Susan L. Connors

Bio: Susan L. Connors is an academic researcher from Harvard University. The author has contributed to research in topics: Autism & Basic fibroblast growth factor. The author has an hindex of 23, co-authored 33 publications receiving 2765 citations. Previous affiliations of Susan L. Connors include Boston Children's Hospital & Kennedy Krieger Institute.

Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia.

Abstract: It has been shown that solid tumors progress in concert with an induction of tumor angiogenesis. It is not known, however, whether a similar phenomenon occurs in leukemia. Angiogenesis was characterized immunohistochemically by factor VIII staining of bone marrow biopsies and quantified by assessment of microvessel density using previously described techniques. We evaluated bone marrow biopsies from 40 children with newly diagnosed, untreated acute lymphoblastic leukemia. In 22 of the patients, we also evaluated angiogenesis after the completion of remission induction chemotherapy. Control specimens were obtained from children undergoing staging evaluations at the time of diagnosis of solid tumors and lymphomas. Microvessels were counted throughout the entire core specimen in consecutive x 200 fields, and a median count per field (cpf) was calculated. In addition, the number of microvessels in the single x 200 field with the highest microvessel density was designated as the "hot spot." Biopsies from children with leukemia and from controls showed median microvessel densities of 42 and 6 counts per field, respectively (P < or = 0.0001). Microvessel density of the hot spots of leukemia specimens and controls were also significantly different, 51 and 8, respectively (P < or = 0.0001). A computer-aided three-dimensional reconstruction model of bone marrow vascularity showed a complex, arborizing branching of microvessels in leukemic specimens compared with single, straight microvessels without branching in controls. Urinary basic fibroblast growth factor, a potent angiogenic factor, was measured in 22 of the children with newly diagnosed leukemia and in 39 normal, age-matched controls. Urinary basic fibroblast growth factor levels were increased in all 22 patients before treatment, were variable during induction chemotherapy, and demonstrated statistically insignificant decreases at the time of complete remission. These findings suggest that leukemia cells induce angiogenesis in the bone marrow and that leukemia might be angiogenesis dependent and raise the possibility for a role of antiangiogenic drugs in the treatment of leukemia.

Sulforaphane treatment of autism spectrum disorder (ASD)

Abstract: Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medico-economic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13–27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)—derived from broccoli sprout extracts—or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50–150 µmol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015–0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation.

Phase I Clinical Trial of Recombinant Human Endostatin Administered as a Short Intravenous Infusion Repeated Daily

Abstract: PURPOSE: To perform a phase I trial of recombinant human endostatin (rhEndostatin; EntreMed, Rockville, MD) given as a daily 20-minute intravenous (IV) injection in adult patients with refractory solid tumors. PATIENTS AND METHODS: The daily dose was increased from 15 to 240 mg/m2 by a factor of 100% in cohorts of three patients. In the absence of dose-limiting toxicity, uninterrupted treatment was continued until the tumor burden increased by more than 50% from baseline. Correlative studies included dynamic contrast-enhanced magnetic resonance imaging of tumor blood flow, urinary vascular endothelial growth factor and basic fibroblast growth factor levels, rhEndostatin serum pharmacokinetics, and monitoring of circulating antibodies to rhEndostatin. RESULTS: There were no notable treatment related toxicities among 15 patients receiving a total of 50 monthly cycles of rhEndostatin. One patient with a pancreatic neuroendocrine tumor had a minor response and two patients showed disease stabilization. Linear...

VEGF, PF4 and PDGF are elevated in platelets of colorectal cancer patients

Abstract: Platelets sequester angiogenesis regulatory proteins which suggests an avenue for developing biomarkers to monitor disease. We describe a comparison of angiogenesis regulatory proteins found in platelets of colorectal cancer patients and normal controls. Platelet and plasma content of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF), platelet factor 4 (PF4), thrombospondin-1 (TSP-1) and endostatin in 35 patients with colon cancer were compared with 84 age-matched healthy controls using ELISAs. We standardized the platelet preparation procedure, introduced process controls and normalized the respective protein levels to platelet numbers using an actin ELISA. Statistically significant differences were found in the median levels of VEGF, PF4 and PDGF in platelets of patients with cancer compared to healthy individuals. Platelet concentrations in cancer patients versus controls were: VEGF 1.3 versus 0.6 pg/106, PF4 18.5 versus 9.4 ng/106, and PDGF 34.1 versus 21.0 pg/106. Multivariable logistic regression analysis indicated that PDGF, PF4 and VEGF were independent predictors of colorectal carcinoma and as a set provided statistically significant discrimination (area under the curve = 0.893, P < .0001). No significant differences were detected for bFGF, endostatin, or TSP-1. Reference Change Value analysis determined that the differences seen were not clinically significant. Plasma levels yielded no correlations.

Angiogenesis in cancer and other diseases

Abstract: Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases Concentrated efforts in this area of research are leading to the discovery of a growing number of pro- and anti-angiogenic molecules, some of which are already in clinical trials The complex interactions among these molecules and how they affect vascular structure and function in different environments are now beginning to be elucidated This integrated understanding is leading to the development of a number of exciting and bold approaches to treat cancer and other diseases But owing to several unanswered questions, caution is needed

Angiogenesis: an organizing principle for drug discovery?

Abstract: Angiogenesis--the process of new blood-vessel growth--has an essential role in development, reproduction and repair. However, pathological angiogenesis occurs not only in tumour formation, but also in a range of non-neoplastic diseases that could be classed together as 'angiogenesis-dependent diseases'. By viewing the process of angiogenesis as an 'organizing principle' in biology, intriguing insights into the molecular mechanisms of seemingly unrelated phenomena might be gained. This has important consequences for the clinical use of angiogenesis inhibitors and for drug discovery, not only for optimizing the treatment of cancer, but possibly also for developing therapeutic approaches for various diseases that are otherwise unrelated to each other.

Clinical translation of angiogenesis inhibitors.

Abstract: Angiogenesis inhibitors are a new class of drugs, for which the general rules involving conventional chemotherapy might not apply. The successful translation of angiogenesis inhibitors to clinical application depends partly on the transfer of expertise from scientists who are familiar with the biology of angiogenesis to clinicians. What are the most common questions that clinicians ask as they begin to test angiogenesis inhibitors in cancer clinical trials?

Moyamoya Disease and Moyamoya Syndrome

Abstract: Moyamoya disease is a cerebrovascular condition predisposing affected patients to stroke in association with progressive stenosis of the intracranial internal carotid arteries and their proximal branches. Patients with characteristic moyamoya vasculopathy plus associated conditions are categorized as having moyamoya syndrome. This review describes the demographic characteristics, pathogenesis, evaluation, and treatment of moyamoya disease and syndrome.

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

Abstract: Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism.