors may one day be used to treat tendon injuries. This article provides a summary of the use of growth factors on tendon injuries including contemporary research, delivery methods, and future directions in this field.

Animals↗
PubMed2002

A comparative study of growth-inhibitory effects of isoflavones and their metabolites on human breast and prostate cancer cell lines.

The possible growth-inhibitory properties of the recently synthesized novel metabolite 1-(2,4-dihydrobenzoyl)-1-(4-hydroxyphenyl)ethylene (2-de-O-DMA) and six other metabolites of isoflavones were investigated and compared with those of the major isoflavones genistein, daidzein, and glycitein on human breast noncancer and breast and prostate cancer cell lines in vitro. The novel metabolite 2-de-O-DMA was found to be a more potent inhibitor than genistein on human breast cancer MCF-7, MDA-MB-468, and SK-BR-3 cells and breast noncancer MCF-10A cells. In prostate cancer cell lines, LNCaP and DU145, 2-de-O-DMA elicited a six- to sevenfold more potent inhibition than genistein. Flow cytometric analysis showed that 2-de-O-DMA and genistein blocked cells at the G2/M phase of the cell cycle. Genistein and 2-de-O-DMA led to apoptosis of a variety of cancer cell lines. The rapid response of growth inhibition induced by 2-de-O-DMA compared with genistein strongly suggests that the observed antiproliferation effects elicited by this novel metabolite are mediated via a biological pathway different from that induced by genistein. 2-de-O-DMA, a novel metabolite of isoflavone, could have a potential role in chemopreventive and chemotherapeutic treatment of hormonal breast and prostate cancers.

Apoptosis↗
PubMed2004

Abnormal gene expression profiles in human ovaries from polycystic ovary syndrome patients.

Polycystic ovary syndrome (PCOS) represents the most common cause of anovulatory infertility and affects 5-10% of women of reproductive age. The etiology of PCOS is still unknown. The current study is the first to describe consistent differences in gene expression profiles in human ovaries comparing PCOS patients vs. healthy normoovulatory individuals. The microarray analysis of PCOS vs. normal ovaries identifies dysregulated expression of genes encoding components of several biological pathways or systems such as Wnt signaling, extracellular matrix components, and immunological factors. Resulting data may provide novel clues for ovarian dysfunction in PCOS. Intriguingly, the gene expression profiles of ovaries from (long-term) androgen-treated female-to-male transsexuals (TSX) show considerable overlap with PCOS. This observation provides supportive evidence that androgens play a key role in the pathogenesis of PCOS. Presented data may contribute to a better understanding of dysregulated pathways in PCOS, which might ultimately reveal novel leads for therapeutic intervention.

Adult↗
PubMed2005

The nuclear xenobiotic receptor pregnane X receptor: recent insights and new challenges.

The nuclear receptor pregnane X receptor (PXR) plays a key but structurally enigmatic role in human biology. This ligand-regulated transcription factor responds to a diverse array of chemically distinct ligands, including many endogenous compounds and clinical drugs, and regulates the expression of a critical set of protective gene products involved in xenobiotic and endobiotic metabolism. The structural basis of this receptor's remarkable and unique promiscuity is just now coming into focus. We examine the importance of mobile regions novel to the nuclear receptor ligand-binding domain fold in the ability of PXR to respond to a variety of small and large agonists. We also review the functional roles played by PXR in numerous biological pathways and outline emerging areas for the future examination of this key nuclear xenobiotic receptor.

Amino Acid Sequence↗
PubMed2006

RNA aptamers binding the double-stranded RNA-binding domain.

Specific RNA recognition of proteins containing the double-strand RNA-binding domain (dsRBD) is essential for several biological pathways such as ADAR-mediated adenosine deamination, localization of RNAs by Staufen, or RNA cleavage by RNAse III. Structural analysis has demonstrated the lack of base-specific interactions of dsRBDs with either a perfect RNA duplex or an RNA hairpin. We therefore asked whether in vitro selections performed in parallel with individual dsRBDs could yield RNAs that are specifically recognized by the dsRBD on which they were selected . To this end, SELEX experiments were performed using either the second dsRBD of the RNA-editing enzyme ADAR1 or the second dsRBD of Xlrbpa, a homolog of TRBP that is involved in RISC formation. Several RNA families with high binding capacities for dsRBDs were isolated from either SELEX experiment, but no discrimination of these RNAs by different dsRBDs could be detected. The selected RNAs are highly structured, and binding regions map to two neighboring stem-loops that presumably form stacked helices and are interrupted by mismatches and bulges. Despite the lack of selective binding of SELEX RNAs to individual dsRBDS, selected RNAs can efficiently interfere with RNA editing in vivo.

Adenosine Deaminase↗
PubMed2001

Array of hope for gene technology.

A Washington-based bioinformatics company is developing sophisticated DNA microarrays that should help researchers measure and analyze gene expression faster, more economically, and with greater precision than ever before possible. The FlexJet system, as the microarray product is known, uses inkjet technology to propel microscopic strands of DNA nucleotides onto slides, "printing" arrays of DNA molecules in a process not unlike the manner in which a printer deposits ink onto paper, forming distinct patterns of characters and images. Microarray technology may revolutionize the field of toxicogenomics by helping scientists target new drugs, discover gene function, determine biologic pathways, and better understand diseases such as cancer, cystic fibrosis, and cardiovascular disease at the molecular level.

Computers↗
PubMed1999

The evolving role of platelet glycoprotein IIb/IIIa inhibitors in the management of acute coronary syndromes.

OBJECTIVE: To briefly discuss the pathophysiology of acute coronary syndromes (ACS) and to present the clinical data currently available regarding the use of platelet glycoprotein (GP) IIb/IIIa inhibitors in the management of ACS. DATA SOURCES: Literature on antithrombotic therapy in ACS was identified using a MEDLINE search (January 1988-September 1998), along with the Agency on Health Care Policy and Research guidelines for the management of unstable angina. Abstracts from recent scientific meetings were also reviewed. STUDY SELECTION: Review articles from the cardiology literature (pathophysiology) and randomized, controlled clinical trials of currently approved platelet GP IIb/IIIa inhibitors in ACS were evaluated. Ex vivo platelet aggregation studies and pharmacology literature were also included. Abstract data were included to illustrate specific points when published literature was not available. DATA EXTRACTION: Study data were evaluated based on study design, outcome parameters, and adverse drug reactions. Clinical information from review articles was evaluated based on applicability to the treatment of ACS. DATA SYNTHESIS: Platelet adhesion and aggregation are pivotal events in the pathophysiology of ACS. The GP IIb/IIIa inhibitors represent a new and unique class of drugs that block fibrinogen and von Willebrand factor-mediated platelet aggregation, the common end point of all biologic pathways of platelet aggregation. Three agents are currently approved by the Food and Drug Administration: abciximab, a monoclonal antibody; eptifibatide, a synthetic peptide; and tirofiban, a synthetic nonpeptide. CONCLUSIONS: Clinical trial data demonstrate efficacy of all three GP IIb/IIIa inhibitors in reducing the combined end point of morbidity and mortality in patients undergoing angioplasty. Eptifibatide and tirofiban also reduce the combined end point of morbidity and mortality in patients with unstable angina. These data expand the present role of platelet GP IIb/IIIa inhibitors by providing evidence for their effectiveness in the medical treatment of ACS. However, the specific role that these agents will have in the management of ACS is yet to be fully defined.

Acute Disease↗
PubMed1999

Adenovirus-mediated gene therapy of osteoblasts in vitro and in vivo.

Modulation of biological pathways governing osteogenesis may accelerate osseous regeneration and reduce the incidence of complications associated with fracture healing. Transforming growth factor beta1 (TGF-beta1) is a potent growth factor implicated in the regulation of osteogenesis and fracture repair. The use of recombinant proteins, however, has significant disadvantages and has limited the clinical utility of these molecules. Targeted gene therapy using adenovirus vectors is a technique that may circumvent difficulties associated with growth factor delivery. In this study, we investigate the efficacy of replication-deficient adenoviruses containing the human TGF-beta1 and the bacterial lacZ genes in transfecting osteoblasts in vitro and osseous tissues in vivo. We demonstrate that adenovirus-mediated gene therapy efficiently transfects osteoblasts in vitro with the TGF-beta1 virus causing a marked up-regulation in TGF-beta1 mRNA expression even 7 days after transfection. Increased TGF-beta1 mRNA expression was efficiently translated into protein production and resulted in approximately a 46-fold increase in TGF-beta1 synthesis as compared with control cells (vehicle- or B-galactosidase-transfected). Moreover, virally produced TGF-beta1 was functionally active and regulated the expression of collagen IalphaI (5-fold increase) and the vascular endothelial growth factor (2.5-fold increase). Using an adenovirus vector encoding the Escherichia coli LacZ gene, we demonstrated that adenovirus-mediated gene transfer efficiently transfects osteoblasts and osteocytes in vivo and that transfection can be performed by a simple percutaneous injection. Finally, we show that delivery of the hTGF-beta1 gene to osseous tissues in vivo results in significant changes in the epiphyseal plate primarily as a result of increased thickness of the provisional calcification zone.

Adenoviridae↗
PubMed2005

Using microarrays to facilitate positional cloning: identification of tomosyn as an inhibitor of neurosecretion.

Forward genetic screens have been used as a powerful strategy to dissect complex biological pathways in many model systems. A significant limitation of this approach has been the time-consuming and costly process of positional cloning and molecular characterization of the mutations isolated in these screens. Here, the authors describe a strategy using microarray hybridizations to facilitate positional cloning. This method relies on the fact that premature stop codons (i.e., nonsense mutations) constitute a frequent class of mutations isolated in screens and that nonsense mutant messenger RNAs are efficiently degraded by the conserved nonsense-mediated decay pathway. They validate this strategy by identifying two previously uncharacterized mutations: (1) tom-1, a mutation found in a forward genetic screen for enhanced acetylcholine secretion in Caenorhabditis elegans, and (2) an apparently spontaneous mutation in the hif-1 transcription factor gene. They further demonstrate the broad applicability of this strategy using other known mutants in C. elegans,Arabidopsis, and mouse. Characterization of tom-1 mutants suggests that TOM-1, the C. elegans ortholog of mammalian tomosyn, functions as an endogenous inhibitor of neurotransmitter secretion. These results also suggest that microarray hybridizations have the potential to significantly reduce the time and effort required for positional cloning.

Journal Article↗
PubMed2024

A comprehensive analysis of ribonucleotide reductase subunit M2 for carcinogenesis in pan-cancer.

BACKGROUND: Although there is evidence that ribonucleotide reductase subunit M2 (RRM2) is associated with numerous cancers, pan-cancer analysis has seldom been conducted. This study aimed to explore the potential carcinogenesis of RRM2 in pan-cancer using datasets from The Cancer Genome Atlas (TCGA). METHODS: Data from the UCSC Xena database were analyzed to investigate the differential expression of RRM2 across multiple cancer types. Clinical data such as age, race, sex, tumor stage, and status were acquired to analyze the influence of RRM2 on the clinical characteristics of the patients. The role of RRM2 in the onset and progression of multiple cancers has been examined in terms of genetic changes at the molecular level, including tumor mutational burden (TMB), microsatellite instability (MSI), biological pathway changes, and the immune microenvironment. RESULTS: RRM2 was highly expressed in most cancers, and there was an obvious correlation between RRM2 expression and patient prognosis. RRM2 expression is associated with the infiltration of diverse immune and endothelial cells, immune checkpoints, tumor mutational burden (TMB), and microsatellite instability (MSI). Moreover, the cell cycle is involved in the functional mechanisms of RRM2. CONCLUSIONS: Our pan-cancer study provides a comprehensive understanding of the carcinogenesis of RRM2 in various tumors.

Humans↗
PubMed2026

Exploring cross-category relationships between symptoms in people with hypermobile EDS (hEDS) to identify disability patterns.

BACKGROUND: Hypermobile Ehlers-Danlos Syndrome (hEDS) is a connective tissue disorder with variable symptom presentation across multiple organ systems and significant morbidity. Little is known about hEDS etiology and identifying patterns of symptom co-occurrence can reveal previously unidentified relationships between phenotypes and inform studies of underlying disease pathophysiology for symptoms that may share functional biological pathways. In this exploratory analysis, we specifically assessed the distribution of symptoms in case and controls to identify clusters of co-occurring symptoms. METHODS: We have interrogated clinically relevant symptom areas in 47 females with hEDS, 36 age-matched female controls and 8 hypermobile patients without chronic pain. Studied symptoms include general health, mental health, body pain, vitality and energy, autonomic symptoms, bleeding, and gastrointestinal symptoms. We conducted hierarchal clustering on principle components (HCPC) to identify groups and compared the groups for the previously described symptoms. Radial plots were used to identify relationships between severe symptom categories. RESULTS: Our analysis reveals statistically significantly more severe symptoms in all categories in people with hEDS compared with age- and sex-matched controls and asymptomatic hypermobile patients. HCPC identified clearly separated Low, Moderate, and High symptom groups within participants. The Low dysfunction groups include nearly all controls and hypermobile patients without chronic pain. The High dysfunction group includes ~60% of people with hEDS, while around 40% are in the Moderate dysfunction cluster. Cluster solutions for all participants were stable with moderate fit (silhouette 0.64; Jaccard boot mean 0.91). Group level radial plots showed high bleeding severity across all symptom clusters, while disproportional severity of general health, physical function, limitation of role due to physical symptoms, pain, and social functioning deficits differentiates the High from Moderate and Low Dysfunction clusters. CONCLUSION: Using this analysis at the group level has revealed patterns suggesting a progression of disease symptoms. People with hypermobility do not uniformly have severe symptoms but instead have some symptoms that differentiate from non-hypermobile individuals. While exploratory, using a radar multi-symptom analysis may be used to evaluate disproportionately severe symptoms contributing to the patterns of global symptom severity. These include pain but also ability to perform roles, suggesting strong utility of physical and occupational therapies to emphasize coping. This may also allow better targeting of etiological studies and may have additional utility at an individual level to develop symptom management strategies.

Humans↗
PubMed2005

Eating disorders: from twin studies to candidate genes and beyond.

Substantial effort has been put into the exploration of the biological background of eating disorders, through family, twin and molecular genetic studies. Family studies have shown that anorexia (AN) and bulimia nervosa (BN) are strongly familial, and that familial etiologic factors appear to be shared by both disorders. Twin studies often focus on broader phenotypes or subthreshold eating disorders. These studies consistently yielded moderate to substantial heritabilities. In addition, there has been a proliferation of molecular genetic studies that focused on Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) AN and BN. Seven linkage regions have been identified in genome-wide screens. Many genetic association studies have been performed, but no consistent association between a candidate gene and AN or BN has been reported. Larger genetic association studies and collaborations are needed to examine the involvement of several candidate genes and biological pathways in eating disorders. In addition, twin studies should be designed to assist the molecular work by further exploring genetic determinants of endophenotypes, evaluating the magnitude of contribution to liability of measured genotypes as well as environmental risk factors related to eating disorders. In this manner twin and molecular studies can move the field forward in a mutually informative way.

Anorexia↗
PubMed2001

Familial nonmedullary thyroid neoplasia.

Thyroid carcinoma accounts for less than 1% of all human malignancies and carries one of the highest overall familial relative risks as compared with cancers from other sites. This is particularly true for medullary carcinoma, as well as for carcinomas of follicular cell origin in general, where inheritance has been implicated in 2.5 to 6.3% of the cases. Familial nonmedullary thyroid tumors show a variety of genetic mechanisms implicated in thyroid tumorigenesis and occur in several tumor-prone traits (e.g., familial adenomatous polyposis [FAP] and Cowden's disease [CD]) or as the only or dominant inherited manifestation. The latter group includes the most common familial papillary carcinoma, in which environmental factors such as radiation exposure may also play an important etiological role. Familial follicular cell tumors show a variety of morphological features ranging from benign thyroid nodulation to carcinoma, usually develop in young individuals, and tend to be multicentric--an indication for total thyroidectomy to avoid tumor recurrence and potential risk of malignant transformation. The pathologist may play an important role in the histological interpretation of familial nonmedullary thyroid tumors, which may lead to further clinicogenetical investigations of the affected patient and family screening. Familial follicular cell thyroid neoplasms show a complex molecular biological pathway of tumorigenesis when compared between themselves and with their sporadic counterparts.

Adenocarcinoma, Follicular↗
PubMed2002

Microarray technology and its application on nicotine research.

Since its development, microarray technique has revolutionized almost all fields of biomedical research by enabling high-throughput gene expression profiling. Using cDNA microarrays, thousands of genes from various organisms have been examined with respect to differentiation/development, disease diagnosis, and drug discovery Nevertheless, research on nicotine using cDNA microarrays has been rather limited. Therefore, it is our intention in this article to report the findings of our cDNA microarray study on nicotine. We first present an overview of the microarray technology, particularly focusing on the factors related to microarray design and analysis. Second, we provide a detailed description of several newly identified biological pathways in our laboratory, such as phosphatidylinositol signaling and calcium homeostasis, which are involved in response to chronic nicotine administration. Additionally, we illustrate how comparisons between microarray studies help identify candidate genes that potentially may explain the observed inverse association between smoking and schizophrenia. Lastly, given the early stage of microarray research on nicotine, we elaborate on the need for an efficient analysis of genetic networks to further enhance our understanding of the mechanisms involved in nicotine abuse and addiction.

Animals↗