Martin Trepel's research while affiliated with Universität Augsburg and other places
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Publications (89)
Ever declining autopsy rates have been a concern of pathologists as well as clinicians for decades. Notably, in the field of oncology, data on autopsies and discrepancies between clinical and autoptic diagnoses are particularly scarce. In this retrospective study, we show the effect of a simple catalog of measures consisting of a different approach...
The brain vasculature supplies neurons with glucose and oxygen, but little is known about how vascular plasticity contributes to brain function. Using longitudinal in vivo imaging, we reported that a substantial proportion of blood vessels in the adult brain sporadically occluded and regressed. Their regression proceeded through sequential stages o...
Abstract Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and secondary resistance to currently available therapies in most cases. Therefore, despite recent advances in the treatment of this disease, it is still considered to be incurable in the majority of cases. MCL B cells retain their B cell antigen receptor (BCR) ex...
Objective:
Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits.
Methods:
In a mouse model of IP we admi...
Libraries displaying random peptides on the surface of adeno-associated virus (AAV) are powerful tools for the generation of target-specific gene therapy vectors. However, for unknown reasons the success rate of AAV library screenings is variable and the influence of the production procedure has not been thoroughly evaluated. During library screeni...
Introduction:
Despite substantial recent advances, there is still an unmet need for better therapies in B-cell non Hodgkin lymphomas (B-NHL), especially in relapsed or refractory disease. Many novel targeted drugs have been developed based on a better molecular understanding of B-NHL. Areas covered: This article focuses on chronic lymphocytic leuk...
Adeno-associated virus (AAV) has emerged as a very promising gene therapy vector. To enable tissue-directed gene expression, many artificially generated AAV variants have been established, often isolated from large pools of mutated capsids. Random peptide libraries displayed on AAV capsids have been used successfully to select vectors targeted to a...
Head and neck squamous cell carcinomas (HNSCC) exhibiting resistance to the EGFR targeting drug cetuximab poses a challenge to their effective clinical management. Here we report a specific mechanism of resistance in this setting based upon the presence of a single nucleotide polymorphism encoding EGFR-K521 (K-allele), which is expressed in >40% of...
The past two decades of lymphoma research have uncovered the essential role of the B-cell antigen receptor (BCR) pathway in lymphoma biology. This resulted in the development of targeted inhibitors for the treatment of several B-cell malignancies, especially chronic lymphocytic leukemia (CLL),
There is a lack of treatment options for many rare genetic disorders. Gene therapy represents a promising and innovative approach to fill this gap. One of such rare disorders is incontinentia pigmenti caused by X-linked deletions or mutations in the Nemo gene. The disease affects the skin, teeth, and eyes and, most importantly, it leads to a severe...
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Gene therapy critically relies on vectors that combine high transduction efficiency with a high degree of target specificity and that can be administered through a safe intravenous route. The lack of suitable vectors, especially for gene therapy of brain disorders, represents a major obstacle. Therefore, we applied an in vivo screening system of ra...
Vectors mediating strong, durable, and tissue-specific transgene expression are mandatory for safe and effective gene therapy. In settings requiring systemic vector administration, the availability of suited vectors is extremely limited. Here, we present a strategy to select vectors with true specificity for a target tissue from random peptide libr...
We report a case of a large three-level spinal osteosarcoma infiltrating the adjacent aorta. This is the first case in which a combined modified three-level en bloc corpectomy with resection and replacement of the adjacent aorta was successful as a part of interdisciplinary curative treatment.
Case report.
The surgical procedure was performed as a...
Fragestellung
Die Radiotherapie ist eine effektive Behandlung maligner Tumorerkrankungen, deren Einsatz jedoch durch die lokale Wirkung, interindividuelle Unterschiede in der DNA-Reparaturkapazität sowie akute und chronische Nebenwirkungen durch Kollateralschäden an gesunden Geweben limitiert wird. Es stellt sich also die Frage nach Optionen zur we...
Monoclonal B-cell lymphocytosis (MBL) and monoclonal gammopathy of undetermined significance (MGUS) result from clonal expansions of mature B or plasma cells. Here, we set out to determine the immunophenotypic/monoclonal immunoglobulin (M protein) features and co-prevalence of MBL and MGUS in a hospital-based cohort of 1909 non-hematooncological pa...
Libraries of randomised peptides displayed on phages or viral particles are essential tools in a wide spectrum of applications. However, there is only limited understanding of a library's fundamental dynamics and the influences of encoding schemes and sizes on their quality. Numeric properties of libraries, such as the expected number of different...
Adeno-associated viral (AAV) vectors yield high potential for clinical gene therapy but, like for other vectors systems, they frequently do not sufficiently transduce the target tissue and their unspecific tropism prevents their application for multifocal diseases such as disseminated cancer. Targeted AAV vectors have been obtained from random AAV...
This protocol outlines the steps required to perform ex vivo validation of in vivo near-infrared fluorescence (NIRF) xenograft imaging experiments in mice using fluorophore labelled nanobodies and conventional antibodies.
First we describe how to generate subcutaneous tumors in mice, using antigen-negative cell lines as negative controls and antige...
The utility of nanobodies and conventional antibodies for in vivo imaging is well known, but optimum dosing and timing schedules for one versus the other have not been established. We aimed to improve specific tumor imaging in vivo with nanobodies and conventional antibodies using near-infrared fluorescence (NIRF) imaging. We used ARTC2 expressed o...
Background:
Collateral damage to surrounding tissues by ionizing radiation (IR) may cause severe side effects of radiotherapy which requires limitation of total IR dosage. Therefore, specific targeting of tumor cells to enhance tumor-radiosensitivity is needed. One potential target is the Ataxia telangiectasia mutated kinase (ATM). ATM is a keypla...
Anti-tumor immunity in chronic lymphocytic leukemia (CLL) is hampered by highly dysfunctional T-cells. While certain T-cell subsets have been reported to be of prognostic significance in this disease, their interplay is complex and it remains incompletely understood which of these subsets significantly drive CLL progression. Here, we determined imm...
INTRODUCTION: The pathobiology mediating the development of primary central nervous system lymphoma (PCNSL) and its exclusive manifestation in the brain and spinal cord is still poorly understood. The monoclonal B-cell receptor expressed in PCNSL cells have a germinal center typology, suggesting previous antigen contact and antigen-based selection...
BackgroundMedian OS after surgery in curative intent for non-metastasized pancreas cancer ranges under study conditions from 17.9 months to 23.6 months. Tumor recurrence occurs locally, at distant sites (liver, peritoneum, lungs), or both. Observational and autopsy series report local recurrence rates of up to 87% even after potentially “curative”...
The identity of the proliferative compartment of myeloma progenitor cells remains a matter of debate. Polymerase chain reaction-based studies suggested pre-switch "clonotypic" B cells sharing the immunoglobulin (Ig) rearrangement of the malignant plasma cell (M-PC), to circulate in the blood and possess stem cell-like properties. Here, we disprove...
The large size of conventional antibodies impedes tissue penetration and renal elimination, resulting in suboptimal in vivo targeting. Here we assess the utility of nanobodies and nanobody-Fc-fusion proteins as alternatives to monoclonal antibodies as theranostics, using T cell ADP-ribosyltransferase 2 (ART2) as a model antigen for specific targeti...
The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases plays an important role in the biology of many cancers. In breast and gastric cancer, and maybe also additional tumor types, HER2 and its homo- or heterodimerization with HER1 or HER3 are essential for cancer cell growth and survival. Breast cancer patients overexp...
Embodiments of the invention are generally directed to compositions and methods of delivering one or more transgene to a target cell, such as a tumor cell, in a site-specific manner to achieve enhanced expression and to constructs and compositions useful in such applications. In certain aspects, expression from a therapeutic nucleic acid may be ass...
To the editor:
Chronic lymphocytic leukemia (CLL) may be driven by antigen recognition through the B-cell receptor (BCR).[1][1][⇓][2][⇓][3][⇓][4][⇓][5][⇓][6]–[7][7] A recent paper in Nature [8][8] suggested a new mechanism for such antigenic drive by functionally characterizing an
The number of tumor-infiltrating lymphocytes is functionally important and correlates with clinical outcome in several tumor entities. Herein we explore the impact of the density of T and B lymphocytes in prostate cancer tissue on prostate-specific antigen (PSA) recurrence after prostatectomy in 3261 prostate cancer tissue samples. The number of pr...
Receptor-targeted therapies have become standard in the treatment of various lymphomas. In view of its unparalleled specificity for the malignant B-cell clone, the B-cell receptor (BCR) on B cell lymphoma cells is a potential therapeutic target. We have used two BCR epitope mimicking peptides binding to the Burkitt's lymphoma cell lines CA46 and SU...
In multiple myeloma, circulating "clonotypic" B cells, that express the immunoglobulin rearrangement of the malignant plasma cell clone, can be indirectly detected by PCR. Their role as potential "feeder" cells for the malignant plasma cell pool remains controversial. Here we established for the first time an approach that allows direct tracking of...
Primer design for (semi-nested) PCRs.
(DOC)
Libraries based on the insertion of random peptide ligands into the capsid of adeno-associated virus type 2 (AAV2) have been widely used to improve the efficiency and selectivity of the AAV vector system. However, so far only libraries of 7-mer peptide ligands have been inserted at one well-characterized capsid position. Here, we expanded the combi...
Molecules differentially expressed in blood vessels among organs or between damaged and normal tissues, are attractive therapy targets; however, their identification within the human vasculature is challenging. Here we screened a peptide library in cancer patients to uncover ligand-receptors common or specific to certain vascular beds. Surveying ~2...
We have demonstrated the potential of random peptide libraries displayed on adeno-associated virus (AAV)2 to select for AAV2 vectors with improved efficiency for cell type-directed gene transfer. AAV9, however, may have advantages over AAV2 because of a lower prevalence of neutralizing antibodies in humans and more efficient gene transfer in vivo....
Spontaneous complete remission (CR) is a rare, poorly understood phenomenon in acute myeloid leukemia (AML). We describe the 10-year follow-up of a patient with MLL-AF9-positive AML (Müller et al. Eur J Haematol 73:62-66, 2004), including ex vivo antileukemic immune responses which may contribute to the long-lasting spontaneous CR (tantamount to cu...
Efficiency and specificity of viral vectors are vital issues in gene therapy. Insertion of peptide ligands into the adeno-associated viral (AAV) capsid at receptor binding sites can re-target AAV2-derived vectors to alternative cell types. Also, the use of serotypes AAV8 and -9 is more efficient than AAV2 for gene transfer to certain tissues in viv...
B-cell receptors (BCRs) and their recognition of specific epitopes may play a pivotal role in the development and progression of chronic lymphocytic leukemia (CLL). In this study, the authors set up a model system to explore epitope reactivity and its clinical relevance in CLL.
Epitope-mimicking peptides were selected from phage display libraries o...
Déf.: Groupe hétérogène de tumeurs malignes de la bouche, du nez et de la partie supérieure du système respiratoire.
CLL B-cell receptor binding to protein extracts from stromal cells. Primary nurse-like cells (NLCs) and the murine stromal cell line M210B4 alone or after co-culture with primary CLL cells were lysed and separated by one-dimensional gel electrophoresis. The reactivity of polyclonal IgG and the CLL BCRs Ig014, Ig015 and Ig022 was tested by Western b...
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Survival of CLL cells depends on their close contact with stromal cells in lymphatic tissues, bone marrow and blood. This microenvironmental regulation of CLL cell survival involves the stromal secretion of chemo- and cytokines as well as the expression of adhesion...
Vectors based on adeno-associated virus (AAV) are promising tools for gene therapy. The production of strongly toxic vectors, for example for cancer-directed gene transfer, is often unfeasible due to uncontrolled expression of toxic genes in vector-producing cells. Using an approach based on transcriptional repression, we have created novel AAV vec...
Selection of targeted vectors from virus display peptide libraries is a versatile and efficient approach to improve vector specificity and efficiency. This strategy has been used to target various cell types in vitro. Here, we report the screening of an adeno-associated virus type 2 (AAV2) display peptide library in vivo to select vectors specifica...
The human epidermal growth factor receptor (HER) family of growth factor receptor tyrosine kinases (RTKs) plays an important role in the biology of many cancers. In breast cancer, HER2 and its homo- or heterodimerization with HER1 or HER3 are essential for cancer cell growth and survival. Patients overexpressing HER2 have a poor prognosis, which ca...
Efficient and specific delivery of genes to the cell type of interest is a crucial issue in gene therapy. Adeno-associated virus (AAV) has gained particular interest as gene vector recently and is therefore the focus of this chapter. Its low frequency of random integration into the genome and the moderate immune response make AAV an attractive plat...
Suicide gene transfer is the most commonly used cytotoxic approach in cancer gene therapy; however, a successful suicide gene therapy depends on the generation of efficient targeted systemic gene delivery vectors. We recently reported that selective systemic delivery of suicide genes such as herpes simplex virus thymidine kinase (HSVtk) to tumor en...
Background:
Integrins are cell adhesion receptors involved in development, angiogenesis, blood clotting, inflammation and cancer. Abnormal integrin expression is a hallmark of cancer and angiogenic endothelial cells. Integrin-targeted therapy is, therefore, considered a promising novel treatment approach in oncology.
Objective:
We describe the b...
Targeting viral vectors to certain tissues in vivo has been a major challenge in gene therapy. Cell type-directed vector capsids can be selected from random peptide libraries displayed on viral capsids in vitro but so far this system could not easily be translated to in vivo applications. Using a novel, PCR-based amplification protocol for peptide...
B-cell receptors (BCR) on chronic lymphocytic leukemia (CLL) cells have stereotyped hypervariable regions, categorizing approximately 20% of all patients into one of almost 50 BCR subsets with nearly identical receptors. This suggests common antigen recognition in some CLL patients. We explored the binding pattern of recombinant CLL BCRs Fab fragme...
Acute myeloid leukemia was among the first malignancies to be cured by drug therapy alone, but overall survival rates remain unsatisfactory and have changed little over the past 20 years. Conventional chemotherapeutic regimens, which almost invariably include cytarabine and anthracyclines, are untargeted, and more specific therapies are needed.
We...
AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA
635
PHY906 is a novel formulated Chinese medicine for adjuvant cancer chemotherapy. Traditionally, this formula has been used for the treatment of gastrointestinal ailments like diarrhea. In our animal studies, we found that the co-administration of PHY906 with Irinotecan (CPT-11) could signif...
Depending on their physiologic location and functional state, vascular endothelial cells express surface receptors differentially. Recognition of this molecular diversity is essential for the development of targeted therapies. Random phage display peptide libraries can be selected in vitro on recombinant proteins or on intact cells. After systemic...
For acute myeloid leukemia (AML), gene therapy may be used to treat patients refractory to conventional chemotherapy. However, availability of vectors sufficiently and specifically transducing this cell type is very limited.
Here we report the selection of capsid-modified adeno-associated viral (AAV) vectors targeting Kasumi-1 AML cells by screenin...
Interleukin-2 (IL-2) and its receptor (IL-2R) play a major role in cellular immunity. The monoclonal antibodies basiliximab and daclizumab directed against the IL-2R subunit CD25 are widely used to prevent graft or host rejection after allogeneic tissue transplantation. Although these antibodies have been used for this purpose for many years, their...
![Figure 6: VLA-4 (|[alpha]|4|[beta]|1 integrin) as a candidate for the...](profile/Tobias-Berg-6/publication/6551711/figure/fig2/AS:267630040842270@1440819382671/VLA-4-alpha4beta1-integrin-as-a-candidate-for-the-CPLDIDFYC-receptor-a_Q320.jpg)
Ligands specifically binding to leukemia cells may be used for drug targeting, resulting in more effective treatment with less side effects. Little is known about receptors specifically expressed on acute myeloid leukemia (AML) cells or ligands thereof. We selected random phage display peptide libraries on Kasumi-1 AML cells. A peptide with the seq...
Bacteriophage (phage) evolved as bacterial viruses, but can be adapted to transduce mammalian cells through ligand-directed targeting to a specific receptor. We have recently reported a new generation of hybrid prokaryotic-eukaryotic vectors, which are chimeras of genetic cis-elements of recombinant adeno-associated virus and phage (termed AAVP). T...
![Figure 4: HPLC purification of [18F]FEAU: semi-preparative column, 10%...](profile/Amin-Hajitou/publication/6414553/figure/fig6/AS:281150099607600@1444042816006/HPLC-purification-of-18FFEAU-semi-preparative-column-10-MeCN-water-flow-rate-40-ml_Q320.jpg)
![Figure 5: QC analysis of [18F]FEAU: product injected with standard...](profile/Amin-Hajitou/publication/6414553/figure/fig4/AS:281149336244241@1444042633482/QC-analysis-of-18FFEAU-product-injected-with-standard-FEAU-analytical-column-10_Q320.jpg)
Non-invasive imaging of transgene expression requires the appropriate combination of a reporter gene and a reporter probe. [18F]FEAU positron emission tomography (PET) is used for the assessment of herpes simplex virus type-1 thymidine kinase gene expression. Hybrid AAV phage (termed AAVP) can be adapted to transduce mammalian cells by targeting to...
Random peptide ligands displayed on viral capsids are emerging tools for selection of targeted gene transfer vectors even without prior knowledge of the potential target cell receptor. We have previously introduced adeno-associated viral (AAV)-displayed peptide libraries that ensure encoding of displayed peptides by the packaged AAV genome. A major...
Rituximab is a monoclonal antibody widely used in the treatment of malignant lymphoma and autoimmunity. Its epitope within the B-cell antigen CD20 is largely unknown. We used phage display libraries to select peptides binding to rituximab. Enriched peptides showed 2 sequence patterns: one motif (CALMIANSC) is related to (170)ANPS(173) within CD20,...
Merging tumor targeting and molecular-genetic imaging into an integrated platform is limited by lack of strategies to enable systemic yet ligand-directed delivery and imaging of specific transgenes. Many eukaryotic viruses serve for transgene delivery but require elimination of native tropism for mammalian cells; in contrast, prokaryotic viruses ca...
Heterogeneity of the microvasculature in different organs has been well documented by multiple methods including in vivo phage display. However, less is known about the diversity of blood vessels within functionally distinct regions of organs. Here, we combined in vivo phage display with laser pressure catapult microdissection to identify peptide l...
Spontaneous remission in patients with acute myeloid leukemia (AML) is a rarely reported phenomenon of usually short duration. The etiology remains unclear, but an association with preceding blood transfusions or bacterial infections has been reported. Triggered immune responses are suggested to play a potential role in the development of spontaneo...
We show that a membrane-associated protease, aminopeptidase A (APA), is upregulated and enzymatically active in blood vessels of human tumors. To gain mechanistic insight, we evaluated angiogenesis in APA null mice. We found that, although these mice develop normally, they fail to mount the expected angiogenic response to hypoxia or growth factors....
Characterizing the molecular diversity of the cell surface is critical for targeting gene therapy. Cell type-specific binding ligands can be used to target gene therapy vectors. However, targeting systems in which optimum eukaryotic vectors can be selected on the cells of interest are not available. Here, we introduce and validate a random adeno-as...
Here we report on the identification of peptides targeting the X-inhibitor of apoptosis protein (XIAP). XIAP functions as a caspase inhibitor and is a member of the inhibitors of apoptosis (IAP) family of proteins. IAPs are often overexpressed in cancers and leukemias and are associated with an unfavorable clinical prognosis. We have selected pepti...
Autoimmune hemolytic anemia results from an IgM antibody (Ab)–red cell interaction and is referred to as cold hemagglutinin disease (CHD). CHD is most commonly associated with infectious or lymphoproliferative diseases but may also be coupled with malignancies or autoimmune or immunodeficiency
The vascular endothelium expresses differential receptors depending on the functional state and tissue localization of its cells. A method to characterize this receptor heterogeneity with phage display random peptide libraries has been developed. Using this technology, several peptide ligands have been isolated that home to tissue-specific endothel...
The molecular diversity of receptors in human blood vessels remains largely unexplored. We developed a selection method in which peptides that home to specific vascular beds are identified after administration of a peptide library. Here we report the first in vivo screening of a peptide library in a patient. We surveyed 47,160 motifs that localized...
Factors that determine the immunogenicity of an antigen in vivo are still largely unknown. Direct administration of antigens into lymphatic organs appears to enhance immune response. We hypothesized that systemically targeting antigens to lymphatic tissue in vivo might modulate immunity. To test this hypothesis, we measured the humoral immune respo...
The human parvovirus adeno-associated virus type 2 (AAV-2) possesses many features that make it an attractive vector for gene delivery in vivo. However, its broad host range may limit its usefulness and effectivity in several gene therapy applications in which transgene expression needs to be limited to a specific organ or cell type. In this study,...
At the forefront of medicine, Gene Therapy brings you the latest research into genetic and cell-based technologies to treat disease. It also publishes Progress & Prospects reviews and News and Commentary articles, which highlight the cutting edge of the field.
Gene therapy would be considerably more effective if vectors could be targeted to specific organs or tissues after systemic administration. We previously developed an in vivo selection system to isolate organ- and tumor-homing peptides from phage display peptide libraries. The peptides isolated by this approach bind to receptors expressed in vascul...
Citations
... Targeting of BECs has also been studied in targeting lysosomal disorders where the carriers were further endocytosed by glia and neurons for neurodevelopment [78,79]. Other examples of endothelial targeting include gene therapy to endothelial cells to treat epileptic seizures [80], restoration of brain glucose levels by targeting D-glucose transporter type 1 expressed on BECs [81], endothelial augmentation to repair the deficiency of monocarboxylate transporter-8 responsible for the polarization of BBB [82]. Furthermore, if the drug delivered via a carrier undergoes receptor-mediated transcytosis, it could alternatively be transported to the abluminal side, i.e., into the brain parenchyma and exhibit its efficacy [83]. ...
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... Because these receptors are expressed on wide range of cells, AAV has an intrinsically broad tropism and lacks the specificity needed to deliver genes to a particular tissue(s) or organ (s). While some success in targeting AAV to specific tissues has been achieved with capsid engineering by mutagenesis-based random screening and/or insertion of non-viral protein moieties into the capsid [21][22][23][24] it is prohibitively labor-intensive to impart new specificity on AAV. Therefore, we predicted that lassografting would enable us to readily alter the specificity of AAV in a modular fashion using pre-optimized peptide pharmacophores from RaPID. ...
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... The homing peptide on the phage coat protein combines with target molecules in vascular endothelial cells. A mass screening of the phage allows for the selective detection of targeted phage peptides, which combine into tumor blood vessels (17)(18)(19). Using this method, an increasing number of peptides targeting the tumor vasculature can be identified. ...
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... Table 1) with confocal immunofluorescence for the distribution of plasma membrane-associated PHB and c-Kit at different clinical stages. For this analysis, we used the rhodamine-tagged peptide CKGGRAKDC, which is known to selectively bind PHB in adipose endothelial cells and the cell surface of drug-resistant lung cancer cells, [25,31,32] to stain for PHB in the membrane raft domain and Alexa 488 to stain for c-Kit. Our results showed that c-Kit and PHB colocalized in the membrane raft domain of ovarian serous carcinoma but not in normal ovarian tissue (Fig. 2a). ...
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... Moreover, administration of rAAV-PSMA2-shRNA to a BLBC xenograft mouse model resulted in reduced tumor growth. In another AAV-based strategy, delivery of heart-specific miRNA sequences (miRT-1d) supported tumor-specific transgene expression and almost complete elimination in heart tissue [90]. Furthermore, insertion of the therapeutic suicide gene HSV-TK showed significant inhibition of tumor growth in polyoma middle T transgenic mice with multifocal breast tumors. ...
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... In this design, ~16% of the sequences will contain a premature stop codon in the varied region. 59 The ring and loop libraries were cloned into pET28, and multiple transformations were performed with chemically competent E. coli. The transformed cells were then diluted and plated to obtain ~1,000 colonies per 10 cm plate with each colony presumed to encode a unique FusA variant. ...
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... Alongside retroviruses, the adeno-associated virus (AAV) has been used as a platform for peptide library display. Here, capsid diversification combined with phenotypic screening was primarily used as a means of achieving re-targeted tropism [34,[127][128][129][130][131]. Normally, AAV libraries are produced in human cells, such as HEK 293T or HeLa [132]. ...
... AAV2.5, obtained by replacing five residues in the AAV2 capsid with corresponding orthogonal residues of AAV1 [146] and several other variants generated by variable combinations of 32 capsids' amino acids [252], improved muscle transduction compared with parental serotype 2 or 1 but were not assessed for whole-body distribution. Three AAV2 variants, AAV2i8, a chimeric capsid obtained by replacing a receptor-binding hexapeptide motif in the AAV2 capsid with corresponding residues in the AAV8 capsid [253], and two variants obtained by peptide insertions in a hypervariable loop [254,255] showed equivalent or improved targeting in skeletal muscles, with an important reduction in the liver in comparison with AAV2. AAV2i8 was also shown to be less likely to be serum-neutralized than the parental capsid [253]. ...
... Over 10 continuous working days (16)(17)(18)(19)(23)(24)(25)(26) in 2018, the authors of this study reviewed all complete blood count (CBC) results performed on all visiting patients from the outpatient, inpatient and health examination departments in Zhongshan Hospital, Fudan University. CBC are performed on more than 2000 patients daily and more than 98% of whom are patients visiting non-haematological department. ...
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... For instance, vasculature targeting peptides containing RGD (arginine/glycine/aspartic acid) motif specifically bind to integrins or cell surface molecules or receptors overexpressed on tumor blood vessels [49]. The cyclic peptide CNGRC containing the NGR (asparagine/glycine/arginine) motif selectively targets angiogenic endothelial cells [52]. Another peptide, TLTYTWS-binding to collagen IV and processed by proteolytic activity of MMP-2-has been identified by phage display and showed the inhibition of tumor-homing capabilities in a lung carcinoma mouse model, with consequent antiangiogenic effects [53]. ...
