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Results for “Pathway informed transformer”

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PubMed2003

Signal dispersal and transduction through the endocytic pathway.

During cell signalling, information that is encoded by ligands travels from one place, the source, to another, the target, where signals are transduced by receptors. Evidence has emerged recently that uncovers a role for the endocytic pathway in the secretion of ligands at the source, their dispersion through developing target tissues and the transduction of the signals from endocytic compartments. As a result, endosomes have become the focus of attention in cell-cell communication studies.

Animals↗

PubMed2001

Odor encoding as an active, dynamical process: experiments, computation, and theory.

We examine early olfactory processing in the vertebrate and insect olfactory systems, using a computational perspective. What transformations occur between the first and second olfactory processing stages? What are the causes and consequences of these transformations? To answer these questions, we focus on the functions of olfactory circuit structure and on the role of time in odor-evoked integrative processes. We argue that early olfactory relays are active and dynamical networks, whose actions change the format of odor-related information in very specific ways, so as to refine stimulus identification. Finally, we introduce a new theoretical framework ("winnerless competition") for the interpretation of these data.

Animals↗

PubMed2001

Pain management. An organizational perspective.

To sustain optimal pain-relieving care for acutely and critically ill patients, organizations must have systems in place to support evidence-based interventions, facilitate expert practice in the area of pain management, and encourage ongoing communication among patients, families, and providers. The key to success may be to create an organizational culture that is supportive of all practitioners to use effectively the many therapeutic options available to manage pain. Although redesigning structures to support pain management care can be done with relative ease, altering the culture of the practice environment and the behavior of care providers may prove more challenging. Cultural changes occur slowly, but as the practice changes do take hold, so do the results. The steps to change an organizational culture around pain management include understanding the existing system and involving key formal and informal leaders. Most experts recommend not attacking the existing culture head-on but living the culture you are trying to create and understanding that the transformation is not going to take place overnight. The use of evidence-based collaborative practice and quality improvement models may be a key to improving the practice environment for pain management. Evidenced-based pain management practice combined with an organizational commitment to optimal pain management for all patients helps to create and sustain the environment to effect the change.

Attitude of Health Personnel↗

PubMed1972

Nuclear DNA sequences present in human leukemic cells and absent in normal leukocytes.

The central purpose of the present study was to test the proposition that the nuclear DNA of every human cell contains whatever information is necessary and sufficient for transformation to malignancy. The experiments were made possible by our earlier identification in human leukemic cells of particulate elements encapsulating 70S RNA and RNA-directed DNA polymerase. The [(3)H]DNA synthesized by these particles was used as a probe, through molecular hybridization, to normal and leukemic DNA. The results obtained establish that leukemic nuclear DNA contains particle-related sequences that cannot be detected in normal leukocytes. This outcome does not support the virogene-oncogene theory, which postulates the inclusion of at least one complete copy of oncogenic information in the genome of every normal cell. The data suggest that we may not be forced to cope with an omnipresent DNA segment coding for malignancy. Under the circumstances, we can perhaps entertain more hopeful pathways leading to the control and cure of cancer.

DNA↗

PubMed1995

Cellular bases for the control of retinogeniculate signal transmission.

The dorsal lateral geniculate nucleus (LGN) is the major thalamic relay for retinal signals en route to cortex. However, LGN cells operate as more than just a simple relay of their retinal inputs. Rather, they function as a variable gate, determining what, when, and how much retinal information gets passed to visual cortex. Two factors that are key to this control are the innervation patterns and electrophysiological membrane properties of geniculate cells. This paper discusses three active membrane properties and the manner in which they modulate the transfer of retinal signals to cortex. They are the low threshold calcium (Ca2+) conductance, a transient potassium (K+) conductance, and NMDA receptor-mediated excitatory postsynaptic potentials (EPSPs). The low-threshold Ca2+ conductance transforms a geniculate cell from a state of single spike activity to one of bursting discharge, the potassium current leads to a delay in membrane depolarization to reach spike threshold, and NMDA receptor activity modulates EPSP amplitude and duration near spike threshold. Additionally, we consider how nonretinal inputs, such as the ascending cholinergic pathway from the brainstem parabrachial region and the descending pathway from layer VI of visual cortex, influence the expression of these membrane properties through their control of membrane potential.

Acetylcholine↗

PubMed2003

Molecular control of the cell cycle in cancer: biological and clinical aspects.

The RB1 pathway and the p53 pathway represent important, interconnected biochemical units frequently perturbed in human cancer. Essential tumor protective mechanisms, such as cellular growth control and apoptosis, are regulated through these systems. Comprehensive studies of these pathways, including most known pathway components, have not been performed in NHL. We therefore analyzed the involvement of aberrations of these pathways in NHLs from the population-based West-Danish NHL registry, LYFO registry, as well as in a series of neurofibromatosis 1-related tumors. The aim of the studies was to obtain information about extent and interrelation of alterations of pathway components, as well as clinical information such alterations might provide. We found that alteration of components of one or both of these pathways are very common, occurring in the vast majority of DLCLs. Our data suggest that the pathways are not entirely linear in lymphomagenesis. The p53 pathway components MDM2 and p53 were frequently altered in the same lymphoma indicating that the role of MDM2 in lymphomagenesis is not entirely dependent on the downstream target, p53. The linearity of the RB1 pathway was clearer as only 1 of 34 DLCLs showed aberration of more than one of the components cyclin D3, p16INK4A, and pRB. An intriguing novel observation was that p16INK4A inactivation was associated with increased expression of cdk4, a kinase target of p16INK4A inhibitory function. This could indicate the existence of a regulatory feedback loop between p16INK4A and cdk4. Cyclin D3 has yet to be established as an oncoprotein. Our finding of cyclin D3 overexpression in a significant number of DLCLs (including all thyroid lymphomas analyzed), as well as the intimate inverse relation to other RB1 pathway alterations suggest, that cyclin D3 is important in lymphomagenesis. However, further studies are needed to implicate cyclin D3 definitively as an oncoprotein. Our data contain several lines of evidence supporting roles of CDKN2A and MDM2 in progression of neoplastic disease. We found that loss of p16INK4A coincided with transformation of neurofibromas to malignant peripheral nerve sheath tumors in neurofibromatosis 1 patients. Furthermore, one DLCL lost CDKN2A from diagnosis to relapse. MDM2 overexpression was more frequent in aggressive than in indolent lymphomas, and in follicle center lymphomas none of our follicle center grade I/II lymphomas overexpressed MDM2. In contrast, MDM2 was overexpressed in 60% of grade III/diffuse follicle center lymphomas. Clinical correlations revealed novel and interesting findings. Both p53 disruption and low expression of E2F-1 correlated with poor response of aggressive lymphomas to treatment. Chemotherapeutic regimens used in lymphoma treatment are based on apoptosis induction, and as both E2F-1 and p53 are regulators of apoptosis, it is possible that the observed treatment failure is associated with reduced E2F-1- and p53-mediated apoptosis. Survival analyses revealed numerous novel and potentially important findings. Several of the studied cell cycle regulators carried independent prognostic value in various subsets of lymphomas. In DLCL, both p16INK4A inactivation and reduced E2F-1 expression conferred shortened survival. p53 alteration was associated with poor prognosis of both B-cell and, especially, T-cell lymphoma. Low expression of p27, a cell cycle regulator haplo-insufficient for tumor suppression, predicted poor outcome in indolent and aggressive lymphoma, and overexpression of cyclin D3 was associated with poor prognosis in indolent lymphomas. Finally, MDM2 overexpression identified among patients with follicle center lymphomas, extranodal marginal zone lymphomas, and mantle cell lymphomas cases with poor prognosis. While these results must necessarily be confirmed on larger prospective series of patients, the data nonetheless suggest that valuable prognostic information can be provided by studies of these cell cycle regulators.

Cell Cycle Proteins↗

PubMed1999

Cortical columnar processing in the rat whisker-to-barrel system.

Controlled whisker stimulation and single-unit recordings were used to elucidate response transformations that occur during the processing of tactile information from ventral posterior medial thalamus (VPM) through cortical columns in the rat whisker/barrel cortex. Whiskers were either deflected alone, using punctate ramp-and-hold stimuli, or in combination with a random noise vibration applied simultaneously to two or more neighboring whiskers. Quantitative data were obtained from five anatomically defined groups of neurons based on their being located in: VPM, layer IV barrels, layer IV septa, supragranular laminae, and infragranular laminae. Neurons in each of these populations displayed characteristic properties related to their response latency and time course, relative magnitudes of responses evoked by stimulus onset versus offset, strength of excitatory responses evoked by the noise stimulus, and/or the degree to which the noise stimulus, when applied to neighboring whiskers, suppressed or facilitated responses evoked by the columnar whisker. Results indicate that within layer IV itself there are at least two anatomically distinct networks, barrel and septum, that independently process afferent information, transforming thalamic input in similar but quantitatively distinguishable ways. Transformed signals are passed on to circuits in supragranular and infragranular laminae. In the case of supragranular neurons, evidence suggests that circuits there function in a qualitatively different fashion from those in layer IV, diminishing response differentials between weak and strong inputs, rather than enhancing them. Compared to layer IV, the greater heterogeneity of receptive field properties in nongranular layers suggests the existence of multiple, operationally distinct local circuits in the output layers of the cortical column.

Animals↗

PubMed1986

The control of retinogeniculate transmission in the mammalian lateral geniculate nucleus.

In the mammalian visual system, the lateral geniculate nucleus is commonly thought to act merely as a relay for the transmission of visual information from the retina to the visual cortex, a relay without significant elaboration in receptive field properties or signal strength. However, many morphological and electrophysiological observations are at odds with this view. Only 10-20% of the synapses found on geniculate relay neurons are retinal in origin. Roughly half of all synapses derive from cells in layer VI of visual cortex; roughly one third are inhibitory and GABAergic, derived either from interneurons or from cells of the nearby perigeniculate nucleus. Most of the remaining synapses probably derive from cholinergic, noradrenergic, and serotonergic sites within the brainstem reticular formation. Moreover, recent biophysical studies have revealed several ionic currents present in virtually all thalamic neurons. One is a Ca2+-dependent K+ current underlying the afterhyperpolarization (or the IAHP), which may last up to 100-200 ms following an action potential. Activation of the IAHP leads to spike frequency adaptation in response to a sustained, suprathreshold input. Intracellular recordings from other neuronal preparations have shown that the IAHP can be blocked by noradrenaline or acetylcholine, leading to an increased cellular excitability. Another ionic current results from a voltage- and time-dependent Ca2+ conductance that produces a low threshold spike. Activation of this conductance transforms a geniculate neuron from a state of faithful relay of information to one of bursting behavior that bears little relationship to the activity of its retinal afferents. We propose that state-dependent gating of geniculate relay cells, which may represent part of the neuronal substrate involved in certain forms of selective visual attention, can be effected through at least three different mechanisms: conventional GABAergic inhibition, which is largely controlled via brainstem and cortical afferents through interneurons and perigeniculate cells; the IAHP, which is controlled via noradrenergic and cholinergic afferents from the brainstem reticular formation; and the low threshold spike, which may be controlled by GABAergic inputs, cholinergic inputs, and/or the corticogeniculate input, although other possibilities also exist. Furthermore, it seems likely that gating functions involving the corticogeniculate pathway are suited to attentional processes within the visual domain (e.g., saccadic suppression), whereas brainstem inputs seem more likely to have more global effects that switch attention between sensory systems.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed2006

Genetic localization and heterologous expression of validamycin biosynthetic gene cluster isolated from Streptomyces hygroscopicus var. limoneus KCCM 11405 (IFO 12704).

The validamycin biosynthetic gene cluster was isolated from Streptomyces hygroscopicus var. limoneus KTCC 1715 (IFO 12704) using a pair of degenerated PCR primers designed from the sequence of AcbC, 2-epi-5-epi-valiolone synthase in the acarbose biosynthesis. The nucleotide sequence analysis of the 37-kb DNA region revealed 22 complete ORFs including vldA, the acbC ortholog. Located around vldA, vldB to K were predicted to encode adenyltransferase, kinase, ketoreductase (or epimerase/dehydratase), glycosyltransferase, aminotransferase, dehydrogenase, phosphatase/phosphomutase, glycosyl hydrolase, transport protein, and glycosyltransferase, respectively. Apparently absent were any regulatory components within the sequenced region. The disruption of vldA abolished the validamycin biosynthesis and the plasmid-based complementation with vldABC restored production to the vldA-mutant; this substantiated that vldABC are essential to validamycin biosynthesis. This finding enabled us to discover the complete validamycin biosynthetic cluster. The cosmid clone of pJWS3001 harboring the 37-kb DNA region conferred validamycin-accumulation to Streptomyces lividans, indicating that the entire gene cluster of validamycin biosynthesis had been isolated. Additionally, Streptomyces albus, transformed with pJWS3001, produced a high level of alpha-glucosidase inhibitory activity in a R2YE liquid culture, which highlights the portability of the cluster within Streptomyces. The product of vldI was characterized as a glucoamylase (kcat, 32 s(-1); K(m), 5 mg/ml of starch) that does not play any apparent role in the validamycin biosynthesis. In order to characterize the upstream region, a vldW knockout was achieved via gene-replacement. A phenotypic study of the resulting mutant revealed that vldW is not essential for the host's ability to control Pellicularia filamentosa growth. The current information suggests that vldA to vldH is the genetic region essential to validamycin biosynthesis. This promises excellent opportunities to elucidate biosynthetic route(s) to the validamycin complex and to engineer the pathway for industrial application.

Bacterial Proteins↗

PubMed2004

Axial patterning of C. elegans male sensilla identities by selector genes.

The fan and rays of the C. elegans male tail constitute a compound sensory organ essential for mating. Within this organ, the individual sensilla, known as rays, have unique identities. We show that ray identities are patterned by a selector gene mechanism in a manner similar to other serially homologous axial structures. One selector gene that promotes the identities of a subset of the rays is the Hox gene egl-5. Within EGL-5-expressing rays, further patterning is provided by a Pax-6 homolog and a signal of the TGFbeta family. These genes and pathway coordinately specify multiple ray properties affecting all three terminal ray cell types. These properties include complex patterns of FMRFamide-like (FaRP) neuropeptides, serotonin (5HT) and dopamine expression, and ray morphology. Differences in these differentiated characteristics give each sensillum a unique identity and potentially endow the compound ray organ with a higher-order information gathering capacity.

Animals↗

PubMed2003

New directions in testicular cancer; molecular determinants of oncogenesis and treatment success.

Metastatic testicular cancer is highly curable with conventional cytotoxic drugs. This is in contrast to most other metastatic solid tumours which can only be palliated with chemotherapy achieving only a modest impact on overall survival. If we could understand at the molecular level why chemotherapy is so effective in the treatment of testicular cancer, we may be better able to move other forms of metastatic cancer into the curable bracket. Most cytotoxic drugs appear to induce cell death by activating intracellular apoptotic mechanisms. Thus, the ability of a cancer to activate and execute such mechanisms in response to treatment is paramount in determining the effectiveness of chemotherapy. The basic study of cancer molecular biology is providing some insight into the proteins involved in this process and the ability to apply this information to actual human tumours is essential to rationalise clinical treatment failures at a molecular level. Testicular cancer provides an excellent model system in this analysis. Whereas there are large numbers of patients that are cured by chemotherapy, there are some whose cancers become resistant to treatment. An understanding of testicular cancer molecular biology may allow the identification of the genes regulating such a crucial behavioural switch. It may then be possible to manipulate specific signalling pathways to overcome drug resistance. This review focuses on recent developments in our understanding of the molecular biology of testicular cancer. A number of key players have been implicated including p53, pRb, cyclin D2, p INK proteins, c-kit and the bcl-2 family of proteins. The exact manner by which cellular transformation occurs has still not been established, but it is clear that many of the above proteins also have important roles in normal spermatogenesis. This is a developmental phase when the generation of genetic diversity is at a premium, but when selective apoptotic mechanisms are paramount. We discuss why this may be relevant to the behaviour of germ cell tumours and address possible reasons why they can become resistant to conventional therapy.

Antineoplastic Agents↗

PubMed2006

Fate of chemical warfare agents and toxic industrial chemicals in landfills.

One component of preparedness for a chemical attack is planning for the disposal of contaminated debris. To assess the feasibility of contaminated debris disposal in municipal solid waste (MSW) landfills, the fate of selected chemical warfare agents (CWAs) and toxic industrial chemicals (TICs) in MSW landfills was predicted with a mathematical model. Five blister agents [sulfur mustard (HD), nitrogen mustard (HN-2), lewisite (L), ethyldichloroarsine (ED), and phosgene oxime (CX)], eight nerve agents [tabun (GA), sarin (GB), soman (GD), GE, GF, VX, VG, and VM], one riot-control agent [CS], and two TICs [furan and carbon disulfide] were studied. The effects of both infiltration (climate) and contaminant biodegradability on fate predictions were assessed. Model results showed that hydrolysis and gas-phase advection were the principal fate pathways for CWAs and TICs, respectively. Apart from CX and the TICs, none of the investigated compounds was predicted to persist in a landfill for more than 5 years. Climate had little impact on CWA/TIC fate, and biodegradability was only important for compounds with long hydrolysis half-lives. Monte Carlo simulations were performed to assess the influence of uncertainty in model input parameters on CWA/TIC fate predictions. Correlation analyses showed that uncertainty in hydrolysis rate constants was the primary contributor to variance of CWA fate predictions, while uncertainty in the Henry's Law constant and landfill gas-production rate accounted for most of the variance of TIC fate predictions. CWA hydrolysates were more persistent than the parent CWAs, but limited information is available on abiotic or biotic transformation rates for these chemicals.

Biodegradation, Environmental↗

PubMed1994

Phylogenetic inference under the pure drift model.

When pairwise genetic distances are used for phylogenetic reconstruction, it is usually assumed that the genetic distance between two taxa contains information about the time after the two taxa diverged. As a result, upon an appropriate transformation if necessary, the distance usually can be fitted to a linear model such that it is expressed as the sum of lengths of all branches that connect the two taxa in a given phylogeny. This kind of distance is referred to as "additive distance." For a phylogenetic tree exclusively driven by random genetic drift, genetic distances related to coancestry coefficients (theta XY) between any two taxa are more suitable. However, these distances are fundamentally different from the additive distance in that coancestry does not contain any information about the time after two taxa split from a common ancestral population; instead, it reflects the time before the two taxa diverged. In other words, the magnitude of theta XY provides information about how long the two taxa share the same evolutionary pathways. The fundamental difference between the two kinds of distances has led to a different algorithm of evaluating phylogenetic trees when theta XY and related distance measures are used. Here we present the new algorithm using the ordinary-least-squares approach but fitting to a different linear model. This treatment allows genetic variation within a taxon to be included in the model. Monte Carlo simulation for a rooted phylogeny of four taxa has verified the efficacy and consistency of the new method. Application of the method to human population was demonstrated.

Animals↗

PubMed1999

Overexpression of a dominant-negative allele of SEC4 inhibits growth and protein secretion in Candida albicans.

Candida albicans SEC4 was cloned by complementing the Saccharomyces cerevisiae sec4-8 mutation, and its deduced protein product (Sec4p) was 63% identical to S. cerevisiae Sec4p. One chromosomal SEC4 allele in C. albicans CAI4 was readily disrupted by homologous gene targeting, but efforts to disrupt the second allele yielded no viable null mutants. Although this suggested that C. albicans SEC4 was essential, it provided no information about this gene's functions. Therefore, we constructed a mutant sec4 allele encoding an amino acid substitution (Ser-28-->Asn) analogous to the Ser-17-->Asn substitution in a trans-dominant inhibitor of mammalian Ras protein. GAL1-regulated expression plasmids carrying the mutant sec4 allele (pS28N) had minimal effects in glucose-incubated C. albicans transformants, but six of nine transformants tested grew very slowly in galactose. Incubation of pS28N transformants in galactose also inhibited secretion of aspartyl protease (Sap) and caused 90-nm secretory vesicles to accumulate intracellularly, and plasmid curing restored growth and Sap secretion to wild-type levels. These results imply that C. albicans SEC4 is required for growth and protein secretion and that it functions at a later step in the protein secretion pathway than formation of post-Golgi secretory vesicles. They also demonstrate the feasibility of using inducible dominant-negative alleles to define the functions of essential genes in C. albicans.

Alleles↗

PubMed2026

(Re)imagining the Future of Genetic Counseling: A Reflexive Qualitative Analysis of Sociopolitical Power, Cultural Safety, Systemic Racism, and Comparative Practice in the United Kingdom, Aotearoa New Zealand and, Australia.

Genetic counseling is undergoing a rapid transformation as genomic medicine becomes embedded within mainstream healthcare systems. At the same time, the profession is being challenged to respond to systemic racism, colonial legacies, technological change, and evolving expectations regarding equity and justice. Historically, genetic counseling emerged within twentieth-century medical genetics and was influenced by political, social, scientific, and medical forces that included eugenic ideology, values, and practices. The profession has since evolved substantially toward psychosocial, patient-centered, and non-directive models of care. Contemporary debates regarding "newgenics" or "neugenics" further demonstrate how concerns regarding equity, reproductive ethics, disability, and genomic stratification continue to shape genomic healthcare discourse. This qualitative reflexive practice paper explores how systemic racism, colonial legacy, cultural safety and structural power shape genetic counseling practice in the United Kingdom (UK), Aotearoa New Zealand and Australia, and how these forces continue to reshape the profession's future identity. A reflexive, narrative, and comparative qualitative approach was employed, grounded in the authors' lived professional experiences across UK and Australasian contexts and informed by purposively selected policy, professional and scholarly literature relating to cultural safety, dignity, anti-racism, and Human Rights-Based Decision-Making. Through iterative reflexive dialogue, comparative analysis, and thematic synthesis, four interrelated themes were developed examining sociopolitical context, systemic racism, cultural safety and technologization within contemporary genetic counseling practice. Comparative analysis identified substantial differences in how culturally responsive practice is conceptualized and operationalized across settings. In Aotearoa, cultural safety is strongly shaped by Te Tiriti o Waitangi, bicultural accountability, and Māori sovereignty frameworks. In Australia, culturally safer genomic care has increasingly developed through Indigenous-led initiatives and workforce reform, including the Australian Alliance for Indigenous Genomics (ALIGN). In contrast, UK practice remains largely situated within equality, diversity, and inclusion (EDI) frameworks that may insufficiently address systemic racism and structural power within increasingly diverse populations. Reflexive clinical examples demonstrated how inequities may emerge through undocumented patient values, standardized pathways, assumptions regarding autonomy, and misinterpretation of culturally specific communication styles. Re-imagining the future of genetic counseling requires more than just technological advancement. It requires reflexive engagement with dignity, inequity, and the sociopolitical realities of the populations served. These insights re-imagine a culturally grounded, socially responsive future for genetic counseling in an era shaped by genomic mainstreaming, digital transformation, artificial intelligence and workforce reform and one in which the profession remains ethically anchored, relationally attuned, and committed to justice-oriented practice.

Humans↗

PubMed1999

Extracellular modulation of the Hedgehog, Wnt and TGF-beta signalling pathways during embryonic development.

Localized embryonic expression of members of the Hedgehog, Wnt and TGF-beta families of secreted factors has been shown to organize pattern and provide positional information in many developing systems. Recently, several extracellular factors have been described that act either as facilitators or inhibitors of the activities of those secreted proteins. The variety of molecular strategies involved in the extracellular modulation of signalling activities in the embryo underscores the importance of maintaining a tight spatial and temporal control of the activities of organizing centers during development.

Animals↗

PubMed1997

Biosynthesis of vitamin B12: the multi-enzyme synthesis of precorrin-4 and factor IV.

BACKGROUND: In order to study the biosynthesis of vitamin B12, it is necessary to produce various intermediates along the biosynthetic pathway by enzymic methods. Recently, information on the organisation of the biosynthetic pathway has permitted the selection of the set of enzymes needed to biosynthesise any specific identified intermediate. The aim of the present work was to use recombinant enzymes in reconstituted multi-enzyme systems to biosynthesise particular intermediates. RESULTS: The products of the cobG and cobJ genes from Pseudomonas denitrificans were expressed heterologously in Escherichia coli to afford good levels of activity of the corresponding enzymes, CobG and CobJ. Aerobic incubation of precorrin-3A with the CobG enzyme alone yielded precorrin-3B. When CobJ and S-adenosyl-L-methionine were included in the incubation, the product was precorrin-4. Both precorrin 3B and precorrin-4 are known precursors of vitamin B12 and their availability has allowed new mechanistic studies of enzymic transformations. CONCLUSIONS: Our results show that the expression of the CobG and CobJ enzymes has been successful, thus facilitating the biosynthesis of two precursors of vitamin B12. This lays the foundation for the structure determination of CobG and CobJ as well as future enzymic experiments focusing on later steps of vitamin B12 biosynthesis.

Bacterial Proteins↗

PubMed1994

Report of a meeting: molecular basis of cancer therapy.

There has been an explosive increase in information relevant to the pathways that determine growth signal transduction, regulation of the cell cycle, mechanism of action of oncogenes and tumor suppressors, and mechanisms of programmed cell death (apoptosis). Additional information is needed to determine the targets for anticancer therapy that are most likely to lead to cancer cell death and/or growth cessation. Current experimental clinical approaches are directed toward killing cells with unique cancer-related phenotypes, such as cell surface antigens or growth factor receptors, or altering the host immune system to attack cancer cells. The following major therapeutic targets were identified during the course of this conference: 1) Reduce activity of gene products associated with stimulation of cell growth and increase activity of gene products that inhibit growth. The major principle here is that genes known to be sufficient for malignant transformation (such as Ras, Raf, and Bcr-Abl) and genes whose expression is necessary, but not sufficient, for malignant transformation (such as some cyclins) both may be important targets for anticancer drugs. The reason genes necessary but not sufficient for cell growth are targets is that progression through the cell cycle is based on a series of "on-off" switches whose activation depends on critical levels of specific kinases and phosphatases. Subtle differences in concentration or activity of these regulators, as may be found in cancer cells, could profoundly influence the position of the switch. There are many ways to affect activity of gene products, including use of anti-sense or ribozyme targeting of mRNAs; manipulation of regulatory controls (i.e., state of phosphorylation of Raf and p53; effect of SOS and GAP on Ras, etc.); alteration of essential covalent modifications (i.e., farnesylation of Ras which is essential for its association with the plasma membrane); and various forms of gene therapy to introduce genes (i.e., addition of wild-type p53) or to reduce activity of genes essential for growth (i.e., dominant negative receptor mutants). 2) Interfere with protein-protein or DNA-protein interactions that are needed for the activity of oncogenes and/or growth factors or the transcription factors essential for cell growth. This approach has been demonstrated to work in vitro to interfere with SH2-tyrosine phosphate interactions (i.e., Grb-2 and EGF receptor) and Ras-Raf interactions using specific peptides (J. Downward), but to be useful therapeutically it must be possible to introduce stable low-molecular-weight drugs into cells to affect these interactions.(ABSTRACT TRUNCATED AT 400 WORDS)

Antigens, Neoplasm↗