Trial to Assess the Safety, Attenuation and Immunogenicity of Genetically-attenuated p52-/p36-/sap1- Plasmodium Falciparum Parasites (GAP3KO) Administered Via Infected Anopheles Stephensi Mosquitoes to Malaria-Naïve Adults
Study designed to evaluate safety and tolerability of a genetically attenuated P. falciparum (GAP3KO) that arrests early in the liver stage of the parasite life cycle. Study will also confirm the attenuation of the GAP3KO parasites using peripheral blood smears. Secondary objectives are to evaluate the humoral immune responses to GAP3KO.
Synaptic Adaptations of CA1 Pyramidal Neurons Induced by a Highly Effective Combinational Antidepressant Therapy
1区 · 医学
作者: Marchetti, Cristina ; Tafi, Elisiana ; Middei, Silvia ; Rubinacci, Maria A. ; Restivo, Leonardo ; Ammassari-Teule, Martine ; Marie, Helene
Antidepressants (AD) need to be chronically administered (weeks to months) to provide beneficial effects. Evidence suggests that combined administration of inhibitors of monoamine reuptake and phosphodiesterase type 4 allows a highly effective therapeutic action. Also, this coadministration more rapidly boosts the cyclic adenosine monophosphate (cAMP) pathway, which is normally activated during chronic treatment of single compounds. Little is known, however, about how this augmentation therapy affects the core mechanism of glutamatergic plasticity. We therefore investigated how in vivo combinational subchronic rolipram and imipramine (scRI) treatment affects depressive behavior, cAMP-dependent transcription, and glutamatergic transmission in the hippocampus, a region critically implicated in depression.
Antidepressant properties of scRI were investigated through the forced swim test. Changes in cAMP-dependent transcription and synaptic transmission of CA1 pyramidal cells were explored with green fluorescent protein, enzyme-linked immunosorbent assay, electrophysiology recordings, and Golgi-Cox staining.
We demonstrate that scRI displays robust antidepressant properties compared with single-drug treatments and increases hippocampal c-Fos expression and brain-derived neurotrophic factor protein levels. These effects are accompanied by a specific increase in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptors in already existing synapses. Finally, both acute and subchronic treatments led to enhancement of long-term potentiation but differently affected spine density and morphology, with scRI administration specifically resulting in a large increase in stubby spines.
We conclude that scRI is highly effective in providing antidepressive effects, including the hippocampal transcriptional alterations normally observed with longer single-drug treatments. Furthermore, we identified scRI-induced modifications in glutamatergic transmission that probably underlie the beneficial action of this combinational therapy.
1996-08-15·Transplantation2区 · 医学
Effect of repetitive high-dose treatment with soluble complement receptor type 1 and cobra venom factor on discordant xenograft survival
2区 · 医学
作者: Candinas, Daniel ; Lesnikoski, Beth-Ann ; Robson, Simon C. ; Miyatake, Tsukasa ; Scesney, Susanne M. ; Marsh, Henry C. Jr. ; Ryan, Una S. ; Dalmasso, Agustin P. ; Hancock, Wayne W. ; Bach, Fritz H.
Hyperacute xenograft rejection may be modified by the activation and depletion of complement (C) using cobra venom factor (CVF). This method of prolonging xenograft survival is toxic and associated with systemic inflammation, which may potentially contribute to the pathologic features of delayed xenograft rejection. Soluble complement receptor type 1 (sCR1) inhibits both the classical and alternative C pathways and thus limits the production of proinflammatory products such as the anaphylatoxins. Hence, we investigated the effects of various sCR1 and CVF regimens, and combinations thereof, in the discordant guinea pig-to-Lewis rat cardiac xenograft model. Mean graft survival time (MST) was significantly prolonged with repetitive dosing (MST=22 hr) or continuous infusion of sCR1 (MST=32 hr) as compared with unmodified controls (MST=15 min). However, sCR1 did not prevent intragraft deposition of C3 or neutrophil infiltration and resulted in only partial inhibition of C-mediated hemolytic activity in vitro. Grafts in rats treated with a single dose of CVF (MST=67 hr) or repetitive doses of CVF (MST=69 hr) survived significantly longer than those treated with sCR1 alone, and lacked C3 deposition or neutrophil accumulation. Sera from these animals were completely depleted of C-mediated hemolytic activity. Animals treated with a single dose of CVF, or sCRI plus a single dose of CVF (MST=64 hr), had similar xenograft survival times. However, immunohistologic studies showed that addition of sCR1 to a single dose of CVF resulted in decreased macrophage activation and reduced levels of cytokines (tumor necrosis factor-alpha and interleukin-1beta) within xenografts as compared with that in recipients treated with CVF alone. Such decreased macrophage activation may result from the binding of C4b by sCR1, since combination therapy was associated with decreased intragraft C4b as compared with either therapy alone. High doses of sCR1 were well tolerated by rats and significantly prolonged discordant xenograft survival (MST=32 hr), although not to the same extent as CVF. The modification of the intragraft immune responses seen with CVF/sCR1 combination therapy may augment further therapeutic manipulations to achieve discordant xenograft survival without the attendant toxicity associated with repeated CVF administration.
)--Sarah Cannon Research Institute (SCRI), one of the world’s leading oncology research organizations conducting clinical trials, is pleased to announce that Vivek Subbiah, MD, has joined the organization as Chief, Early-Phase Drug Development. In his role, Dr. Subbiah will oversee SCRI’s nine drug development units and lead the expansion of early-phase capabilities and programs across the organization’s growing research network of more than 1,300 physicians at more than 250 locations in 24 states.
A transformative and experienced leader in cancer clinical trial design and implementation, Dr. Subbiah comes to SCRI from the University of Texas MD Anderson Cancer Center where he was an Associate Professor in the Department of Investigational Cancer Therapeutics (A Phase I Program). During his near 15-year tenure there, Dr. Subbiah held several leadership roles including Executive Director, Medical Oncology Research, MD Anderson Cancer Network as well as Clinical Medical Director, Division of Cancer Medicine where he oversaw both the outpatient and inpatient clinical care delivery operations for the Phase I program.
“Vivek is a globally recognized key opinion leader for precision medicine and early-phase research,” said Howard A. “Skip” Burris, III, MD, President, SCRI. “His role in leading many drugs to FDA approval including developing tumor agnostic approaches to target mutations like RET and BRAF are now benefiting countless patient populations. We look forward to the impact he will continue to make in drug development in his new role at SCRI.”
Dr. Subbiah has served as the Principal Investigator in over 100 phase I/II trials and co-investigator in over 200 clinical trials and is known for his leadership in several first-in-human and practice-changing studies that directly led to approvals from the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and other agencies across the world. Furthermore, he has an exceptional track record of effectively bringing together multidisciplinary clinical trials teams, early career physician investigators, and physicians in training, all with the shared commitment to bringing novel therapies to patients with cancer. Having trained in both pediatric hematology & oncology as well as adult medical oncology, Dr. Subbiah is uniquely positioned to bring cutting-edge therapeutics across the age continuum from adolescent/young adults (AYAs) to older adults with cancer.
“It is an exciting time to be in oncology. We are at the cusp of the next generation of personalized medicine that requires rapid and effective patient access to clinical trials,” said Dr. Subbiah. “SCRI’s unparalleled reach across the US and UK, along with an agile organizational culture, will help us to accelerate progress against cancer. With a national network of remarkable oncology physicians, clinical teams, molecular profiling talent and technology, patients across the country can access innovative and personalized cancer treatments in their own backyard."
SCRI has played a pivotal role in cancer drug development, having conducted more than 650 first-in-human clinical trials since its inception and contributed to research that has led to the majority of new cancer therapies approved by the FDA in the last three decades. While Dr. Subbiah will be based in Nashville, TN, he will focus on expanding early-phase drug development programs across SCRI’s entire network.
Dr. Subbiah has authored over 350 peer-reviewed publications in several high-impact journals such as The New England Journal of Medicine, Nature Medicine, Journal of Clinical Oncology, JAMA Oncology, Cancer Discovery, Lancet Oncology, Nature Reviews Clinical Oncology, Lancet Diabetes and Endocrinology, and Clinical Cancer Research. He is on the editorial board of prestigious journals and is a member of the ESMO Precision Oncology Working group. He is the recipient of two NIH R01 funding awards and has received many awards including Andrew Sabin Family fellowship for 2021-2022 and The Emil Frei III Award for Translational Research in 2021.
After finishing his medical education in India, Dr. Subbiah completed a combined residency program in Internal Medicine and Pediatrics at Case Western Reserve University, MetroHealth, Cleveland, Ohio. He received board-certifications in both Internal Medicine and Pediatrics and has completed fellowships in both Adult and Pediatric Oncology at MD Anderson.
Sarah Cannon Research Institute (SCRI) is one of the world’s leading oncology research organizations conducting community-based clinical trials. In 2022, SCRI formed a joint venture with former US Oncology Research to enhance clinical trial access and availability across the country. Focused on advancing therapies for patients over the last three decades, SCRI is a leader in drug development. It has conducted more than 650 first-in-human clinical trials since its inception and contributed to pivotal research that has led to the majority of new cancer therapies approved by the FDA today. The combined research network brings together more than 1,300 physicians who are actively accruing patients to clinical trials at more than 250 locations in 24 states across the US. Please
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