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PubMed1990

Target selection by cortical axons: alternative mechanisms to establish axonal connections in the developing brain.

We have described our studies of the development of projections from layer 5 of the rat neocortex to subcortical targets in the midbrain and hindbrain. The major points are briefly summarized here. 1. Layer-5 neurons extend a primary axon out of cortex and along a spinally directed trajectory, bypassing all of their targets in the midbrain and hindbrain. These targets are later contacted exclusively by collaterals formed by a delayed interstitial branching of the primary axon, not by growth cone bifurcation. 2. Collateral branches only form at stereotypic positions, not randomly along the length of the axon. Thus, specific cues identify branch points, and the length of the primary axon well behind its growth cone responds to these cues. 3. Layer-5 neurons in diverse areas of cortex initially develop the same basic set of collateral branches, although they will permanently retain different subsets of the initial common set. Therefore, branch cues are recognized by layer-5 neurons independent of whether the collateral projection formed is functionally appropriate for the cortical region in which the neuron resides. 4. In vitro and in vivo evidence indicates that one of the major branches, which forms the corticopontine projection, is induced and directed into its target, the basilar pons, by a diffusible, target-derived, tropic signal. Thus, a chemotropic cue promotes recognition of the basilar pontine target by the primary layer-5 axons. 5. In this system, then, target selection is not the responsibility of the growth cone of the primary axon.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

Unusual target selectivity of perisomatic inhibitory cells in the hilar region of the rat hippocampus.

Perisomatic inhibitory innervation of all neuron types profoundly affects their firing characteristics and vulnerability. In this study we examined the postsynaptic targets of perisomatic inhibitory cells in the hilar region of the dentate gyrus where the proportion of potential target cells (excitatory mossy cells and inhibitory interneurons) is approximately equal. Both cholecystokinin (CCK)- and parvalbumin-immunoreactive basket cells formed multiple contacts on the somata and proximal dendrites of mossy cells. Unexpectedly, however, perisomatic inhibitory terminals arriving from these cell types largely ignored hilar GABAergic cell populations. Eighty-ninety percent of various GABAergic neurons including other CCK-containing basket cells received no input from CCK-positive terminals. Parvalbumin-containing cells sometimes innervated each other but avoided 75% of other GABAergic cells. Overall, a single mossy cell received 40 times more CCK-immunoreactive terminals and 15 times more parvalbumin-positive terminals onto its soma than the cell body of an average hilar GABAergic cell. In contrast to the pronounced target selectivity in the hilar region, CCK- and parvalbumin-positive neurons innervated each other via collaterals in stratum granulosum and moleculare. Our observations indicate that the inhibitory control in the hilar region is qualitatively different from other cortical areas at both the network level and the level of single neurons. The paucity of perisomatic innervation of hilar interneurons should have profound consequences on their action potential generation and on their ensemble behavior. These findings may help explain the unique physiological patterns observed in the hilus and the selective vulnerability of the hilar cell population in various pathophysiological conditions.

Animals↗

PubMed1983

Spontaneous cytotoxic T cells in murine spleen-cell cultures. II. Distinguishing between spontaneous cytotoxic T cells and NK cells according to kinetics and target selectivity.

Cytotoxic T cells that arise spontaneously in cultures (SCTL) appear to be distinct from natural killer (NK) cells. The specificity of these two types of cytotoxic cell populations has been compared by direct cytotoxicity and cold target inhibition tests. The SCTL population consists of an array of cytotoxic cells each of which is specific for a series of target cells. The NK cells had a more limited range of target selectivity although at least two types of NK effector cells were detected on the basis of specificity measurements.

Animals↗

PubMed2001

Short-term priming, concurrent processing, and saccade curvature during a target selection task in the monkey.

In human subjects, two mechanisms for improving the efficiency of saccades in visual search have recently been described: color priming and concurrent processing of two saccades. Since the monkey provides an important model for understanding the neural underpinnings of target selection in visual search, we sought to explore the degree to which the saccadic system of monkeys uses these same mechanisms. Therefore, we recorded the eye movements of rhesus monkeys performing a simple color-oddity pop-out search task, similar to that used previously with human subjects. The monkeys were rewarded for making a saccade to the odd-colored target, which was presented with an array of three distractors. The target and distractors were randomly chosen to be red or green in each trial. Similar to what was previously observed for humans, we found that monkeys show the influence of a cumulative, short-term priming mechanism which facilitates saccades when the color of the search target happens to repeat from trial to trial. Furthermore, we found that like humans, when monkeys make an erroneous initial saccade to a distractor, they are capable of executing a second saccade to the target after a very brief inter-saccadic interval, suggesting that the two saccades have been programmed concurrently (i.e. in parallel). These results demonstrate a close similarity between human and monkey performance. We also made a new observation: we found that when monkeys make such two-saccade responses, the trajectory of the initial saccade tends to curve toward the goal of the subsequent saccade. This provides evidence that the two saccade goals are simultaneously represented on a common motor map, supporting the idea that the movements are processed concurrently. It also indicates that concurrent processing is not limited to brain areas involved in higher-level planning; rather, such parallel programming apparently occurs at a low enough level in the saccadic system that it can affect saccade trajectory.

Animals↗

PubMed2002

Selective targeting of angiogenic tumor vasculature by vascular endothelial-cadherin antibody inhibits tumor growth without affecting vascular permeability.

Vascular endothelial-cadherin (VE-cadherin) is an endothelial cell-specific adhesion molecule that is localized exclusively at cell-cell contacts referred to as adherens junctions. VE-cadherin-mediated adhesion is crucial for proper assembly of vascular structures during angiogenesis as well as for maintenance of a normal vascular integrity. We have shown previously that a monoclonal antibody (BV13) to VE-cadherin not only inhibits the formation of vascular tubes during tumor angiogenesis but also disrupts adherens junctions of normal vasculature with a concomitant increase in vascular permeability. The goal of the current studies was to block VE-cadherin function during angiogenesis without disrupting existing junctions on normal endothelium. Using in vitro screening assays to test for functional blocking of adherens junction formation and in vivo assays to detect antibody effects on vascular permeability in normal tissues, we have identified a novel blocking antibody (E4G10) that inhibits VE-cadherin function during angiogenesis but does not disrupt existing adherens junctions on normal vasculature. E4G10 inhibited formation of vascular tubes in vivo in the Matrigel plug and corneal micropocket assays. E4G10 also inhibited tumor growth in three models of mouse and human tumors via an antiangiogenic mechanism. Examination of normal mouse and tumor tissues showed that E4G10 bound to endothelial cells in a subset of tumor vasculature but not to normal vasculature. Bromodeoxyuridine labeling experiments showed that E4G10 specifically targeted a subset of tumor endothelium that is undergoing active cell proliferation, which likely reflects the activated, angiogenic endothelium. These findings indicate that VE-cadherin can be selectively targeted during states of pathological angiogenesis, despite its ubiquitous distribution throughout the entire vasculature. Our data also suggest that antibody E4G10 recognizes VE-cadherin epitopes that are only accessible on endothelial cells forming new adherens junctions, such as in angiogenic tumor vasculature.

Adherens Junctions↗

PubMed2004

Significance of selectively targeted apoptotic rete cells in graft-versus-host disease.

Considerable data exist regarding the mechanisms of allostimulation and homing (the effector phases) in graft-versus-host disease (GVHD). Current dogma suggests that target specificity involves preferential injury to epithelial surfaces of the skin and squamous mucosae, liver, and gut. Little attention has been devoted, however, to mechanisms of cellular targeting or to whether heterogeneity exists in target tissues with regard to a threshold for cellular injury. A recent breakthrough in understanding the target stage of GVHD indicates that the predominant pathway of injury to squamous epithelial cells involves apoptosis. Moreover, apoptotic injury may be associated or unassociated with local T-cell infiltration and involves phenotypically and antigenically distinctive epithelial cells within the basal layer of the skin and squamous mucosa. These cells are confined to rete ridges in the skin and retelike prominences in the dorsal tongue and are designated as selectively targeted apoptotic rete (STAR) cells. The discovery of STAR cells in GVHD paves the way for speculation and experimentation to determine why these subpopulations are selectively vulnerable and how soluble and cellular effectors of apoptosis contribute to their ultimate demise. Novel approaches to GVHD treatment derived from understanding mechanisms of selective epithelial injury are likely to use strategies to render target cells less susceptible to the apoptosis that is ultimately responsible for organ dysfunction and failure.

Animals↗

PubMed2003

Sequential memory-guided saccades and target selection: a neural model of the frontal eye fields.

We present a neural model of the frontal eye fields. It consists of several retinotopic arrays of neuron-like units that are recurrently connected. The network is trained to make memory-guided saccades to sequentially flashed targets that appear at arbitrary locations. This task is interesting because the large number of possible sequences does not permit a pre-learned response. Instead locations and their priority must be maintained in active working memory. The network learns to perform the task. Surprisingly, after training it can also select targets in visual search tasks. When targets are shown in parallel it chooses them according to their salience. Its search behavior is comparable to that of humans. It exhibits saccadic averaging, increased reaction times with more distractors, latency vs accuracy trade-offs, and inhibition of return. Analysis of the network shows that it operates like a queue, storing the potential targets in sequence for later execution. A small number of unit types are sufficient to encode this information, but the manner of coding is non-obvious. Units respond to multiple targets similar to quasi-visual cells recently studied [Exp. Brain Res. 130 (2000) 433]. Predictions are made that can be experimentally tested.

Fixation, Ocular↗

PubMed2004

Target-selected mutagenesis of the rat.

The rat is one of the most extensively studied model organisms, and with its genome being sequenced, tools to manipulate gene function in vivo have become increasingly important. We here report proof of principle for target-selected mutagenesis as a reverse genetic or knockout approach for the rat.

Animals↗

PubMed2002

Selective targeting of tumoral vasculature: comparison of different formats of an antibody (L19) to the ED-B domain of fibronectin.

We recently demonstrated that a human recombinant scFv, L19, reacting with the ED-B domain of fibronectin, a marker of angiogenesis, selectively targets tumoral vasculature in vivo. Using the variable regions of L19, we constructed and expressed a human "small immunoprotein" (SIP) and a complete human IgG1 and performed biodistribution studies in tumor-bearing mice to compare the blood clearance rate, in vivo stability and performance in tumor targeting of the 3 L19 formats [dimeric scFv (scFv)(2), SIP and IgG1]. The accumulation of the different antibody formats in the tumors studied was a consequence of the clearance rate and in vivo stability of the molecules. Using the SIP, the %ID/g in tumors was 2-5 times higher than that of the (scFv)(2), reaching a maximum 4-6 hr after injection. By contrast, the accumulation of IgG1 in tumors constantly rose during the experiments. However, due to its slow clearance, the tumor-blood ratio of the %ID/g after 144 hr was only about 3 compared to a ratio of 10 for the (scFv)(2) and 70 for the SIP after the same period of time. The different in vivo behavior of these 3 completely human L19 formats could be exploited for different diagnostic and/or therapeutic purposes, depending on clinical needs and disease. Furthermore, the fact that ED-B is 100% homologous in human and mouse, which ensures that L19 reacts equally well with the human and the murine antigen, should expedite the transfer of these reagents to clinical trials.

Animals↗

PubMed1993

Selective targeting of human lymphokine-activated killer cells by CD3 monoclonal antibody against the interferon-inducible high-affinity Fc gamma RI receptor (CD64) on autologous acute myeloid leukemic blast cells.

The potential of the CD3 monoclonal antibody (MoAb) OKT3 to selectively target lymphokine-activated killer (LAK) cells and T-cell clones in vitro against autologous tumor cells was studied using material from patients with acute leukemias (19 acute myeloid leukemias [AML], and 3 acute lymphoblastic leukemias [ALL]). Cytotoxicity mediated by patient LAK cells against AML blasts, but not against ALL cells and autologous Epstein-Barr virus-transformed B cells, was enhanced 1.5-fold to 9.3-fold by OKT3 in all AML patients studied. The following findings suggest that the major target molecule on AML cells for OKT3-coated LAK cells is the high-affinity Fc receptor for IgG (Fc gamma RI; CD64): (1) susceptibility to killing by OKT3-coated effector LAK cells segregated with target cell expression of CD64; (2) preincubation of AML blasts with monomeric OKT3 (murine IgG2a), the Fc portion of which is known to have preferential binding affinity to CD64, resulted in lysis by autologous T cells that were not spontaneously cytotoxic; (3) OKT3-dependent increase in lysis of primary and relapsed AML cells by autologous T-cell clones correlated with the amount of target cell expression of CD64; (4) anti-leukemic cytotoxicity of OKT3-coated T cells could partially be inhibited by monomeric human Ig, the natural ligand of CD64; and (5) expression of CD64 (Fc gamma RI) on fresh AML cells could be increased by interferon-gamma (IFN-gamma) and IFN-alpha translating into further enhancement of lysis by autologous OKT3-coated LAK cells. Nonmalignant CD34+ cells sorted from peripheral blood were found to lack expression of CD64 and hence were not affected by OKT3-triggered T-cell targeting, as detected by colony formation assays. In conclusion, the in vitro data presented provide a rationale for the combined clinical use of recombinant interleukin-2, IFN-gamma, and low doses of CD3 MoAb to eliminate AML cells while sparing nonmalignant hematopoietic progenitor cells, for example, in the setting of purging procedures for autologous bone marrow transplantation.

Antigens, CD↗

PubMed2004

Automatic target selection for structural genomics on eukaryotes.

A central goal of structural genomics is to experimentally determine representative structures for all protein families. At least 14 structural genomics pilot projects are currently investigating the feasibility of high-throughput structure determination; the National Institutes of Health funded nine of these in the United States. Initiatives differ in the particular subset of "all families" on which they focus. At the NorthEast Structural Genomics consortium (NESG), we target eukaryotic protein domain families. The automatic target selection procedure has three aims: 1) identify all protein domain families from currently five entirely sequenced eukaryotic target organisms based on their sequence homology, 2) discard those families that can be modeled on the basis of structural information already present in the PDB, and 3) target representatives of the remaining families for structure determination. To guarantee that all members of one family share a common foldlike region, we had to begin by dissecting proteins into structural domain-like regions before clustering. Our hierarchical approach, CHOP, utilizing homology to PrISM, Pfam-A, and SWISS-PROT chopped the 103,796 eukaryotic proteins/ORFs into 247,222 fragments. Of these fragments, 122,999 appeared suitable targets that were grouped into >27,000 singletons and >18,000 multifragment clusters. Thus, our results suggested that it might be necessary to determine >40,000 structures to minimally cover the subset of five eukaryotic proteomes.

Algorithms↗

PubMed2002

Selective targeting of the nuclear factor-kappaB pathway enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated pancreatic cancer cell death.

BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor family, selectively induces apoptosis in various cancer cells; however, certain cancers can evade TRAIL-mediated apoptosis. FLICE-like inhibitory protein (FLIP), an inhibitor of caspase-8, (also known as FLICE) is regulated by the transcription factor nuclear factor-kappaB (NF-kappaB) and can contribute to TRAIL resistance. The purpose of our study was to determine whether inhibition of NF-kappaB can enhance TRAIL-mediated pancreatic cancer cell death and decrease FLIP levels. METHODS: The human pancreatic cancer cell lines MIA PaCa-2 and L3.6 were treated with TRAIL, NEMO-binding domain (NBD) peptide (a novel selective NF-kappaB inhibitor), or a combination of both. Cell viability and apoptosis were measured. Gel mobility shift assays were performed to assess NF-kappaB binding activity. Western blots were performed to assess FLIP levels after treatment with NBD or infection with an adenovirus encoding mutated IkappaBalpha. RESULTS: The aggressive L3.6 cell line was resistant to TRAIL treatment, whereas MIA PaCa-2 cells were sensitive to TRAIL. The combination of TRAIL and NBD significantly decreased cell viability and increased apoptosis in L3.6 cells. Cellular levels of FLIP were decreased by inhibition of NF-kappaB (either by NBD treatment or mutant IkappaBalpha infection). CONCLUSIONS: Our findings demonstrate resistance of the aggressive L3.6 pancreatic cell line to TRAIL treatment alone; inhibition of NF-kappaB by NBD increased TRAIL-mediated cell death and decreased FLIP protein levels. Novel agents that selectively target the NF-kappaB pathway may be useful adjuvant therapies for chemoresistant pancreatic cancers.

Apoptosis↗

PubMed2001

Selective targeting of tumour neovasculature by a radiohalogenated human antibody fragment specific for the ED-B domain of fibronectin.

Angiogenesis is a characteristic feature of many aggressive tumours and other disorders. Antibodies capable of binding to new blood vessels, but not to mature vessels, could be used as selective targeting agents for immunoscintigraphic and radioimmunotherapeutic applications. Here we show that scFv(L19), a recombinant human antibody fragment with sub-nanomolar affinity for the ED-B domain of fibronectin, a marker of angiogenesis, can be stably labelled with iodine-125 and astatine-211 with full retention of immunoreactivity, using a trimethyl-stannyl benzoate bifunctional derivative. Biodistribution studies in mice bearing two different types of tumour grafted subcutaneously, followed by ex vivo micro-autoradiographic analysis, revealed that scFv(L19) rapidly localises around tumour blood vessels, but not around normal vessels. Four hours after intravenous injection of the stably radioiodinated scFv(L19), tumour to blood ratios were 6:1 in mice bearing the F9 murine teratocarcinoma and 9:1 in mice bearing an FE8 rat sarcoma. As expected, all other organs (including kidney) contained significantly less radioactivity than the tumour. Since the ED-B domain of fibronectin has an identical sequence in mouse and man, scFv(L19) is a pan-species antibody and the results presented here suggest clinical utility of radiolabelled scFv(L19) for the scintigraphic detection of angiogenesis in vivo. Furthermore, it should now be possible to investigate scFv(L19) for the selective delivery of 211At to the tumour neovasculature, causing the selective death of tumour endothelial cells and tumour collapse.

Animals↗

PubMed1997

Selective targeting of bioactive compounds to mitochondria.

Mitochondrial function can be manipulated selectively by targeting bioactive compounds to mitochondria in living cells. Current targeting mechanisms involve harnessing either the mitochondrial membrane potential or the mitochondrial protein-import machinery to take up molecules linked to lipophilic cations or mitochondrial signal peptides, respectively. Compounds localized like this have been used in studies of mitochondrial metabolism and show potential as anticancer drugs. In addition, because mitochondria play a role in many critical cell processes, mitochondrial targeting has the potential to protect, repair or kill cells selectively, and may become a key tool in the development of gene therapy for mitochondrial DNA diseases.

Antineoplastic Agents↗

PubMed1994

Selective targeting of malignant cells with cytotoxin-folate conjugates.

Previous work has shown that proteins can be nondestructively delivered into the cytoplasm of folate receptor-bearing cells if the proteins are conjugated to folic acid prior to addition to cells. In view of other reports suggesting the membrane receptor for folic acid is vastly overexpressed on tumor cells, we decided to explore whether malignant cells might be selectively targeted in a co-culture with nontransformed cells using ligated folate as the targeting agent. Exploiting the cytotoxicity of the ribosome-inactivating toxin, momordin, to assay successful intracellular protein delivery, we demonstrate that HeLa and KB cells (two malignant human cell lines) can be selectively and quantitatively killed in co-cultures with WI38 and Hs67 cells (two normal human cell types). Not only are the normal cells not damaged by treatment of the co-cultures with momordin-folate, but their rates of proliferation actually accelerate, presumably due to increased availability of nutrients otherwise consumed by the transformed cells. Analysis of folate receptor number before and after momordin-folate treatment indicates that receptor density may be a good predictor of toxin-folate sensitivity. Taken together, the data suggest that conjugates of folic acid with cytotoxic proteins warrant further examination as possible tumor-specific chemotherapeutic agents.

Antimetabolites↗

PubMed2001

Selective targeting to the hyperactive beta-catenin/T-cell factor pathway in colon cancer cells.

Many colon cancers suffer mutations in either the adenomatous polyposis coli or beta-catenin genes that lead to stabilization of beta-catenin and activation of downstream T-cell factor (Tcf) target genes. We have developed a novel approach targeting colon cancer cells based on their aberrant beta-catenin/Tcf signaling pathway. A recombinant adenovirus, in which an apoptosis gene fadd is under the control of the promoter containing Tcf-responsive elements, selectively and efficiently kills colon cancer cells in which the beta-catenin/Tcf pathway is hyperactivated. Our data therefore provide a conceptual proof that aberrantly activated Wnt/beta-catenin/Tcf pathways can be used to selectively target colon cancers.

Apoptosis↗

PubMed2003

Selective targeted delivery of TNFalpha to tumor blood vessels.

We sought to enhance the selective toxicity of tumor necrosis factor alpha (TNFalpha) to permit its systemic use in cancer therapy. Because ligand-targeted therapeutics have proven successful in improving the selective toxicity of drugs, we prepared a fusion protein (L19mTNFalpha) composed of mouse TNFalpha and a high-affinity antibody fragment (L19 scFv) to the extradomain B (ED-B) domain of fibronectin, a marker of angiogenesis. L19mTNFalpha was expressed in mammalian cells, purified, and characterized. L19mTNFalpha was an immunoreactive and biologically active homotrimer. Radiolabeled L19mTNFalpha selectively targeted tumor neovasculature in tumor-bearing mice, where it accumulated selectively and persistently (tumor-to-blood ratio of the percentage of injected dose per gram [%ID/g] of 700, 48 hours from injection). L19mTNFalpha showed a greater anticancer therapeutic activity than both mTNFalpha and TN11mTNFalpha, a control fusion protein in which an antibody fragment, irrelevant in the tumor model used, substituted for L19. This activity was further dramatically enhanced by its combination with melphalan or the recently reported fusion protein L19-IL2. In conclusion, L19mTNFalpha allows concentrating therapeutically active doses of TNFalpha at the tumor level, thus opening new possibilities for the systemic use of TNFalpha in cancer therapy.

Adenocarcinoma↗

PubMed2001

Novel galactosylated liposomes for hepatocyte-selective targeting of lipophilic drugs.

Novel galactosylated neutral liposomes containing cholesten-5-yloxy-N-(4-((1-imino-2-beta-D-thiogalactosylethyl)amino)butyl)formamide (Gal-C4-Chol) as a "homing" device were developed for hepatocyte-selective drug targeting. Distearoylphosphatidylcholine (DSPC)/cholesterol (Chol) (60:40) and DSPC/Chol/Gal-C4-Chol (60:35:5) liposomes were prepared and labeled with [3H]cholesteryl hexadecyl ether (CHE). [3H]Prostaglandin E1 (PGE1) and [14C]probucol were incorporated in liposomes as model lipophilic drugs. After intravenous injection of the liposomes, mice were sacrificed at suitable time periods, and the lung, liver, kidney, spleen, and heart were excised. DSPC/Chol/Gal-C4-Chol liposomes rapidly disappeared from the blood, and 85% of the dose had accumulated in the liver within 10 min compared with hepatic accumulation of DSPC/Chol liposomes of 12%. The liver was perfused with collagenase, and liver parenchymal cells (PC) and liver nonparenchymal cells (NPC) were separated by centrifugal differentiation to determine the cellular distribution. The PC/NPC ratios for DSPC/Chol/Gal-C4-Chol and DSPC/Chol liposomes were 15.1 and 1.1, respectively. The hepatic uptake of DSPC/Chol/Gal-C4-Chol liposomes, but not that of DSPC/Chol liposomes, was significantly inhibited by the predosing of galactosylated bovine serum albumin. [14C]Probucol and [3H]PGE1 incorporated in DSPC/Chol/Gal-C4-Chol liposomes was also efficiently delivered to the liver. In conclusion, newly developed galactosylated liposomes have been proven to be a useful carrier for hepatocyte-selective targeting that will have many practical applications.

Animals↗