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1.
Pasqualini R Arap W 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(1):257-259
Production of monoclonal antibodies requires immortalization of splenocytes by somatic fusion to a myeloma cell line partner (hybridomas). Although hybridomas can be immortal, they may depend on a feeder cell layer and may be genetically unstable. Since the inception of hybridoma technology, efforts to improve efficiency and stability of monoclonal antibody-producing cell lines have not brought about substantial progress. Moreover, suitable human multiple myeloma-derived cell lines for the production of human antibodies have been very difficult to develop. Here we report a strategy that greatly simplifies the generation of antibodies and eliminates the need for hybridomas. We show that splenocytes derived from transgenic mice harboring a mutant temperature-sensitive simian virus 40 large tumor antigen under the control of a mouse major histocompatibility promoter are conditionally immortal at permissive temperatures and produce monoclonal antibodies. This simple approach may become a method of choice for generation and production of both polyclonal and monoclonal antibodies with advantages in high-throughput discovery and antibody-based immunotherapy. 相似文献
2.
Paul F. Lebeau Hanny Wassef Jae Hyun Byun Khrystyna Platko Brandon Ason Simon Jackson Joshua Dobroff Susan Shetterly William G. Richards Ali A. Al-Hashimi Kevin Doyoon Won Majambu Mbikay Annik Prat An Tang Guillaume Par Renata Pasqualini Nabil G. Seidah Wadih Arap Michel Chrtien Richard C. Austin 《The Journal of clinical investigation》2021,131(2)
Individuals harboring the loss-of-function (LOF) proprotein convertase subtilisin/kexin type 9 Gln152His variation (PCSK9Q152H) have low circulating low-density lipoprotein cholesterol levels and are therefore protected against cardiovascular disease (CVD). This uncleavable form of proPCSK9, however, is retained in the endoplasmic reticulum (ER) of liver hepatocytes, where it would be expected to contribute to ER storage disease (ERSD), a heritable condition known to cause systemic ER stress and liver injury. Here, we examined liver function in members of several French-Canadian families known to carry the PCSK9Q152H variation. We report that PCSK9Q152H carriers exhibited marked hypocholesterolemia and normal liver function despite their lifelong state of ER PCSK9 retention. Mechanistically, hepatic overexpression of PCSK9Q152H using adeno-associated viruses in male mice greatly increased the stability of key ER stress-response chaperones in liver hepatocytes and unexpectedly protected against ER stress and liver injury rather than inducing them. Our findings show that ER retention of PCSK9 not only reduced CVD risk in patients but may also protect against ERSD and other ER stress–driven conditions of the liver. In summary, we have uncovered a cochaperone function for PCSK9Q152H that explains its hepatoprotective effects and generated a translational mouse model for further mechanistic insights into this clinically relevant LOF PCSK9 variant. 相似文献
3.
Hitomi Hosoya Andrey S. Dobroff Wouter H. P. Driessen Vittorio Cristini Lina M. Brinker Fernanda I. Staquicini Marina Cardó-Vila Sara D’Angelo Fortunato Ferrara Bettina Proneth Yu-Shen Lin Darren R. Dunphy Prashant Dogra Marites P. Melancon R. Jason Stafford Kohei Miyazono Juri G. Gelovani Kazunori Kataoka C. Jeffrey Brinker Richard L. Sidman Wadih Arap Renata Pasqualini 《Proceedings of the National Academy of Sciences of the United States of America》2016,113(7):1877-1882
A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.A long-term goal in contemporary cancer nanomedicine has been to design and generate drug delivery systems that improve the narrow therapeutic window associated with conventional chemotherapeutics (1, 2). Conceptually, several nanotechnology-based entity candidates, including protocells (3), biosynthetic nanoparticles (NPs), viruses, and liposome-based nanoparticles, could be targeted for active delivery through a defined cell surface ligand receptor system and/or physically triggered for finely tuned cargo release (2, 4, 5).Numerous efforts have been made to functionalize NPs by combining them with antibodies, aptamers, peptides, vitamins, or carbohydrates (6–8), but the majority of studies involve untargeted nanoplatforms (4, 9). In practice, targeting NPs is far from trivial, and ongoing challenges include synthesis and purification, selection of an appropriate ligand receptor, and specific composition for NP conjugation. Even the conjugation reaction itself may alter the binding of the tumor-targeting moiety to its receptor through conformational changes, steric freedom restriction, or orientation distortion (10, 11). Unfortunately, the cost-to-benefit ratio of these modifications often elevate the complexity of the NP synthesis, complicating regulatory hurdles because of formulations that are heterogeneous or difficult to reproduce (10, 12, 13).To minimize such drawbacks, NPs can be functionalized via virus-based nanoplatforms as an alternative for targeted cargo delivery (14–16). In particular, filamentous bacteriophage (phage)—a prokaryotic virus—is an attractive candidate to develop a bionanomedicine for cancer therapeutics because phage particles are cost-effectively produced with biological uniformity, as well as being physically robust and stable under harsh conditions (17). Notably, phage-based nanoplatforms are biocompatible and nonpathogenic with eukaryotic organisms and are able to preserve the desired cell targeting and internalization (18). Moreover, phage particles are ideal for incorporating other NPs, which can be released after reaching the tumor site. An admixture of colloidal gold NP (AuNP) with phage particles spontaneously organizes into hydrogel network-like fractal structures (19, 20). These hydrogel networks offer convenient multifunctional integration within a single entity for tumor targeting, enhanced fluorescence and dark-field microscopy, near-infrared (NIR) photon-to-heat conversion, and surface-enhanced Raman scattering (SERS)-based detection (20, 21).In the present work, we developed a tumor targeting theranostic (meaning a combination of therapeutics and diagnostics) hydrogel-based nanoplatform that enables ligand-directed tumor targeting, multimodal imaging capability, and triggered therapeutic cargo release. Our data suggest that targeted hydrogel photothermal therapy represents a functional theranostic approach (fostering “see and treat, treat and see”) in the diagnosis and management of tumors. 相似文献
4.
Roxana de Fátima Camelo Albuquerque Cinthia Esbrile Moraes Carbonara Rita de Cássia T. Martin Luciene Machado dos Reis Climério Pereira do Nascimento Sérgio Samir Arap Rosa M.A. Moysés Vanda Jorgetti Fábio L.M. Montenegro Rodrigo Bueno de Oliveira 《Surgery》2018,163(2):381-387
Background
Parathyroidectomy (PTx) decreases the mortality rate of refractory secondary hyperparathyroidism (rSHP) due to chronic kidney disease. A consensus regarding which techniques of PTx are associated with better outcomes is not available. The aims of this study are to evaluate the clinical and laboratory evolution of 49 hemodialysis patients with rSHP who underwent PTx using different techniques.Methods
Patients underwent subtotal PTx (sub-PTx) or total PTx with autotransplantation (AT) of 45 (PTx-AT45) or 90 parathyroid fragments (PTx-AT90) and were followed for 12 months. We analyzed the expression of proliferating cell nuclear antigen (PCNA), calcium-sensing receptor (CasR), vitamin D receptor (VDR), fibroblast growth factor receptor-1 (FGFR1), sodium-dependent phosphate cotransporter-1 (PIT1), and Klotho in parathyroid glands.Results
Baseline median serum intact parathyroid hormone (iPTH) levels were 1,466 (1,087–2,125) pg/mL; vascular calcification scores correlated with serum iPTH (r?=?0.529; P?=?.002) and serum phosphate levels (r?=?0.389; P?=?.028); and Klotho expression was negatively correlated with serum phosphate levels (r?=??0.4; P?=?.01). After 12 months, serum iPTH and alkaline phosphatase levels were significantly controlled in all groups, as was bone pain. The proportions of patients with serum iPTH levels within the ranges recommended by Kidney Disease: Improving Global Outcomes were similar among the treatment groups. During the hungry bone disease (HBS), patients received 3,786?g (1,412–7,580) of elemental calcium, and a trend toward a positive correlation between the cumulative calcium load at the end of follow up and VC score post-PTx was noted (r?=?0.390; P?=?.06). Two cases evolved to clinically uncontrolled hyperparathyroidism in the sub-PTx group. The expression patterns of PCNA, VDR, CasR, PIT1, FGFR1, and Klotho in parathyroid glands did not correlate with serum systemic iPTH levels or the duration of HBS.Conclusions
All 3 operative techniques were effective at controlling rSHP, both in clinical and laboratory terms. Neither the quantity nor quality of parathyroid fragments influenced serum systemic iPTH and AT-iPTH levels. The cumulative calcium load appeared to correlate with the VC score and may have affected its progression. The effects of phosphate restriction on Klotho expression in human parathyroid glands and the subsequent decrease in FGF23 resistance must be addressed in further studies. 相似文献5.
6.
Identification of receptor ligands with phage display peptide libraries. 总被引:18,自引:0,他引:18
E Koivunen W Arap D Rajotte J Lahdenranta R Pasqualini 《Journal of nuclear medicine》1999,40(5):883-888
With the development and maturation of the technology of displaying peptides on bacteriophage, it has become possible to isolate peptide ligands to various targets. In the phage display strategy, up to 10(9) peptides of different permutations are expressed on the surface of filamentous phage. Thus, peptides capable of binding target molecules in vitro and even target tissues in vivo can be identified. In recent years, a series of libraries that display degenerate peptides of different lengths have been constructed, and specific ligands to cell surface receptors, such as integrins, have been isolated. In the in vivo biopanning, peptides targeting distinct organs or tumors have been rescued after intravenous administration of phage libraries into mice. In one application, the isolated peptide ligands have been used to direct a cytotoxic drug to tumor vasculature in mice. Further applications in radioimaging and radiotherapy are being investigated. 相似文献
7.
Glauco R. Souza Fernanda I. Staquicini Dawn R. Christianson Michael G. Ozawa J. Houston Miller Renata Pasqualini Wadih Arap 《Biomedical microdevices》2010,12(4):597-606
The development of improved methods for targeted cell detection is of general interest in many fields of research and drug
development. There are a number of well-established techniques for the study and detection of biomarkers expressed in living
cells and tissues. Many of them rely on multi-step procedures that might not meet ideal assay requirements for speed, cost,
sensitivity, and specificity. Here we report and further validate an approach that enables spontaneous molecular assembly
to generate biologically active networks of bacteriophage (phage) assembled with gold (Au) nanoparticles (termed Au-phage
nanoshuttles). Here, the nanoshuttles preserve the cell binding and internalization attributes mediated by a displayed peptide
targeted to a cell surface receptor. The organization of such targeted assemblies can be further manipulated to be used as
a mutimodal detection assembly, and they can be characterized as fractal nanostructures by angle-dependent light scattering
fractal dimension analysis. Targeted Au-phage nanoshuttles offer multiple functionalities for nanotechnology-based sensing
and reporting, including enhanced florescence and improved contrast for darkfield microscopy. 相似文献
8.
Three cases of duplicate exstrophy are described and the theoretical mechanisms of embryogenesis discussed. In all 3 cases there was classic pelvic skeletal deformity. Urinary control was normal in 2 of the 3 patients. The surgical approach consisted of plastic repair of the abdominal wall defect in all patients and correction of urinary incontinence in 1 patient. 相似文献
9.
10.
Chronic splenomegaly in Nairobi, Kenya. II. Portal hypertension 总被引:1,自引:0,他引:1
K M De Cock S Awadh R S Raja B M Wankya R A Jupp B Slavin T K Arap Siongok P H Rees J Bertrand S B Lucas 《Transactions of the Royal Society of Tropical Medicine and Hygiene》1987,81(1):107-110
Eighty-five patients with chronic splenomegaly and proven oesophageal varices were studied at Kenyatta National Hospital, Nairobi. The major defined groups were hepatosplenic schistosomiasis (24%), cirrhosis (20%) and portal vein occlusion (11%). Hyper-reactive malarial splenomegaly (tropical splenomegaly syndrome) was considered as the cause of oesophageal varices in only one patient. In 26% of cases liver biopsy was non-diagnostic and the extrahepatic portal vein was demonstrated radiologically to be patent. Such patients were thought to be suffering from idiopathic portal hypertension, not previously described elsewhere in Africa. Hepatitis B surface antigen was detected in 12% of controls and in 58% of patients with cirrhosis (p less than 0.001). Some serological marker of previous hepatitis B virus infection was present in 92% of patients with cirrhosis and in 79% of controls. Kamba patients from Machakos and Kitui Districts were significantly more prevalent than expected among these 85 cases of portal hypertension. 相似文献