Perinatal Factors and Emotional, Cognitive, and Behavioral Dysregulation in Childhood and Adolescence.

OBJECTIVE: This cohort study assessed perinatal factors known to be related to maternal and neonatal inflammation and hypothesized that several would be associated with emotional, cognitive, and behavioral dysregulation in youth. METHOD: The Environmental influences on Child Health Outcomes (ECHO) is a research consortium of 69 pediatric longitudinal cohorts. A subset of 18 cohorts that had both Child Behavior Checklist (CBCL) data on children (6-18 years) and information on perinatal exposures including maternal prenatal infections was used. Children were classified as having the CBCL-Dysregulation Profile (CBCL-DP) if the sum of their T scores for 3 CBCL subscales (attention, anxious/depressed, and aggression) was ≥180. Primary exposures were perinatal factors associated with maternal and/or neonatal inflammation, and associations between these and outcome were assessed. RESULTS: Approximately 13.4% of 4,595 youth met criteria for CBCL-DP. Boys were affected more than girls (15.1% vs 11.5%). More youth with CBCL-DP (35%) were born to mothers with prenatal infections compared with 28% of youth without CBCL-DP. Adjusted odds ratios indicated the following were significantly associated with dysregulation: having a first-degree relative with a psychiatric disorder; being born to a mother with lower educational attainment, who was obese, had any prenatal infection, and/or who smoked tobacco during pregnancy. CONCLUSION: In this large study, a few modifiable maternal risk factors with established roles in inflammation (maternal lower education, obesity, prenatal infections, and smoking) were strongly associated with CBCL-DP and could be targets for interventions to improve behavioral outcomes of offspring. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

The feasibility and utility of hair follicle sampling to measure FMRP and FMR1 mRNA in children with or without fragile X syndrome: a pilot study.

BACKGROUND: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability in males and the most common single gene cause of autism. This X-linked disorder is caused by an expansion of a trinucleotide CGG repeat (> 200 base pairs) on the promotor region of the fragile X messenger ribonucleoprotein 1 gene (FMR1). This leads to the deficiency or absence of the encoded protein, fragile X messenger ribonucleoprotein 1 (FMRP). FMRP has a central role in the translation of mRNAs involved in synaptic connections and plasticity. Recent studies have demonstrated the benefit of therapeutics focused on reactivation of the FMR1 locus towards improving key clinical phenotypes via restoration of FMRP and ultimately disease modification. A key step in future studies directed towards this effort is the establishment of proof of concept (POC) for FMRP reactivation in individuals with FXS. For this, it is key to determine the feasibility of repeated collection of tissues or fluids to measure FMR1 mRNA and FMRP. METHODS: Individuals, ages 3 to 22 years of age, with FXS and those who were typically developing participated in this single-site pilot clinical biomarker study. The repeated collection of hair follicles was compared with the collection of blood and buccal swabs for detection of FMR1 mRNA and FMRP and related molecules. RESULTS: There were n = 15 participants, of whom 10 had a diagnosis of FXS (7.0 ± 3.56 years) and 5 were typically developing (8.2 ± 2.77 years). Absolute levels of FMRP and FMR1 mRNA were substantially higher in healthy participants compared to full mutation and mosaic FXS participants and lowest in the FXS boys. Measurement of FMR1 mRNA and FMRP levels by any method did not show any notable variation by collection location at home versus office across the various sample collection methodologies of hair follicle, blood sample, and buccal swab. CONCLUSION: Findings demonstrated that repeated sampling of hair follicles in individuals with FXS, in both, home, and office settings, is feasible, repeatable, and can be used for measurement of FMR1 mRNA and FMRP in longitudinal studies.

Association of prenatal modifiable risk factors with attention-deficit hyperactivity disorder outcomes at age 10 and 15 in an extremely low gestational age cohort.

Background: The increased risk of developing attention-deficit hyperactivity disorder (ADHD) in extremely preterm infants is well-documented. Better understanding of perinatal risk factors, particularly those that are modifiable, can inform prevention efforts. Methods: We examined data from the Extremely Low Gestational Age Newborns (ELGAN) Study. Participants were screened for ADHD at age 10 with the Child Symptom Inventory-4 (N = 734) and assessed at age 15 with a structured diagnostic interview (MINI-KID) to evaluate for the diagnosis of ADHD (N = 575). We studied associations of pre-pregnancy maternal body mass index (BMI), pregestational and/or gestational diabetes, maternal smoking during pregnancy (MSDP), and hypertensive disorders of pregnancy (HDP) with 10-year and 15-year ADHD outcomes. Relative risks were calculated using Poisson regression models with robust error variance, adjusted for maternal age, maternal educational status, use of food stamps, public insurance status, marital status at birth, and family history of ADHD. We defined ADHD as a positive screen on the CSI-4 at age 10 and/or meeting DSM-5 criteria at age 15 on the MINI-KID. We evaluated the robustness of the associations to broadening or restricting the definition of ADHD. We limited the analysis to individuals with IQ ≥ 70 to decrease confounding by cognitive functioning. We evaluated interactions between maternal BMI and diabetes status. We assessed for mediation of risk increase by alterations in inflammatory or neurotrophic protein levels in the first week of life. Results: Elevated maternal BMI and maternal diabetes were each associated with a 55-65% increase in risk of ADHD, with evidence of both additive and multiplicative interactions between the two exposures. MSDP and HDP were not associated with the risk of ADHD outcomes. There was some evidence for association of ADHD outcomes with high levels of inflammatory proteins or moderate levels of neurotrophic proteins, but there was no evidence that these mediated the risk associated with maternal BMI or diabetes. Conclusion: Contrary to previous population-based studies, MSDP and HDP did not predict ADHD outcomes in this extremely preterm cohort, but elevated maternal pre-pregnancy BMI, maternal diabetes, and perinatal inflammatory markers were associated with increased risk of ADHD at age 10 and/or 15, with positive interaction between pre-pregnancy BMI and maternal diabetes.

Investigating Potential Biomarkers in Autism Spectrum Disorder.

BACKGROUND: Early identification and treatment of individuals with autism spectrum disorder (ASD) improves outcomes, but specific evidence needed to individualize treatment recommendations is lacking. Biomarkers that could be routinely measured within the clinical setting could potentially transform clinical care for patients with ASD. This demonstration project employed collection of biomarker data during regular autism specialty clinical visits and explored the relationship of biomarkers with clinical ASD symptoms. METHODS: Eighty-three children with ASD, aged 5-10 years, completed a multi-site feasibility study integrating the collection of biochemical (blood serotonin, urine melatonin sulfate excretion) and clinical (head circumference, dysmorphology exam, digit ratio, cognitive and behavioral function) biomarkers during routine ASD clinic visits. Parents completed a demographic survey and the Aberrant Behavior Checklist-Community. Cognitive function was determined by record review. Data analysis utilized Wilcoxon two-sample tests and Spearman correlations. RESULTS: Participants were 82% male, 63% White, 19% Hispanic, with a broad range of functioning. Group means indicated hyperserotonemia. In a single regression analysis adjusting for race and median household income, higher income was associated with higher levels of blood serotonin and urine melatonin sulfate excretion levels (p = 0.004 and p = 0.04, respectively). Melatonin correlated negatively with age (p = 0.048) and reported neurologic problems (p = 0.02). Dysmorphic status correlated with higher reported stereotyped behavior (p = 0.02) and inappropriate speech (p = 0.04). CONCLUSION: This demonstration project employed collection of multiple biomarkers, allowed for examination of associations between biochemical and clinical measures, and identified several findings that suggest direction for future studies. This clinical research model has promise for integrative biomarker research in individuals with complex, heterogeneous neurodevelopmental disorders such as ASD.

New Therapeutic Options for Fragile X Syndrome.

PURPOSE OF REVIEW: The purpose of this review is to provide an overview of current research and clinical practice guidelines in fragile X syndrome (FXS) with regard to therapeutic approaches in the management of this condition. The authors summarize and discuss findings from relevant preclinical studies and results from clinical trials in human subjects with FXS. Additionally, we provide an outline of the basic framework for understanding and providing educational and psychosocial supports for these individuals. RECENT FINDINGS: Current treatments in FXS are largely symptom based and focused on managing associated psychiatric and behavioral co-morbidities. While data from animal studies has been promising in providing targeted treatments to correct the underlying deficits at the cellular level, there have not been as robust findings in human trials. There are several targeted treatments for FXS currently under development. Individuals with FXS present with several behavioral challenges including anxiety, social withdrawal, ADHD, hyperarousal, self-injury, and aggression. Therapeutic services are often necessary, such as behavioral intervention, speech and language therapy, occupational therapy, and individualized educational support; adjunctive psychopharmacologic treatment is often helpful as well. It is important to address these symptoms and weigh the evidence for the use of medications that target the underlying neurobiology and pathophysiology of the syndrome.

An exploration of posttraumatic growth, loneliness, depression, resilience, and social capital among survivors of Hurricane Katrina and the Deepwater Horizon Oil Spill.

The aim of this study was to examine the relationships among posttraumatic growth (PTG), loneliness, depression, psychological resilience, and social capital among survivors of Hurricane Katrina in 2005 and the Deepwater Horizon oil spill in 2010. The survey was administered to a spatially stratified, random sample of households in the three coastal counties of Mississippi. A total of 216 participants were included in this study who lived in close proximity to the Gulf of Mexico coastline during both disasters. Results from structural equation modeling analyses indicated that there was a significant and inverse relationship between PTG and loneliness. Conversely, a direct relationship was not found between PTG and depressive symptoms; instead, the results revealed an indirect relationship between PTG and depressive symptoms through loneliness. Social capital was related to loneliness only indirectly through PTG, while psychological resilience was related to loneliness both directly and indirectly through PTG. Understanding the relationships among these factors, particularly the importance of PTG, can provide insight into the long-term adaptation among those who have survived multiple disasters. Further, these findings may lead to nuanced methods for behavioral health practitioners in assessing and treating individuals with symptoms of depression in disaster-prone communities.

Community Resilience, Psychological Resilience, and Depressive Symptoms: An Examination of the Mississippi Gulf Coast 10 Years After Hurricane Katrina and 5 Years After the Deepwater Horizon Oil Spill.

OBJECTIVE: This study examined the role of community resilience and psychological resilience on depressive symptoms in areas on the Mississippi Gulf Coast that have experienced multiple disasters. METHODS: Survey administration took place in the spring of 2015 to a spatially stratified, random sample of households. This analysis included a total of 294 subjects who lived in 1 of the 3 counties of the Mississippi Gulf Coast at the time of both Hurricane Katrina in 2005 and the Deepwater Horizon oil spill in 2010. The survey included the Communities Advancing Resilience Toolkit (CART) scale, the Connor-Davidson Resilience Scale (CD-RISC 10), and the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: There was a significant inverse relationship between psychological resilience and depressive symptoms and a significant positive relationship between community resilience and psychological resilience. The results also revealed that community resilience was indirectly related to depressive symptoms through the mediating variable of psychological resilience. CONCLUSIONS: These findings highlight the importance of psychological resilience in long-term disaster recovery and imply that long-term recovery efforts should address factors associated with both psychological and community resilience to improve mental health outcomes. (Disaster Med Public Health Preparedness. 2018;12:241-248).

Feasibility of Conducting Autism Biomarker Research in the Clinical Setting.

OBJECTIVE: Recruitment and completion of research activities during regular clinical care has the potential to increase research participation in complex neurodevelopmental disorders. We evaluated the feasibility, and effect on clinical care, of conducting biomarker research within a subspecialty clinical visit for autism spectrum disorder (ASD). METHODS: Children, aged 5 to 10 years, were recruited by providers in ASD clinics at 5 institutions. Biomarkers collected were growth measurements, head circumference, neurologic and dysmorphology examinations, digit ratio (2D:4D) measurement, and platelet serotonin and urinary melatonin sulfate excretion levels. Parents completed the Aberrant Behavior Checklist-Community and a medical/demographic questionnaire. Cognitive level was abstracted from the medical record. Parents and clinicians completed surveys on the effect of the study on the clinical visit. RESULTS: Eighty-three children and their caregivers participated. Factors limiting participation included difficulty reaching families by phone and parent concern about the study blood draw requirement. All children completed at least 4 of 7 planned research activities. Demographic factors, educational placement, and child behavior were not associated with completion of study activities. Lower nonverbal cognitive function was weakly associated with fewer activities completed. Forty-four percent of clinicians reported an effect of the research study on the clinical visit. However, neither parent-reported nor clinician-reported effect was associated with the degree of study activity completion. CONCLUSION: Recruiting study participants in the context of scheduled ASD clinical visits required significant effort. However, once recruited, participants completed most study activities, regardless of behavioral symptom severity. Research activities did not adversely affect the clinical visit.

Adapting to Life after Hurricane Katrina and the Deepwater Horizon Oil Spill: An Examination of Psychological Resilience and Depression on the Mississippi Gulf Coast.

The purpose of this study was to examine relationships among depression, psychological resilience, and other sociodemographic factors of individuals who were highly exposed to Hurricane Katrina in 2005 and the Deepwater Horizon Oil Spill in 2010. A spatially stratified random sample of 294 Mississippi Gulf Coast residents living in close proximity to the Gulf of Mexico were surveyed. Findings indicated that low education attainment, financial hardship, and disaster-related damages increased the likelihood of depression, whereas psychological resilience and having health insurance reduced the odds of depression. Implications for enhancing psychological resilience and increasing access to health insurance are discussed.

Impairments of Social Motor Synchrony Evident in Autism Spectrum Disorder.

Social interactions typically involve movements of the body that become synchronized over time and both intentional and spontaneous interactional synchrony have been found to be an essential part of successful human interaction. However, our understanding of the importance of temporal dimensions of social motor synchrony in social dysfunction is limited. Here, we used a pendulum coordination paradigm to assess dynamic, process-oriented measures of social motor synchrony in adolescents with and without autism spectrum disorder (ASD). Our data indicate that adolescents with ASD demonstrate less synchronization in both spontaneous and intentional interpersonal coordination. Coupled oscillator modeling suggests that ASD participants assembled a synchronization dynamic with a weaker coupling strength, which corresponds to a lower sensitivity and decreased attention to the movements of the other person, but do not demonstrate evidence of a delay in information transmission. The implication of these findings for isolating an ASD-specific social synchronization deficit that could serve as an objective, bio-behavioral marker is discussed.

Relationship among Glutamine, γ-Aminobutyric Acid, and Social Cognition in Autism Spectrum Disorders.

OBJECTIVE: An imbalance of excitatory and inhibitory neurotransmission in autism spectrum disorder (ASD) has been proposed. We compared glutamate (Glu), glutamine (Gln), and γ-aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC) of 13 males with ASD and 14 typically developing (TD) males (ages 13-17), and correlated these levels with intelligence quotient (IQ) and measures of social cognition. METHODS: Social cognition was evaluated by administration of the Social Responsiveness Scale (SRS) and the Reading the Mind in the Eyes Test (RMET). We acquired proton magnetic resonance spectroscopy ((1)H-MRS) data from the bilateral ACC using the single voxel point resolved spectroscopy sequence (PRESS) to quantify Glu and Gln, and Mescher-Garwood point-resolved spectroscopy sequence (MEGA-PRESS) to quantify GABA levels referenced to creatine (Cr). RESULTS: There were higher Gln levels (p=0.04), and lower GABA/Cre levels (p=0.09) in the ASD group than in the TD group. There was no difference in Glu levels between groups. Gln was negatively correlated with RMET score (rho=-0.62, p=0.001) and IQ (rho=-0.56, p=0.003), and positively correlated with SRS scores (rho=0.53, p=0.007). GABA/Cre levels were positively correlated with RMET score (rho=0.34, p=0.09) and IQ (rho=0.36, p=0.07), and negatively correlated with SRS score (rho=-0.34, p=0.09). CONCLUSIONS: These data suggest an imbalance between glutamatergic neurotransmission and GABA-ergic neurotransmission in ASD. Higher Gln levels and lower GABA/Cre levels were associated with lower IQ and greater impairments in social cognition across groups.

"Autism-plus" spectrum disorders: intersection with psychosis and the schizophrenia spectrum.

Patients are often encountered clinically who have autism spectrum disorders (ASD) and also have symptoms suggestive of a comorbid psychotic disorder. A careful assessment for the presence of comorbid disorders is important. However, the core deficits seen in ASD, in social reciprocity, communication, and restricted behaviors and interests, can be mistaken for psychosis. Also, there is a subset of patients who present with a complex neurodevelopmental disorder with impairments that cross diagnostic categories. This article reviews the connections between ASD and psychosis, and highlights the key points to consider in patients who present with these "autism-plus" disorders.

Psychiatrists' use of electronic communication and social media and a proposed framework for future guidelines.

BACKGROUND: Recent and ongoing advances in information technology present opportunities and challenges in the practice of medicine. Among all medical subspecialties, psychiatry is uniquely suited to help guide the medical profession's response to the ethical, legal, and therapeutic challenges--especially with respect to boundaries--posed by the rapid proliferation of social media in medicine. Ironically, while limited guidelines exist for other branches of medicine, guidelines for the responsible use of social media and information technology in psychiatry are lacking. OBJECTIVE: To collect data about patterns of use of electronic communications and social media among practicing psychiatrists and to establish a conceptual framework for developing professional guidelines. METHODS: A structured survey was developed to assess the use of email, texting, and social media among the active membership of the Group for the Advancement of Psychiatry (GAP) to gain insight into current practices across a spectrum of the field and to identify areas of concern not addressed in existing guidelines. This survey was distributed by mail and at an annual meeting of the GAP and a descriptive statistical analysis was conducted with SPSS. RESULTS: Of the 212 members, 178 responded (84% response rate). The majority of respondents (58%) reported that they rarely or never evaluated their online presence, while 35% reported that they had at some time searched for information online about patients. Only 20% posted content about themselves online and few of these restricted that information. Approximately 25% used email to communicate with patients, and very few obtained written consent to do so. CONCLUSION: Discipline-specific guidelines for psychiatrists' interactions with social media and electronic communications are needed. Informed by the survey described here, a review of the literature, and consensus opinion, a framework for developing such a set of guidelines is proposed. The model integrates four key areas: treatment frame, patient privacy, medico-legal concerns, and professionalism. This conceptual model, applicable to many psychiatric settings, including clinical practice, residency training, and continuing medical education, will be helpful in developing discipline-wide guidelines for psychiatry and can be applied to a decision-making process by individual psychiatrists in day-to-day practice.

The role of oxytocin in psychiatric disorders: a review of biological and therapeutic research findings.

LEARNING OBJECTIVES: After participating in this educational activity, the physician should be better able to 1. Identify the biological role of oxytocin in forming attachments. 2. Evaluate the relationship between various neuropsychiatric disorders and oxytocin. 3. Identify clinical implications of using oxytocin to treat various neuropsychiatric disorders. Oxytocin is a peptide hormone integral in parturition, milk letdown, and maternal behaviors that has been demonstrated in animal studies to be important in the formation of pair bonds and in social behaviors. This hormone is increasingly recognized as an important regulator of human social behaviors, including social decision making, evaluating and responding to social stimuli, mediating social interactions, and forming social memories. In addition, oxytocin is intricately involved in a broad array of neuropsychiatric functions and may be a common factor important in multiple psychiatric disorders such as autism, schizophrenia, and mood and anxiety disorders. This review article examines the extant literature on the evidence for oxytocin dysfunction in a variety of psychiatric disorders and highlights the need for further research to understand the complex role of the oxytocin system in psychiatric disease and thus pave the way for developing new therapeutic modalities. Articles were selected that involved human participants with various psychiatric disorders and that either compared oxytocin biology to healthy controls or examined the effects of exogenous oxytocin administration.

Radiation dose to the lens during craniospinal irradiation-an improvement in proton radiotherapy technique.

PURPOSE: To evaluate the effect of angle modification of cranial field proton beam therapy on the radiation dose delivered to the lens during craniospinal irradiation (CSI). METHODS AND MATERIALS: Thirty-nine patients with central nervous system tumors who received CSI with a posterior fossa boost were analyzed for the radiation dose to the lens. Thirteen patients received cranial field treatment using standard opposed-lateral proton beams, and 26 patients received treatment with angled posterior-oblique proton beams. The lens dose in a test case also was evaluated by comparing conventional X-rays with the two proton beam planning methods by using a CMS/Xio three-dimensional planning system. RESULTS: Substantial lens dose sparing was realized with the angling of the cranial proton beams 15 degrees -20 degrees to the posterior. In the 39 treated patients who were analyzed (median age, 7 years), average dose delivered to the lens was decreased by approximately 50% by angling of the proton beams, with the average maximum dose decreasing from 74% to 40% of the prescribed dose (p < 0.0001). Significant lens sparing was seen in patients 10 years and younger (median age, 6 years; p < 0.0001), whereas an insignificant decrease was seen in older patients (median age, 16 years; p = 0.14). With the opposed-lateral technique (median age, 6 years), the lens dose increased significantly with decreasing age (p = 0.002), whereas there was no effect of age on lens dose in the angled beam-treated group (median age, 8.5 years; p = 0.73). CONCLUSION: The present study clearly shows an advantage in sparing of the lens dose by angling the beams used during proton beam CSI. This effect is most pronounced in patients 10 years and younger because of anatomic effects of sinus development.

Evolution of oxygen and glucose concentration profiles in a tissue-mimetic culture system of embryonic stem cells.

A tissue-mimetic culture system (TMCS) in which cells are sandwiched between two glass slides provides an ideal microenvironment for studying the effects of oxygen and nutrient gradients on cells in culture. A mathematical model was utilized to predict the time course of the development of oxygen and glucose concentration gradients within the TMCS. Oxygen and glucose consumption rates of mouse embryonic stem cells were measured as parameters for the model. The model predicts oxygen and glucose concentration profiles directly using a single experimentally controlled variable, the seeding density of cells within the system. The model predicts that the time required for the gradients to reach steady state is inversely related to the cell density, and the penetration depth of the gradients into the TMCS is inversely related to the square root of the cell density. Experimental oxygen concentration measurements were performed at a cell density of 9.1 x 10(6) cells cm(-3), and the gradient was found to develop to a steady-state profile within 20 min and penetrate approximately 2 mm into the TMCS, consistent with the theoretical predictions. This model and the TMCS provide useful tools for investigating the effect of the metabolic microenvironment on cells in culture.

High-resolution recombination patterns in a region of human chromosome 21 measured by sperm typing.

For decades, classical crossover studies and linkage disequilibrium (LD) analysis of genomic regions suggested that human meiotic crossovers may not be randomly distributed along chromosomes but are focused instead in "hot spots." Recent sperm typing studies provided data at very high resolution and accuracy that defined the physical limits of a number of hot spots. The data were also used to test whether patterns of LD can predict hot spot locations. These sperm typing studies focused on several small regions of the genome already known or suspected of containing a hot spot based on the presence of LD breakdown or previous experimental evidence of hot spot activity. Comparable data on target regions not specifically chosen using these two criteria is lacking but is needed to make an unbiased test of whether LD data alone can accurately predict active hot spots. We used sperm typing to estimate recombination in 17 almost contiguous ~5 kb intervals spanning 103 kb of human Chromosome 21. We found two intervals that contained new hot spots. The comparison of our data with recombination rates predicted by statistical analyses of LD showed that, overall, the two datasets corresponded well, except for one predicted hot spot that showed little crossing over. This study doubles the experimental data on recombination in men at the highest resolution and accuracy and supports the emerging genome-wide picture that recombination is localized in small regions separated by cold areas. Detailed study of one of the new hot spots revealed a sperm donor with a decrease in recombination intensity at the canonical recombination site but an increase in crossover activity nearby. This unique finding suggests that the position and intensity of hot spots may evolve by means of a concerted mechanism that maintains the overall recombination intensity in the region.

Placenta growth factor overexpression inhibits tumor growth, angiogenesis, and metastasis by depleting vascular endothelial growth factor homodimers in orthotopic mouse models.

The role of placenta growth factor (PlGF) in pathologic angiogenesis is controversial. The effects of PlGF on growth, angiogenesis, and metastasis from orthotopic tumors are not known. To this end, we stably transfected three human cancer cell lines (A549 lung, HCT116 colon, and U87-MG glioblastoma) with human plgf-2 full-length cDNA. Overexpression of PlGF did not affect tumor cell proliferation or migration in vitro. The growth of PlGF-overexpressing tumors grown orthotopically or ectopically was impaired in all three tumor models. This decrease in tumor growth correlated with a decrease in tumor angiogenesis. The PlGF-overexpressing tumors had decreased vessel density and increased vessel diameter, but vessel permeability was not different from the parental tumors. Tumors overexpressing PlGF exhibited higher levels of PlGF homodimers and PlGF/vascular endothelial growth factor (VEGF) heterodimers but decreased levels of VEGF homodimers. Our study shows that PlGF overexpression decreases VEGF homodimer formation and inhibits tumor progression.

Blocking platelet-derived growth factor-D/platelet-derived growth factor receptor beta signaling inhibits human renal cell carcinoma progression in an orthotopic mouse model.

Renal cell carcinoma is a highly malignant and often fatal disease of the kidney. It is difficult to treat, often because metastases are common at the time of presentation. Platelet-derived growth factor-D (PDGF-D) is a newly discovered member of the PDGF family; its function in tumor progression is largely unknown. Here, we examined the expression level of PDGF-D in human renal cell carcinoma by immunohistochemical staining using tissue arrays. We showed that human renal cell carcinoma expresses high levels of PDGF-D protein. The human renal cell carcinoma cell line SN12-C was stably transfected with pdgf-d cDNA. Overexpression of PDGF-D in SN12-C cells promoted tumor growth, angiogenesis, and metastasis of human renal cell carcinoma in an orthotopic severe combined immunodeficient (SCID) mouse model. PDGF-D overproduction in SN12-C cells increased the proliferation and migration of mural cells in vitro and improved perivascular cell coverage in vivo. Overexpression of PDGF-D led to increased expression of angiopoietin-1 and matrix metalloproteinase-9 in tumor tissues. ShRNAi and Gleevec were used to block PDGF-D expression and PDGF receptor beta (PDGFRbeta) signaling. Inhibition of PDGF-D expression by short hairpin RNA interference (shRNAi) and blockage of PDGFRbeta signaling by Gleevec inhibited the growth and lung metastasis of SN12-C cells grown orthotopically in SCID mice. Thus, PDGF-D is a potential candidate for controlling the progression of metastatic renal cell carcinoma. This opens up an avenue of investigation into novel therapeutic strategies for the treatment of renal cell carcinoma, including the use of recently developed tyrosine kinase inhibitors, such as Gleevec, which inhibit PDGF activity through inhibition of its receptor tyrosine kinase.