Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Critical Pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 541 records · Page 30Linked to original sources
PubMed2006

The Akt inhibitor KP372-1 inhibits proliferation and induces apoptosis and anoikis in squamous cell carcinoma of the head and neck.

Therapies that target signaling pathways critical to the pathogenesis and progression of squamous cell carcinoma of the head and neck (HNSCC) are needed. One such target, phosphatidylinositol 3-kinase, and its downstream target serine/threonine kinase, Akt, are up-regulated in HNSCC. Targeted therapy could consist of inhibitors of these kinases or, alternatively, of inhibitors of the pathways that they regulate. To explore the effect of Akt inhibition on the growth and survival of HNSCC tumors, we evaluated the effect of a novel Akt inhibitor, KP372-1, on the growth, survival, and sensitivity to anoikis of HNSCC cell lines in culture. Using Western blotting of head and neck cancer cell lines and squamous mucosa and carcinoma specimens, we found that Akt was highly phosphorylated in head and neck cancer cell lines and human head and neck squamous carcinoma specimens. Treatment of HNSCC cell lines with KP372-1 blocked the activation of Akt, inhibited head and neck cancer cell proliferation, and induced apoptosis and anoikis in several HNSCC cell lines. Furthermore, KP372-1 decreased the phosphorylation of the S6 ribosomal (Ser240/244) protein, which is a downstream target of Akt. Taken together, these findings indicate that KP372-1 may be a useful therapeutic agent for HNSCC and should be further evaluated in preclinical models of HNSCC.

Apoptosis↗
PubMed2001

Monosomy for the most telomeric, gene-rich region of the short arm of human chromosome 16 causes minimal phenotypic effects.

We have examined the phenotypic effects of 21 independent deletions from the fully sequenced and annotated 356 kb telomeric region of the short arm of chromosome 16 (16p13.3). Fifteen genes contained within this region have been highly conserved throughout evolution and encode proteins involved in important housekeeping functions, synthesis of haemoglobin, signalling pathways and critical developmental pathways. Although a priori many of these genes would be considered candidates for critical haploinsufficient genes, none of the deletions within the 356 kb interval cause any discernible phenotype other than alpha thalassaemia whether inherited via the maternal or paternal line. These findings contrast with previous observations on patients with larger (> 1 Mb) deletions from the 16p telomere and therefore address the mechanisms by which monosomy gives rise to human genetic disease.

Adolescent↗
PubMed2003

Ku80- and DNA ligase IV-deficient plants are sensitive to ionizing radiation and defective in T-DNA integration.

Double-strand break (DSB) repair pathways catalyze the rejoining of broken chromosomes and the integration of transforming DNAs. These processes have been well characterized in bacteria, fungi, and animals. Plants are generally thought primarily to utilize a non-homologous end joining (NHEJ) pathway to repair DSBs and integrate transgenes, as transforming DNAs with large tracts of homology to the chromosome are integrated at random. In order to test the hypothesis that NHEJ is an important pathway for the repair of DSBs in plants, we isolated T-DNA insertion mutations in the Arabidopsis homologs of the Ku80 and DNA ligase IV genes, required for the initiation and completion, respectively, of NHEJ. Both mutants were hypersensitive to the cytostatic effects of gamma radiation, suggesting that NHEJ is indeed a critical pathway for the repair of DSBs. T-DNA insertion rates were also decreased in the mutants, indicating that Ku80 and DNA ligase IV play an important role in either the mechanism or the regulation of T-DNA integration in Arabidopsis.

Alleles↗
PubMed1996

Homocysteine and neural tube defects.

It is now well established that folic acid, when taken periconceptionally, can prevent many neural tube defects. It is also becoming clear that folic acid does not work by correcting a nutritional deficiency in pregnant women. Rather, it appears that a metabolic defect is responsible for these neural tube defects and that this defect or defects can be corrected by a sufficiently large dose of folic acid. Our recent work demonstrates that homocysteine metabolism is likely to be the critical pathway affected by folic acid. We have demonstrated significantly higher homocysteine levels in women carrying affected fetuses than in control women. These findings indicate that one of the enzymes responsible for homocysteine metabolism is likely to be abnormal in affected pregnancies. Animal studies suggest that the conversion of homocysteine to methionine could be the critical step. Rat embryos in culture require methionine for neural tube closure. Methionine synthase, cystathionine synthase, and 5,10 methylene tetrahydrofolate reductase are all important in the metabolism of homocysteine in humans. If methionine synthase is the critical enzyme, it would raise the interesting public health issue that vitamin B-12 might be able to stimulate the abnormal enzyme as folic acid does. Adding vitamin B-12 might make it possible to reduce the dose of folic acid required in fortified food, thus allaying concerns about overexposure to folic acid.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1989

Projections of the nucleus of the optic tract to the nucleus reticularis tegmenti pontis and prepositus hypoglossi nucleus in the pigmented rat as demonstrated by anterograde and retrograde transport methods.

The visual pathways from the nucleus of the optic tract (NOT) to the nucleus reticularis tegmenti pontis (NRTP) and prepositus hypoglossi nucleus (ph) were studied following injections of tritiated leucine into the NOT of pigmented rats. The cell bodies of origin of the pretectal-NRTP, NRTP-ph, and pretectal-ph projections were determined using retrograde horseradish peroxidase (HRP) technique. The pretectum projects strongly to the rostral two-thirds of the central and pericentral subdivisions of the NRTP and sends a remarkably smaller projection to the ph. Both are entirely ipsilateral. The fibers destined for the ph travel with the NOT-NRTP bundle, pass through the NRTP, traverse the medial longitudinal fasciculus, and are distributed to the rostral one-half of the ph. The retrograde HRP studies confirm these pathways. The pretectal projections to the NRTP arise from neurons in the rostromedial NOT; those to the ph are located primarily in the rostral NOT although small numbers are found within the anterior, posterior, and olivary pretectal nuclei. Of major importance is the fact that the ph injections retrogradely label neurons within the NRTP and the adjacent paramedian pontine reticular formation. This NRTP-ph projection is entirely bilateral and arises from parts of both subdivisions of the nucleus targeted by NOT afferents. Both the direct NOT-ph and indirect NOT-NRTP-ph connections provide the anatomical basis for the relay of visual (optokinetic) information to the perihypoglossal complex and, presumably, by virtue of reciprocal ph-vestibular nuclear connections, to the vestibular nuclei itself. Such pathways confirm previous physiological studies in rat and, in particular, clarify the contrasting effects of electrolytic lesions of NRTP in rat which completely abolishes optokinetic nystagmus (OKN) (Cazin et al., 1980a) vs kainic acid lesions which produce only minor effects on OKN slow velocity (Hess et al., 1988). Given these differential effects, one concludes that the critical pathway for OKN passes in relation to, but is not significantly relayed by, the neurons of the NRTP or adjacent pontine tegmentum. The present studies suggest that one such fiber system is the NOT-ph bundle. How this relatively small projection compares to other possible fiber of passage systems remains to be determined electrophysiologically.

Animals↗
PubMed2001

The challenge of pathway and environment-mediated drug resistance.

New insights into cancer biology have allowed the definition of pathways critical to the success of the cancer cell. These include enhanced activity of positive regulators of cell proliferation, including oncogenes, and loss of tumor suppressor gene function; inactivation of cell death or enhancement of srvival functions; activation of telomerase, and enhanced ability of tumor cells to invade and reorganize host stroma. It follows then that these pathways may also mediate drug resistance, in a way that is fundamentally different from classically defined mechanisms for drug resistance which focus on altered handling of the drug or the drug's target by the resistant tumor cell. It is expected that resistance will occur that is predicated on altered pathway predominance in a tumor and altered tumor microenvironment. Cases which exemplify this possibility are presented, including up-regulation of angiogenesis-related regulators in relation to inhibition of EGF-related proliferative and angiogenesis-promoting functions. The implications of this thinking in relation to development of combination regimens targeting distinct pathways are considered.

Antineoplastic Agents↗
PubMed2008

Maternal control of pattern formation in Xenopus laevis.

We review the essential role of maternal factors in pattern formation for Xenopus laevis, focusing on VegT, Vg1, and Wnt11. Results from loss of function experiments demonstrate a clear requirement for these genes in germ layer specification, dorsal-ventral axis formation, and convergence extension. We also discuss these genes in the broader context of metazoan development, exploring whether and how their functions in the X. laevis model organism may or may not be conserved in other species. Wnt11 signaling in particular provides a classic example where understanding context in development is crucial to understanding function. Genomic sequencing, gene expression, and functional screening data that are becoming available in more species are providing invaluable aid to decoding and modeling signaling pathways. More work is needed to develop a comprehensive catalog of the Wnt signaling, T-box, and TGF-beta genes in metazoans both near and far in evolutionary distance. We finally discuss some specific experimental and modeling efforts that will be needed to understand the behavior of these signaling networks in vivo so that we can interpret these critical pathways in an evolutionary framework.

Animals↗
PubMed2006

Immunohistochemical investigation of tumorigenic pathways in small intestinal adenocarcinoma: a comparison with colorectal adenocarcinoma.

Small intestinal adenocarcinoma is an uncommon neoplasm morphologically similar to or indistinguishable from colorectal adenocarcinoma. Although much has been learned about genetic pathways critical to colorectal tumorigenesis, little is known about molecular alterations involved in the development of small intestinal adenocarcinoma. In this study, we immunohistochemically compared non-ampullary small intestinal adenocarcinomas with sporadic colorectal adenocarcinomas for the expression of several proteins known to serve pivotal roles in colorectal tumorigenesis. These included adenomatous polyposis coli and beta-catenin involved in the Wnt signaling pathway, and DNA mismatch repair enzymes hMLH1, hMSH2 and hMSH6 involved in the microsatellite instability pathway. The expression of two important tumor suppressors, p53 and RB, was also examined. The results show that complete loss of adenomatous polyposis coli immunoreactivity, presumably resulting from its gene mutations, was observed in eight of 26 (31%) small intestinal adenocarcinomas and 36 of 51 (71%) colorectal adenocarcinomas (P = 0.0008). Nuclear localization of beta-catenin, an indirect evidence of deregulated Wnt signaling pathway, was observed in 5 (19%) small intestinal adenocarcinomas and 36 (71%) colorectal adenocarcinomas (P<0.0001). Total lack of nuclear staining for one or more of the DNA mismatch repair enzymes occurred in a similar low frequency in both small intestinal and colorectal adenocarcinomas, seen in two of 25 (8%) and 10 of 47 (21%) cases, respectively (P = 0.1958). The frequencies of aberrant p53 and RB expression were also similar between small intestinal and colorectal adenocarcinomas. These observations indicate that defects in the Wnt and microsatellite instability pathways occur in over 90% of colorectal adenocarcinomas, but in only 40% of small intestinal adenocarcinomas. Small intestinal tumorigenesis appears to follow a distinct, yet unidentified, molecular pathway(s) from its colorectal counterpart despite their morphologic similarity.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Hematopoietic precursor cells transiently reestablish permissiveness for X inactivation.

Xist is the trigger for X inactivation in female mammals. The long noncoding Xist RNA localizes along one of the two female X chromosomes and initiates chromosome-wide silencing in the early embryo. In differentiated cells, Xist becomes dispensable for the maintenance of the inactive X, and its function for initiation of silencing is lost. How Xist mediates gene repression remains an open question. Here, we use an inducible Xist allele in adult mice to identify cells in which Xist can cause chromosome-wide silencing. We show that Xist has the ability to initiate silencing in immature hematopoietic precursor cells. In contrast, hematopoietic stem cells and mature blood cells are unable to initiate ectopic X inactivation. This indicates that pathways critical for silencing are transiently activated in hematopoietic differentiation. Xist-responsive cell types in normal female mice show a change of chromatin marks on the inactive X. However, dosage compensation is maintained throughout hematopoiesis. Therefore, Xist can initiate silencing in precursors with concomitant maintenance of dosage compensation. This suggests that Xist function is restricted in development by the limited activity of epigenetic pathways rather than by a change in the responsiveness of chromatin between embryonic and differentiated cell types.

Alleles↗
PubMed2006

From genes to systems: new global strategies for the characterization of NCL biology.

Neuronal ceroid lipofuscinoses (NCL) are rare neurological disorders with a uniform phenotype, caused by mutations in seven known genes. NCL provide a unique model to characterize molecular pathways critical for normal neuronal development and pathological neuronal degeneration. Systems biology based approach utilizes the rapidly developing tools of genomics, proteomics, lipidomics and metabolomics and aims at thorough understanding of the functions of cells, tissues and whole organisms by molecular analysis and biocomputing-assisted modeling. The systems level understanding of NCL is now possible by utilizing different model organisms. Initial work has revealed disturbed metabolic pathways in several NCL disorders and most analyses have utilized the infantile (INCL/CLN1) and juvenile (JNCL/CLN3) disease modeling and utilized mainly human and mouse samples. To date, the data obtained from transcript and lipidomic profiling has pinpointed the role of lipid metabolism and synaptic function in the infantile NCL. Changes in glutamate utilization and amino acid metabolism have been a common theme emerging from the transcript and metabolite profiling of the juvenile NCL. Further experimental models are being developed and systematic sample collection as well as data integration projects are needed. The combined analyses of the global information should provide means to expose all the NCL-associated molecular pathways.

Animals↗
PubMed2001

'Seeing' in the blind hemifield following hemispherectomy.

Destruction of the striate cortex has traditionally been thought to lead to permanent blindness in the contralateral visual field and to the dogma that this region is indispensable for vision in primates. For over 25 years now, evidence has been accumulating that hemianopic human subjects and monkeys possess wide-ranging residual visual capacities or 'blindsight' in the blind part of their visual field. For some researchers, isolated islands of the striate cortex have been associated with patches of degraded vision and made responsible for blindisight. Artefacts such as light scatter, criterion effects, macular sparing, eccentric fixation and minute eye movements have also been linked with the residual vision. For others, the fact that certain aspects of the visual information can be processed without the geniculostriate pathway suggests mediation by the visual subsystems such as extrastriate visual cortical areas which receive visual information via subcortical pathways, that escaped the cortical damage. Subjects who have had a whole cerebral hemisphere removed or disconnected (for the treatment of uncontrollable epilepsy) and who show residual vision in their blind field offer a remarkable opportunity to help clear the controversy regarding the neural substrate of blindsight. Because it is certain that no functional striate or extrastriate cortex remains on the ablated side, these subjects have contributed significantly to identifying the critical pathways involved in blindsight.

Awareness↗
PubMed2005

GLUTAMINE PREVENTS ACTIVATION OF NF-kappaB AND STRESS KINASE PATHWAYS, ATTENUATES INFLAMMATORY CYTOKINE RELEASE, AND PREVENTS ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) FOLLOWING SEPSIS.

Glutamine (GLN) has been shown to attenuate cytokine release from LPS-stimulated human peripheral blood mononuclear cells; however, the in vivo antiinflammatory effect of GLN in polymicrobial sepsis and ARDS is unknown. This study evaluates the effect of GLN on inflammatory cytokine release and the pathways that may mediate antiinflammatory effects of GLN in the lung. Either 0.75 g/kg of GLN or saline placebo (SP) was administered to male rats 1 h after cecal ligation and puncture (CLP). NF-kappaB activation, IKBalpha degradation, phosphorylation of p38 MAPK, ERK, and MKP-1 expression were evaluated in lung tissue 6 h post-CLP. Lung tissue iNOS and eNOS, TNF-alpha, IL-6, and IL-18 cytokines were assayed. Last, lung histopathology for occurrence of ARDS and survival were examined. GLN given 1 h postsepsis led to inhibition of lung tissue NF-kappaB activation (P < 0.001 vs. SP), attenuated degradation of IKBalpha, and inhibited phosphorylation of p38 MAPK, and ERK, pathways critical for cytokine release. GLN treatment increased MKP-1 peptide expression and significantly attenuated TNF-alpha and IL-6 6 h after CLP. IL-18 was attenuated by GLN at multiple time points post-CLP. Further, GLN abrogated increases in lung iNOS expression and enhanced lung eNOS postsepsis. Finally, GLN prevented the histopathologic appearance of ARDS after sepsis and significantly improved survival. These data reveal that GLN exerts an antiinflammatory effect in sepsis that may be mediated via attenuation of multiple pathways of inflammation such as NF-kappaB, p38 MAPK, ERK, and MKP-1. GLN also showed an inhibition of increases in iNOS expression. The antiinflammatory effect of GLN was associated with attenuation of ARDS and mortality.

Animals↗
PubMed2003

Ethanol blocks both basic fibroblast growth factor- and carbachol-mediated neuroepithelial cell expansion with differential effects on carbachol-activated signaling pathways.

We have expanded neuroepithelial cells dissociated from the embryonic rat telencephalon in serum-free defined medium containing basic fibroblast growth factor (bFGF) in order to generate a model neuroepithelium to study the interaction of ethanol with both growth factor- and transmitter-stimulated proliferation. Ethanol blocked proliferation stimulated by bFGF and by carbachol, an agonist at muscarinic acetylcholine receptors, in a dose-dependent manner. In addition, ethanol attenuated autonomous expansion of neuroepithelial cells occurring following withdrawal of bFGF. The latter effect was associated with an increase in the number of apoptotic cells identified by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling labeling. We studied the effects of ethanol on carbachol-stimulated signaling pathways critical to its proliferative effects. Ethanol significantly reduced carbachol-stimulated Ca(2+) signaling, as well as Erk1/Erk2, Akt and cyclic AMP-response element-binding phosphorylations in a dose-dependent manner. Comparison of the potency of ethanol in attenuating carbachol-stimulated proliferation and signal transduction showed that mitogen-activated protein kinase phosphorylation was less sensitive to ethanol than the other parameters. The results indicate that ethanol's suppression of proliferation induced by carbachol in this model neuroepithelium likely involves multiple signaling pathways. These effects in vitro may help to explain the devastating effects of prenatal ethanol exposure in vivo, which contribute to the fetal alcohol syndrome.

Acetylcholine↗
PubMed1998

The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis.

During development, the interaction of stem cell factor (SCF) with its receptor, KIT, is critical for the survival of melanocytes. Limited in vivo human studies have suggested a possible activating role of SCF on adult human melanocytes. In order to study the impact of this pathway on normal melanocyte homeostasis, human skin xenografts were treated with serial injections of recombinant human SCF or a KIT-inhibitory antibody (K44.2). On histologic evaluation, SCF injection increased, whereas KIT inhibition decreased the number, size, and dendricity of melanocytes. Immunohistochemical expression of melanocyte differentiation antigens, including tyrosinase-related-protein-1 and gp100/pmel17, was markedly increased by treatment with SCF, and decreased by K44.2 treatment. The number of Ki67-positive melanocytes was increased in the SCF-treated tissue, suggesting a direct proliferative effect of SCF; conversely, treatment with K44.2 resulted in melanocyte loss, which did not appear reversible with prolonged treatment. These findings demonstrate that the SCF/KIT pathway remains critical in adult human skin, and that pharmacologic modulation of this single pathway can control cutaneous melanocyte homeostasis.

Animals↗
PubMed2006

p38-MAP kinase activation followed by BIM induction is essential for glucocorticoid-induced apoptosis in lymphoblastic leukemia cells.

Glucocorticoids (GC) are common components in chemotherapeutic protocols for lymphoid malignancies. GC-induced apoptosis requires the intrinsic, BCL-2 family-regulated pathway. Treatment of CCRF-CEM (T cell acute lymphoblastic leukemia) cells with the GC, dexamethasone (Dex), activates p38-mitogen activated protein kinase (p38-MAPK) and then induces mRNA transcription and synthesis levels of BIM, a BH3-only pro-apoptotic BCL-2 family member. Dex-induced apoptosis is dramatically inhibited by downregulation of BIM by shRNA or by pretreatment with a p38-MAPK inhibitor, SB203580, which also reduces BIM induction. These findings indicate that BIM induction through p38-MAPK activation is a critical pathway in GC-induced cell death.

Apoptosis↗
PubMed1993

Vaccination against tuberculosis: is BCG more sinned against than sinner?

While extensive experimental studies of tuberculosis (Tb) have provided the foundation data for the discovery of cell-mediated immunity, there remains much to be disclosed about the critical pathways of immunity involved in this infectious process and the factors necessary to produce protective immunity. Studies on the aetiology and pathology of this disease have failed to elucidate the mechanisms of protective immunity. Although Tb research has been neglected for the past 30 years, the re-emergence of Tb worldwide as a significant zoonotic disease has re-focused research in this area. Scientific solutions for the control of Tb in man or domestic animals have not been found using empirical methods. Composite studies involving animal models of experimental infection will be necessary to critically evaluate vaccine efficacy and eludiate the basic immunological mechanisms involved in both disease and immunity. Available data which suggest that disease-related hypersensitivity and immunity are dissociable highlight the prospect that immunity to infection may be induced without compromising the continued need for ongoing systems of immunodiagnosis to exclude disease. In populations with a high prevalence of disease it is likely that a combination of immunodiagnosis, chemotherapy and immunoprophylaxis will be required to eradicate the disease.

Animals↗
PubMed2004

Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts.

Clefts of the lip and/or palate (CL/P) are among the most common birth defects worldwide. The majority are non-syndromic where CL/P occurs in isolation of other phenotypes. Where one or more additional features are involved, clefts are referred to as syndromic. Collectively CL/P has a major clinical impact requiring surgical, dental, orthodontic, speech, hearing and psychological treatments or therapies throughout childhood. The etiology of CL/P is complex and thought to involve both major and minor genetic influences with variable interactions from environmental factors. Using a combination of gene targeting technology and traditional developmental techniques in both mouse and chick, significant progress has been made in the identification of numerous genes and gene pathways critical for craniofacial development. Despite this, it has been a particular source of frustration that mutation screening of specific candidates, association studies and even genome-wide scans have largely failed to reveal the molecular basis of human clefting. Nevertheless, some important findings have recently come from studies involving syndromic forms of the disorder. These include several genes which have now been shown to contribute a major effect on the etiology of CL/P. Furthermore, these genes can also be used to demonstrate a significant overlap between syndromic and non-syndromic CL/P. The study of these syndromic genes and their molecular pathways will provide a useful and informative route with which to gain a better understanding of human craniofacial pathology.

Cleft Lip↗
PubMed2003

Regulator of sex-limitation (Rsl) encodes a pair of KRAB zinc-finger genes that control sexually dimorphic liver gene expression.

Sexually dimorphic expression of a broad array of liver proteins involved in reproduction and xenobiotic metabolism is induced at puberty by sex-specific growth hormone patterns. An additional control of sex-dependent gene expression is conferred by Regulator of sex-limitation (Rsl) alleles. In variant rsl mice, females inappropriately express the male Sex-limited protein, Slp. We recently showed that a panel of male-specific liver genes is repressed by Rsl, accentuating sex differences in a hormone-independent manner. Here we map rsl to a region on Chromosome 13 comprised exclusively of KRAB (Kruppel-associated box) zinc-finger protein (ZFP) genes. Among eight Rsl candidate (Rslcan) genes within the critical genetic interval, the recent duplicates Rslcan-4 and Rslcan-9 both harbor mutations in rsl mice (partial deletion and splice-site inactivation, respectively). Transgenesis with bacterial artificial chromosome (BAC) clones encompassing Rslcan-4 restores male-specific MUP (major urinary protein) expression to rsl mice, whereas a BAC containing Rslcan-9 rescues sex-specific expression of Slp and cytochrome P450 Cyp2d9. Thus, the Rslcan-4 and Rslcan-9 paralogs partitioned regulation of their target genes during evolution. This demonstrates the first biological role for a set of KRAB zinc-finger repressor proteins and reveals the molecular basis of a gene-silencing pathway critical for sexual dimorphism.

Animals↗