The biological and clinical significance of nicks in human chorionic gonadotropin and its free beta-subunit.

Human chorionic gonadotropin (hCG) is a glycoprotein hormone composed of two dissimilar subunits, alpha and beta. Nicks or missing peptide linkages have been found in the beta 44-52 region of the beta-subunit of hCG, whether from pregnancy or trophoblast disease. This article reviews recent reports about the location of nicks in hCG, their origin and occurrence, their effects on the steroidogenic and receptor-binding activities of hCG, and on the immunological activities of hCG and its free beta-subunit. Taken together, the reports show: (1) nicks occur primarily between beta 47 and beta 48, and to a lesser extent between beta 44 and beta 45; (2) the extent of nicking in hCG samples varies widely, from undetectable to 100 percent of molecules; (3) nicks greatly reduce the steroidogenic activity of hCG in vitro (nicked molecules have less than 20 percent of the activity of the intact hormone); (4) nicks may occur at the trophoblast-myometrial interface or in the circulation by the action of human leucocyte elastase or similar leucocytic protease; (5) hCG testing kits using dimer-specific antibodies may not detect nicked molecules and may give different results from those using other antibodies; (6) hCG international reference preparations and the CR series of hCG standards are variably nicked (10 percent to 20 percent), complicating the problem of discordant hCG results in nick-sensitive assays; (7) results from commonly used immunoassays for measurement of the hCG free beta-subunit vary by as much as tenfold because some of the antibodies employed do not detect nick free beta-subunit.     

Radiation-induced bystander effect in healthy G(o) human lymphocytes: biological and clinical significance

To study the bystander effects, G(0) human peripheral blood lymphocytes were X-irradiated with 0.1, 0.5 and 3 Gy. After 24h, cell-free conditioned media from irradiated cultures were transferred to unexposed lymphocytes. Following 48 h of medium transfer, viability, induction of apoptosis, telomere shortening, reactive oxygen species (ROS) levels and micronuclei (after stimulation) were analyzed. A statistically significant decrement in cell viability, concomitant with the loss of mitochondrial membrane potential, telomere shortening, increases in hydrogen peroxide (H(2)O(2)) and superoxide anion (O(2)(-)) with depletion of intracellular glutathione (GSH) level, and higher frequencies of micronuclei, were observed in bystander lymphocytes incubated with medium from 0.5 and 3 Gy irradiated samples, compared to lymphocytes unexposed. Furthermore, no statistically significant difference between the response to 0.5 and 3 Gy of irradiation in bystander lymphocytes, was found. However, when lymphocytes were irradiated with 0.1 Gy, no bystander effect with regard to viability, apoptosis, telomere length, and micronuclei was observed, although a high production of ROS level persisted. Radiation in the presence of the radical scavenger dimethyl sulfoxide (DMSO) suppressed oxidative stress induced by 3 Gy of X-rays with the effective elimination of bystander effects, suggesting a correlation between ROS and bystander signal formation in irradiated cells. The data propose that bystander effect might be mostly due to the reactions of radiation induced free radicals on DNA, with the existence of a threshold at which the bystander signal is not operative (0.1 Gy dose of X-rays). Our results may have clinical implications for health risk associated with radiation exposure.     

Tumor-associated urokinase-type plasminogen activator: biological and clinical significance.

Evidence has accumulated that invasion and metastasis in solid tumors require the action of tumor-associated proteases, which promote the dissolution of the surrounding tumor matrix and the basement membranes. Receptor-bound urokinase-type plasminogen activator (uPA) appears to play a key role in these events. uPA converts plasminogen into plasmin and thus mediates pericellular proteolysis during cell migration and tissue remodeling under physiological and pathophysiological conditions. uPA is secreted as an enzymatically inactive proenzyme (pro-uPA) by tumor cells and stroma cells. uPA exerts its proteolytic function on normal cells and tumor cells as an ectoenzyme after having bound to a high-affinity cell surface receptor. After binding, pro-uPA is activated by serine proteases (e.g. plasmin, trypsin or plasma kallikrein) and by the cysteine proteases cathepsin B or L, resp. Receptor-bound enzymatically active uPA converts plasminogen to plasmin which is bound to a different low-affinity receptor on tumor cells. Plasmin then degrades components of the tumor stroma (e.g. fibrin, fibronectin, proteoglycans, laminin) and may activate procollagenase type IV which degrades collagen type IV, a major part of the basement membrane. Hence receptor-bound uPA will promote plasminogen activation and thus the dissolution of the tumor matrix and the basement membrane which is a prerequisite for invasion and metastasis. Tissues of primary cancer and/or metastases of the breast, ovary, prostate, cervix uteri, bladder, lung and of the gastrointestinal tract contain elevated levels of uPA compared to benign tissues. In breast cancer uPA and PAI-1 antigen in tumor tissue extracts are independent prognostic factors for relapse-free and overall survival.     

The potential biological and clinical significance of the soluble tumor necrosis factor receptors

The role of TNF receptors (TNF-Rs) is not limited to signal transduction but includes extracellular regulatory functions affecting systemic TNF bioavailability. This review summarizes the regulation of TNF-R shedding and its kinetics, the complex interaction between the soluble receptors and their ligand in vitro and in vivo, and the potential diagnostic, prognostic and therapeutic value of the soluble receptors in malignant, inflammatory, infectious and autoimmune disorders.     

Soluble HLA class I molecules: biological significance and clinical implications

Soluble class I human leukocyte antigens (sHLAs) have been detected in serum, sweat, lymphatic fluid, urine and cerebrospinal fluid. Their biological function has, however, remained a puzzle. The physiological concentration of sHLA varies more than tenfold depending on the phenotype of the individual, and is significantly upregulated in various diseases and during inflammation. This suggests that sHLAs might serve as a marker of pathological changes. Recent experiments have shown that, in vitro, sHLAs can modulate T-cell reactivity and induce cell-activated apoptosis, implicating sHLAs in the induction and maintenance of peripheral tolerance. Therefore, sHLAs have the therapeutic potential to induce tolerance to transplants.     

Functional and clinical significance of the architecture of human skeletal muscles

The architectural properties of the triceps surae muscle were studied in vivo in groups of healthy subjects (eight men) and patients with locomotor function disorders (four men and four women) with the ankle joint positioned at a plantar flexion 0° and the knee set at 90° (neutral position). In this position, using ultrasonic scanning, longitudinal ultrasonic images of the medial gastrocnemius (MG), lateral gastrocnemius (LG), and soleus (Sol) muscles were obtained when the subject was relaxed (the passive state) or performed isometric plantar flexion (50% of the maximum voluntary contraction (MVC), the active state). The fascicle lengths, fascicle angles, and muscle thickness were determined. In the passive state, the fascicle lengths of the MG, LG, and Sol muscles in the group of healthy subjects were 33, 35, and 30 mm and the pennation angle, 25°, 19°, and 25°; in the group of patients with motor disorders, 38, 39, and 29 mm and 21°, 19°, and 24°, respectively. The MG, LG, and Sol thicknesses in the group of healthy subjects were 15, 13, and 12 mm, and in the group of patients with motor disorders, 14, 12, and 14 mm, respectively. In the active state (50% of the MVC), the MG, LG, and Sol fiber lengths in the group of healthy subjects shortened by 31, 24, and 18%; the fiber pennation angle increased by 60, 41, and 41%, respectively. In the group of patients with motor disorders, the fiber lengths shortened by 28, 14, and 18% and the fiber pennation angle decreased by 28, 26, and 36%, respectively. The MG, LG, and Sol thicknesses in the group of healthy subjects increased by 9, 22, and 18%, while in the group of patients with motor disorders the thickness decreased by 4% in the MG and increased by 11 and 4% in the LG and Sol muscles, respectively. Different fiber lengths and pennation angles and their changes upon contraction might be related to differences in the force-producing capabilities of the muscles and the viscoelastic properties of muscle tendons and aponeuroses.     

Regulation, clinical and biological significance of cathepsin D in breast cancer

The lysosomal protease, pro-cathepsin D, is overexpressed and secreted by human breast cancers. In estrogen-responsive breast cancer cell lines, estrogens and growth factors stimulate cathepsin D expression through distinct mechanisms. Clinical studies indicate that high cathepsin D concentration in primary breast cancers is correlated with an increased risk of metastasis and particularly useful to orientate node-negative tumors towards an adjuvant therapy.     

Soluble ICAM-1 in breast cancer: clinical significance and biological implications

OBJECTIVES: In previous experiments, we demonstrated a decreased expression of intercellular adhesion molecule I (ICAM-1) on both tumour cells and antigen-presenting cells derived from patients with breast cancer, resulting in an abrogation of antigen presentation and tumour cell lysis. Recently, increased levels of a soluble isoform of ICAM-1 (sICAM-1) have been detected in the sera of breast cancer patients. The present investigation was performed in order to investigate the biological relevance of serum concentrations and the effects of sICAM-1 in patients with breast cancer. PATIENTS AND METHODS: sICAM-1 was determined using a sandwich enzyme immunoassay on sera from 88 patients with various stages of breast cancer and correlated with clinical parameters. The effect of sICAM-1 present in the sera of patients with breast cancer upon unspecific and anti-Her-21/neu antibody-mediated cytotoxicity (ADCC), as well as upon antigen presentation, was determined using a 51Cr-release assay and [3H]thymidine-uptake of T cells after co-incubation with tetanus-toxoid-pulsed antigen-presenting cells. RESULTS: In patients with early breast cancer, serum levels of sICAM-1 were significantly lower compared to patients with metastatic disease, but did not correlate with usual clinical parameters. In patients with metastatic breast cancer, a significant correlation of sICAM-1 with tumour markers CEA and CA 15-3 was observed. No influence of sICAM-1 upon unspecific cytotoxicity, ADCC, or the ability to present antigen was observed. DISCUSSION: The origin of sICAM-1 in the sera of patients with breast cancer remains unknown. In contrast to its membrane-bound isoform, sICAM-1 was increased in the sera of patients with various stages of breast cancer, but its presence did not influence unspecific cytotoxicity, ADCC, or antigen-induced T cell proliferation.     

The biological basis and clinical significance of hormonal imprinting, an epigenetic process

The biological phenomenon, hormonal imprinting, was named and defined by us (Biol Rev, 1980, 55, 47-63) 30?years ago, after many experimental works and observations. Later, similar phenomena were also named to epigenetic imprinting or metabolic imprinting. In the case of hormonal imprinting, the first encounter between a hormone and its developing target cell receptor-usually at the perinatal period-determines the normal receptor-hormone connection for life. However, in this period, molecules similar to the target hormone (members of the same hormone family, synthetic drugs, environmental pollutants, etc), which are also able to bind to the receptor, provoke faulty imprinting also with lifelong-receptorial, behavioral, etc.,-consequences. Faulty hormonal imprinting could also be provoked later in life in continuously dividing cells and in the brain. Faulty hormonal imprinting is a disturbance of gene methylation pattern, which is epigenenetically inherited to the further generations (transgenerational imprinting). The absence of the normal or the presence of false hormonal imprinting predispose to or manifested in different diseases (e.g., malignant tumors, metabolic syndrome) long after the time of imprinting or in the progenies.     

Investigating the evolution and development of biological complexity under the framework of epigenetics

Biological complexity is a key component of evolvability, yet its study has been hampered by a focus on evolutionary trends of complexification and inconsistent definitions. Here, we demonstrate the utility of bringing complexity into the framework of epigenetics to better investigate its utility as a concept in evolutionary biology. We first analyze the existing metrics of complexity and explore the link between complexity and adaptation. Although recently developed metrics allow for a unified framework, they omit developmental mechanisms. We argue that a better approach to the empirical study of complexity and its evolution includes developmental mechanisms. We then consider epigenetic mechanisms and their role in shaping developmental and evolutionary trajectories, as well as the development and organization of complexity. We argue that epigenetics itself could have emerged from complexity because of a need to self‐regulate. Finally, we explore hybridization complexes and hybrid organisms as potential models for studying the association between epigenetics and complexity. Our goal is not to explain trends in biological complexity but to help develop and elucidate novel questions in the investigation of biological complexity and its evolution.     

Neurosteroids and their biological significance

The paper summarizes the current knowledge concerning various aspects of neurosteroid metabolism and mode of action. These steroid compounds including dehydroepiandrosterone, pregnenolone, and their sulfates, as well as progesterone and its tetrahydro metabolites, are synthesized de novo in glial cells of different brain structures both in humans and in animals. Biological effects of neurosteroids and their fundamental and clinical aspects are reviewed.     

Investigating high school students' conceptualizations of the biological basis of learning

Students go to school to learn. How much, however, do students understand about the biological basis of this everyday process? Blackwell et al. (1) demonstrated a correlation between education about learning and academic achievement. Yet there are few studies investigating high school students' conceptions of learning. In this mixed-methods research study, written assessments were administered to 339 high school students in an urban school district after they completed their required biology education, and videotaped interviews were conducted with 15 students. The results indicated that the majority of students know little about the biological basis of learning, even with prompting, and they recall having learned little about it in school. Students appear to believe that people control their own ability to learn, and some have developed personal hypotheses to describe the learning process. On written assessments, 75% of participants demonstrated a nonbiological framework for learning, and, during interviews, 67% of participants revealed misconceptions about the biological basis of learning. Sample quotes of these interviews are included in this report, and the implications of these findings are discussed.     

Uridine phosphorylase 1 associates to biological and clinical significance in thyroid carcinoma cell lines

Thyroid cancer incidence has been continuity increasing worldwide. Uridine phosphorylase 1 (UPP1) is a protein‐coding gene and has been detected that UPP1 was the higher expression in many solid malignancies, just as head and neck cancers, breast cancer, compared with paired normal tissue. But the act of UPP1 in thyroid cancer is not explicit. In this article, we investigate the function of UPP1 expression in thyroid cancer. The Cancer Genome Atlas (TCGA) unpaired thyroid cancer and normal RNA‐seq data were downloaded, and our paired thyroid cancer and normal samples were analysed by a polymerase chain reaction. The expression of UPP1 was regulated by transfected small interfering RNA, and the function of UPP1 was determined via migration, invasion and cell proliferation assays. Western blot assay was achieved to determine the UPP1 expression correlates with the function of 5‐FU regulate epithelial‐mesenchymal transition. The significant upregulation of UPP1 in thyroid cancer tissues compared with normal thyroid tissues was revealed by our data and TCGA data. UPP1 overexpression was significantly correlated with lymph node metastasis, tumour stage and tumour size. In the cell, experiments showed that UPP1 low expression significantly suppressed the migration, invasion and proliferation. Western blot assay proves the effect of UPP1 expression on 5‐FU regulates epithelial‐mesenchymal transition pathway. UPP1 plays a crucial oncogene in thyroid cancer. Our findings indicate that UPP1 might be a biomarker of thyroid cancer and may act by regulating epithelial‐mesenchymal transition (EMT).