Showing papers by "Christina Wang published in 2009"

Prognostic Significance of Growth Kinetics in Newly Diagnosed Glioblastomas Revealed by Combining Serial Imaging with a Novel Biomathematical Model

Abstract: Glioblastomas are the most aggressive primary brain tumors, characterized by their rapid proliferation and diffuse infiltration of the brain tissue. Survival patterns in patients with glioblastoma have been associated with a number of clinicopathologic factors including age and neurologic status, yet a significant quantitative link to in vivo growth kinetics of each glioma has remained elusive. Exploiting a recently developed tool for quantifying glioma net proliferation and invasion rates in individual patients using routinely available magnetic resonance images (MRI), we propose to link these patient-specific kinetic rates of biological aggressiveness to prognostic significance. Using our biologically based mathematical model for glioma growth and invasion, examination of serial pretreatment MRIs of 32 glioblastoma patients allowed quantification of these rates for each patient's tumor. Survival analyses revealed that even when controlling for standard clinical parameters (e.g., age and Karnofsky performance status), these model-defined parameters quantifying biological aggressiveness (net proliferation and invasion rates) were significantly associated with prognosis. One hypothesis generated was that the ratio of the actual survival time after whatever therapies were used to the duration of survival predicted (by the model) without any therapy would provide a therapeutic response index (TRI) of the overall effectiveness of the therapies. The TRI may provide important information, not otherwise available, about the effectiveness of the treatments in individual patients. To our knowledge, this is the first report indicating that dynamic insight from routinely obtained pretreatment imaging may be quantitatively useful in characterizing the survival of individual patients with glioblastoma. Such a hybrid tool bridging mathematical modeling and clinical imaging may allow for stratifying patients for clinical studies relative to their pretreatment biological aggressiveness.

Complementary but Distinct Roles for MRI and 18F-Fluoromisonidazole PET in the Assessment of Human Glioblastomas

Abstract: Glioblastoma multiforme (World Health Organization grade IV) is a highly anaplastic, rapidly proliferating, primary brain neoplasm characterized by diffuse invasion of the normal-appearing tissue peripheral to the contrast-enhanced abnormality seen on clinical imaging (1). These tumors respond poorly to the most aggressive treatments. The current standard of care includes surgical resection, followed by radiation therapy and chemotherapy, with a prognosis of survival generally falling in the range of 6–14 mo (2). MRI and PET play important roles in the assessment of patients with gliomas. 18F-fluoromisonidazole PET (18F-FMISO) allows for imaging of hypoxia in vivo (3,4). On the basis of the biologic links between hypoxia and the aggressiveness of disease, including tumor-induced neoangiogenesis, it is instructive to compare 18F-FMISO images of hypoxia with MRI scans to reveal aspects of new vasculature and invasion. Gadolinium-enhanced T1-weighted MRI (T1Gd) provides morphologic imaging of the blood–brain barrier breakdown in regions of angiogenesis usually surrounding central necrosis (5). Central necrosis appears hypointense when imaged by T1Gd because of the lack of viable vessels. In addition, edema associated with infiltrated glioma cells is hyperintense on T2-weighted MRI (T2). Exposure to ionizing radiation increases the permeability of the vasculature and may affect both T1Gd and T2 (6). PET with the radiotracer 18F-FMISO detects regions of hypoxia independent of the tumor anatomy and perfusion (7). 18F-FMISO is a 2-nitroimidazole derivative that undergoes intracellular reduction in cells that are alive, generating a radical anion. Oxygen acts as an electron acceptor for the 18F-FMISO radical anion. In the absence of oxygen, the unstable 18F-FMISO radical anion is further reduced and covalently bound to intracellular macromolecules and cannot exit the hypoxic cells (8). Binding of 18F-FMISO is proportional to the concentration of oxygen, with significant retention occurring at oxygen levels below 3 mm Hg (9). Thus, 18F-FMISO binds to hypoxic tumor tissue but not to the oxygenated brain or oxygenated tumor (10). The Angiogenic Cascade As tumor cells proliferate, the local tissue becomes relatively oxygen-depleted (hypoxic). Tumor cell growth outstrips vascular development so that oxygen delivery is decreased beyond its diffusion distance. Hypoxia promotes neovascularization through a variety of molecular signals that drive tumor survival (11,12). On the molecular level, hypoxia-inducible factor-1—a transcription factor that is constantly produced but survives only in hypoxic cells—binds to a hypoxic response element that activates the transcription of more than 100 genes, promoting cell survival, invasiveness, and aggressiveness, including vascular endothelial growth factor (VEGF) (13,14). VEGF is a dominant cytokine regulating the expression of growth factor receptor genes at the onset of the angiogenic cascade (15). In its role as an angiogenic factor, VEGF serves to recruit and induce proliferation of vascular endothelial cells. In addition to the role of hypoxia in neoangiogenesis, tumor cells show adaptation to hypoxia by decreasing the proliferation rate, remaining longer in the resting phase G0, and escaping to some degree the impact of conventional treatments that principally target cells in the S phase of their cycle. A greater dose of photon irradiation (2–3 times) is required to kill hypoxic tissue relative to normoxic tissue (16), a factor that further implicates hypoxia in primary tumor recurrence (2). This study considers the assessment of disease burden by 18F-FMISO relative to T1Gd and T2. Motivated by the biologic link between hypoxia and tumor-induced neovasculature and tumor aggressiveness, we analyzed detailed spatial and volumetric data of 18F-FMISO uptake relative to MRI-defined regions. This initial analysis provides the basis for exploring the benefit of combining MRI and PET data into a more complete picture of the disease burden for better disease assessment and prognosis.

Obesity, low testosterone levels and erectile dysfunction.

Abstract: Obesity is an important risk factor for many common diseases including cardiovascular disease (CVD), type 2 diabetes, cancer and erectile dysfunction (ED). Adipose tissues produce a number of adipokines and cytokines, which affect endothelial and metabolic function resulting in insulin resistance and the metabolic syndrome (risks factors for CVD). Both ED and metabolic syndrome improve with a reduction in body mass index (BMI). The relationships among obesity, metabolic syndrome, ED, sex hormone-binding globulin (SHBG) and serum total and free testosterone levels are complex and often confusing to the physician. It is known that BMI is inversely proportional to serum total testosterone concentrations; low serum SHBG levels in obesity contribute to the low serum total testosterone. Recent studies show that BMI is also inversely proportional to free testosterone concentration. The characteristic low serum testosterone concentrations observed in obese men are also present in men with the metabolic syndrome and type 2 diabetes mellitus. A small proportion of men with ED have hypogonadism; however, the proportion increases if these men are obese with manifestations of the metabolic syndrome or type 2 diabetes mellitus. ED is a common symptom in patients with type 2 diabetes who also have low testosterone levels. This review describes the relationships between low serum testosterone concentrations and ED in obese patients and those with metabolic syndrome and type 2 diabetes mellitus.

Combined Transdermal Testosterone Gel and the Progestin Nestorone Suppresses Serum Gonadotropins in Men

Abstract: Context: Testosterone (T) plus progestin combinations are the most promising hormonal male contraceptives. Nestorone (NES), a progestin without estrogenic or androgenic activity, when combined with T may be an excellent candidate for male contraception. Objective: Our objective was to determine the effect of transdermal NES gel alone or with T gel on gonadotropin suppression. Design and Setting: The randomized, unblinded clinical trial was conducted at two academic medical centers. Participants: A total of 140 healthy male volunteers participated. Interventions: One hundred subjects were randomized initially (20 per group) to apply NES gel 2 or 4 mg, T gel 10 g, or T gel 10 g plus NES gel 2 or 4 mg daily for 20 d. Because only about half of the subjects in T plus NES 4 mg group suppressed serum gonadotropins to 0.5 IU/liter or less (suboptimal suppression), two additional groups of 20 men were randomized to apply daily T gel 10 g plus NES gel 6 or 8 mg. Main Outcome Variable: Suppression of serum LH and F...

Mitogen-Activated Protein Kinase Signaling in Male Germ Cell Apoptosis in the Rat

Abstract: Programmed germ cell death is critical for functional spermatogenesis. Increased germ cell apoptosis can be triggered by various regulatory stimuli, including testicular hyperthermia or deprivation of gonadotropins and intratesticular testosterone. We have previously shown the involvement of the mitogen-activated protein kinase (MAPK) 14 in apoptotic signaling of male germ cells across species after hormone deprivation. This study investigates the role of MAPK14 in germ cell apoptosis in rats triggered by testicular hyperthermia. The contributions of the MAPK1/3 and the MAPK8 to male germ cell death were also examined after this intervention. We show that 1) testicular hyperthermia results in induction of both MAPK1/3 and MAPK14 but not MAPK8; 2) inhibition of MAPK1/3 has no effect on the incidence of heat-induced germ cell apoptosis, suggesting that MAPK1/3 signaling may be dispensable for heat-induced male germ cell apoptosis; and 3) activation of MAPK14 and BCL2 phosphorylation are critical for heat-induced male germ cell apoptosis in rats. Thus, unlike the hormone deprivation model, heat stress through activation of the MAPK14 signaling promotes germ cell apoptosis by provoking BCL2 phosphorylation, leading to its inactivation and the subsequent activation of the mitochondria-dependent death pathway. These novel findings point to a critical role of MAPK14 in stage- and cell-specific activation of male germ cell apoptosis triggered by hormone deprivation or heat stress.

Transplanted XY germ cells produce spermatozoa in testes of XXY mice

Abstract: XXY mouse has been characterized as an experimental model for men with Klinefelter's syndrome (XXY male phenotype). To test whether donor XY germ cells could proliferate and differentiate in the XXY testicular environment, donor testicular cells from adult (2-3 months old) and immature (10 days old) XY green fluorescence protein (GFP) transgenic mice were transplanted into the seminiferous tubules of adult (4-7 months old) and young (6 weeks old) XXY recipient mice respectively. Twelve weeks after transplantation, GFP positive spermatogonia were found in 21.74% (five out of 23) of adult XXY recipients who received adult donor cells. The GFP positive segments of seminiferous tubules were observed in 44.44% (four out of nine) young XXY recipients who received donor cells from 10 days old GFP mice. We found using immunohistochemistry and cell morphology that donor-derived GFP positive germ cells were spermatogonia, spermatocytes, round spermatids and spermatozoa in some of the seminiferous tubules of young XXY recipient mice. The results demonstrated that the donor XY germ cells were able to qualitatively complete spermatogenesis in some of the seminiferous tubules of XXY mice.

Effect of mesterolone on serum FSH, LH and plasma testosterone in normal men.

Abstract: Zusammenfassung Um festzustellen, ob der Anspruch, wonach Mesterolon keine Suppression der Gona-dotropinsekretion verursacht, berechtigt ist, wurden jeweils 5 gesunde Manner mit 100 und 200 mg Mesterolon peroral tgl. fur 7 Tage behandelt. Gleichzeitig wurden Serien-bestimmungen von Serum-FSH und -LH, sowie Plasmatestosteron vorgenommen, die sich vor und nach der Behandlung auf eine Dauer von 2 Stunden mit 15 Minuten Inter-vallen erstreckten. Ein geringgradiger Abfall fur FSH, LH und Testosteron konnte in beiden Gruppen beobachtet werden, allerdings lagen die Abfailwerte hoher in der Grup-pe mit niedrigerer Mesterolondosis (100 mg = 21% FSH-Abfall, 19% LH-Abfall und 9% Testosteronabfall; 200 mg = 18% FSH-Abfall, 15% LH-Abfall und 8% Testosteronabfall). In der Diskussion wird auf die Untersuchungen von Laschet (1967) und Petry (1968) verwiesen, die keinerlei Suppression der Uringonadotropine beobachtet hatten; das erklaren die Autoren damit, das die Bioassay-Methode nicht so sensibel reagiert wie der Radioimmunassay und zum anderen damit, das die genannten Autoren niedrigere Mesterolondosen verwendeten. Als uberraschend und zugleich unerklarbar wird die Tatsache angesprochen, das in ihren Befunden der Prozentsatz der FSH- und LH-Suppression deutlich grofier ist bei niedrigerer Mesterolondosis. Resumen Efectos de la mesterolona sobre la FSH, LH y Testosterona plasmatica en hombres normales La mesterolona per os, se ha mostrado como terapia eficaz en pacientes con deficit androgenico y en algunos infertiles con oligospermia. Por otro lado esta substancia, a dosis terapeuticas, no suprime la secretion de gona-dotrofinas. El presente trabajo estudia los efectos de la mesterolona sobre los niveles sericos de FSH, LH y Testosterona en varones normales. Se utilizaron 10 hombres sanos, de 19 a 50 anos. A 5 se les dio 50 mg. de mesterolona 2 veces al dia, ruante 7 dias. A los 5 restantes doble dosis. Se midio por radioimmunoensayo la concentration de FSH, LH y Testosterona. En los pacientes que recibieron 100 mg/dia, se observo, en dos, disminucion de las tres hormonas, en uno no hubo cambios, y en otro disminuyeron la FSH y LH. En to-dos los que recibieron 200 mg/dia, al menos una hormona resulto mas baja despues del tratamiento. Solo en un paciente se observo disminucion de LH y Testosterona al mis-mo tiempo. En conjunto un descenso significativo de FSH ocurrio en 8, y de LH y Testosterona en 5. Los resultados del presente estudio indican que el tratamiento con mesterolona a las dosis comentadas producen supresion de los niveles de FSH, LH y Testosterona en la mayoria de los sujetos.

Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men.

Abstract: Prior studies have demonstrated that combined treatment of testosterone with a progestin induces a more rapid and greater suppression of spermatogenesis than testosterone treatment alone. We hypothesized that the suppressive effects of the combination of testosterone undecanoate (TU) injections plus oral levonorgestrel (LNG) on spermatogenesis may be mediated through a greater perturbation of testicular gene expression than TU alone. To test this hypothesis, we performed open testicular biopsy on 12 different adult healthy subjects: 1) four healthy men as controls; 2) four men 2 wk after TU treatment; and 3) four men 2 wk after TU + LNG administration. RNA isolated from biopsies was used for DNA microarray using the Affymetrix Human Genome U133 Plus 2.0 oligonucleotide microarrays. Gene expression with ≥2-fold changes (P < 0.05) compared with control was analyzed using the National Institutes of Health Database for Annotation, Visualization, and Integrated Discovery 2008 resource. The TU treatmen...

Hypothalamic-Pituitary-Gonadal Axis in Men

Abstract: The male reproductive axis consists of six main components: the extrahypothalamic central nervous system, hypothalamus, pituitary gland, testes, androgen transport and metabolism, and sex-steroid-sensitive target organs. The hypothalamic–pituitary–testicular unit is an integrated system that assures the adequate and appropriate secretion of male hormones and the production of sufficient sperm for the propagation of the species. Each anatomical site is integrated with the others in a classic endocrine-feedback manner, with ample local paracrine and intracrine modulation required for its most effective function. The Leydig cells of the testes are the site of production and secretion of the hormone T, which through its direct action and that of its metabolites, DHT and E2, creates the hormonal milieu required for male sexual development and function and androgen- and estrogen-mediated effects on critical target organs, such as the brain, bone, muscle, liver, skin, bone marrow, and immune systems, and the male reproductive system. The spermatogenic compartment consists of Sertoli cells and germ cells in the seminiferous tubules, which act in an integrated fashion with one another, the Leydig cells, and the pituitary gonadotrophic hormones (luteinizing hormone, LH; and follicle-stimulating hormone, FSH), leading to normal germ cell production. The testes, through their production of steroid and peptide secretory substances, also provide the regulatory feedback control of the hypothalamic and pituitary components of the axis. This chapter focuses on the individual components of the axis and provides an integrative sense of its control and the clinical manifestations associated with hormonal and spermatogenesis dysfunction.

The accuracy of sperm concentration determination by the automated CellSoft semen analyzer before and after discontinuous Percoll gradient centrifugation.

Abstract: Summary: The automated CellSoft semen analyzer identifies human spermatozoa on the basis of user-defined values for cell size and luminosity. Previous studies have shown that the non-sperm particles usually present in seminal plasma would interfere with the computerized determination of sperm concentration by the CellSoft system. Therefore, an effective method to separate the sperm from non-sperm particles would be desirable to obtain accurate determination of sperm concentration. In the present study, sperm concentrations in 72 semen samples before and after discontinuous Percoll gradient centrifugation were determined by the automated CellSoft system and the results compared with those obtained with the routine procedure using thte haemocytomer according to the World Health Organization laboratory manual. The computerized measurement caused a significant overestimation when the sperm concentration in semen was less than 80 × 106/ml. Processing of human semen sample by the simple two-layer discontinuous Percoll gradient centrifugation removed the majority of non-sperm particles and the overestimation by the automated CellSoft system became significant only when the sperm concentration in the final Percoll sperm preparation was less than 10 × 106/ml. These findings indicate that the automated CellSoft semen analyzer has to be improved to allow for the correction of non-sperm particles in seminal plasma or processed sperm samples before it can be used to provide sufficiently accurate sperm concentration results for routine laboratory service or research purposes. Zusammenfassung: Die automatisierte CellSoft Samenanalyse identifiziert menschliche Spermatozoen aufgrund der Zellgrose und -helligkeit. Fruhere Untersuchungen haben gezeigt, das die Computerbestimmung der Samenzellkonzentration nach dem CellSoft-System durch andere Partikel im Seminalplasma beeintrachtigt wird. Daher ware eine wirksame Methode zur Trennung von Spermatozoen und anderen Partikeln fur eine genaue Ermittlung der Samenzellkonzentration wunschenswert. In der vorliegenden Studie wurden die Samenzellkonzentrationen in 72 Spermaproben vor und nach diskontinuierlicher Zentrifugierung im Percoll-Gradienten nach dem automatisierten CellSoft-System bestimmt und mit den im Routineverfahren nach dem WHO-Manual unter Verwendung eines Hamozytometers ermittelten Werten verglichen. Die Computermessung ergab eine erhebliche Uberschatzung bei einer Samenzellkonzentration unter 80 × 106/ml. Durch Aufbereitung der Samenproben im zweischichtigen Percoll-Gradienten wurden andere Partikel grostenteils entfernt, und die Uberschatzung durch das automatisierte CellSoft-System war nur signifikant, wenn die Samenzellkonzentration in der endgultigen Percoll-Samenaufbereitung unter 10 × 106/ml lag. Diese Befunde zeigen, das die automatisierte CellSoft Samenanalyse im Hinblick auf andere Partikel im Seminalplasma bzw. aufbereitete Spermaproben verbessert werden mus, bevor sie im Routinelabor oder fur Forschungszwecke Verwendung finden kann.

Spermatozoal fertilizing capacity in polyzoospermia: a preliminary study.

Abstract: Men with the spermatological symptom of polyzoospermia (greater than 250 X 10(6) sperm/ml) have been reported to seldom impregnate their wives. It was the aim of this study to investigate the spermatozoal fertilizing capacity in polyzoospermia by the human sperm and zona-free hamster ova penetration bioassay. General semen characteristics and in vitro spermatozoal fertilizing capacity were studied in 12 polyzoospermic male partners of couples of infertile marriages. The results were compared with those from a control group of normospermic fertile men (n = 22). No significant differences in sperm motility, normal morphology and in vitro spermatozoal fertilizing capacity were found between the two groups. The polyzoospermic men we studied did not appear to have any defect with the spermatozoal fertilizing capacity, as assessed by the heterologous sperm--ova penetration bioassay. The apparent impairment of fertility and higher abortion rate in couples with polyzoospermic male partners, as described in the literature, may be related to chromosomal aberrations and/or other unknown functional defect of the spermatozoa.

Imaging with a Novel Biomathematical Model Diagnosed Glioblastomas Revealed by Combining Serial Prognostic Significance of Growth Kinetics in Newly

Abstract: Glioblastomas are the most aggressive primary brain tumors,characterized by their rapid proliferation and diffuse infiltra-tion of the brain tissue. Survival patterns in patients withglioblastoma have been associated with a number of clinico-pathologic factors including age and neurologic status, yet asignificant quantitative link to in vivo growth kinetics of eachglioma has remained elusive. Exploiting a recently developedtool for quantifying glioma net proliferation and invasionratesinindividualpatientsusingroutinelyavailablemagneticresonance images (MRI), we propose to link these patient-specific kinetic rates of biological aggressiveness to prognos-tic significance. Using our biologically based mathematicalmodel for glioma growth and invasion, examination of serialpretreatment MRIs of 32 glioblastoma patients allowedquantificationoftheseratesforeachpatient'stumor.Survivalanalyses revealed that even when controlling for standardclinical parameters (e.g., age and Karnofsky performance sta-tus), these model-defined parameters quantifying biologicalaggressiveness (net proliferation and invasion rates) weresignificantly associated with prognosis. One hypothesisgenerated was that the ratio of the actual survival time afterwhatever therapies were used to the duration of survival pre-dicted (by the model) without any therapy would provide atherapeutic response index (TRI) of the overall effectivenessofthetherapies.TheTRImayprovideimportantinformation,not otherwise available, about the effectiveness of the treat-ments in individual patients. To our knowledge, this is thefirstreportindicatingthatdynamicinsightfromroutinelyob-tained pretreatment imaging may be quantitatively useful incharacterizing the survival of individual patients with glio-blastoma.Suchahybridtoolbridgingmathematicalmodelingand clinical imaging may allow for stratifying patientsfor clinical studies relative to their pretreatment biologicalaggressiveness. [Cancer Res 2009;69(23):9133–40]