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1.
Oncogenesis ; 6(1): e295, 2017 Jan 30.
Article in English | MEDLINE | ID: mdl-28134933

ABSTRACT

Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor. From this screening, JQ1, a potent inhibitor of Myc oncogenic network, emerged as the most robust collaborator. Treatment with a combination of VS-6063 and JQ1 synergistically caused an arrest of tumor cells at the G2/M phase and a decrease in the XIAP-linked cell survival. Our subsequent mechanistic analyses indicate that this functional cooperation was strongly associated with the concomitant disruption of activation or expression of FAK and c-Myc as well as their downstream signaling through the PI3K/Akt pathway. In line with these observations, we detected a strong co-amplification or upregulation at genomic or protein level for FAK and c-Myc in a large portion of primary tumors in the TCGA or a local HGSOC patient cohort. Taken together, our results suggest that the integrin-FAK signaling axis and c-Myc synergistically drive cell proliferation, survival and oncogenic potential in HGSOC. As such, our study provides key genetic, functional and signaling bases for the small-molecule-based co-targeting of these two distinct oncogenic drivers as a new line of targeted therapy against human ovarian cancer.

2.
J Neurophysiol ; 96(5): 2488-500, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16914613

ABSTRACT

Delayed excitotoxic neuronal death after insult from exposure to high glutamate concentrations appears important in several CNS disorders. Although delayed excitotoxicity is known to depend on NMDA receptor (NMDAR) activity and Ca(2+) elevation, the electrophysiological mechanisms underlying postinsult persistence of NMDAR activation are not well understood. Membrane depolarization and nonspecific cationic current in the postinsult period were reported previously, but were not sensitive to NMDAR antagonists. Here, we analyzed mechanisms of the postinsult period using parallel current- and voltage-clamp recording and Ca(2+) imaging in primary hippocampal cultured neurons. We also compared more vulnerable older neurons [about 22 days in vitro (DIV)] to more resistant younger (about 15 DIV) neurons, to identify processes selectively associated with cell death in older neurons. During exposure to a modest glutamate insult (20 microM, 5 min), similar degrees of Ca(2+) elevation, membrane depolarization, action potential block, and increased inward current occurred in younger and older neurons. However, after glutamate withdrawal, these processes recovered rapidly in younger but not in older neurons. The latter also exhibited a concurrent postinsult increase in spontaneous miniature excitatory postsynaptic currents, reflecting glutamate release. Importantly, postinsult NMDAR antagonist administration reversed all of these persisting responses in older cells. Conversely, repolarization of the membrane by voltage clamp immediately after glutamate exposure reversed the NMDAR-dependent Ca(2+) elevation. Together, these data suggest that, in vulnerable neurons, excitotoxic insult induces a sustained positive feedback loop between NMDAR-dependent current and depolarization-mediated glutamate release, which persists after withdrawal of exogenous glutamate and drives Ca(2+) elevation and delayed excitotoxicity.


Subject(s)
Glutamic Acid/metabolism , Receptors, N-Methyl-D-Aspartate/physiology , Aging/physiology , Animals , Calcium/metabolism , Calibration , Cell Death/drug effects , Cells, Cultured , Data Interpretation, Statistical , Diagnostic Imaging , Electrophysiology , Feedback, Physiological/physiology , Female , Fluorescent Dyes , Hippocampus/cytology , Hippocampus/drug effects , Indoles , Nerve Net/physiology , Patch-Clamp Techniques , Pregnancy , Rats , Rats, Sprague-Dawley
3.
J Neurosci ; 21(1): 98-108, 2001 Jan 01.
Article in English | MEDLINE | ID: mdl-11150325

ABSTRACT

Although vitamin D hormone (VDH; 1,25-dihydroxyvitamin D(3)), the active metabolite of vitamin D, is the major Ca(2+)-regulatory steroid hormone in the periphery, it is not known whether it also modulates Ca(2+) homeostasis in brain neurons. Recently, chronic treatment with VDH was reported to protect brain neurons in both aging and animal models of stroke. However, it is unclear whether those actions were attributable to direct effects on brain cells or indirect effects mediated via peripheral pathways. VDH modulates L-type voltage-sensitive Ca(2+) channels (L-VSCCs) in peripheral tissues, and an increase in L-VSCCs appears linked to both brain aging and neuronal vulnerability. Therefore, we tested the hypothesis that VDH has direct neuroprotective actions and, in parallel, targets L-VSCCs in hippocampal neurons. Primary rat hippocampal cultures, treated for several days with VDH, exhibited a U-shaped concentration-response curve for neuroprotection against excitotoxic insults: lower concentrations of VDH (1-100 nm) were protective, but higher, nonphysiological concentrations (500-1000 nm) were not. Parallel studies using patch-clamp techniques found a similar U-shaped curve in which L-VSCC current was reduced at lower VDH concentrations and increased at higher (500 nm) concentrations. Real-time PCR studies demonstrated that VDH monotonically downregulated mRNA expression for the alpha(1C) and alpha(1D) pore-forming subunits of L-VSCCs. However, 500 nm VDH also nonspecifically reduced a range of other mRNA species. Thus, these studies provide the first evidence of (1) direct neuroprotective actions of VDH at relatively low concentrations, and (2) selective downregulation of L-VSCC expression in brain neurons at the same, lower concentrations.


Subject(s)
Calcitriol/metabolism , Calcium Channels, L-Type/metabolism , Hippocampus/metabolism , Neurons/metabolism , Neuroprotective Agents/pharmacology , Animals , Calcitriol/classification , Calcitriol/pharmacology , Calcium Channels, L-Type/genetics , Cell Count , Cell Survival/drug effects , Cells, Cultured , Culture Media, Serum-Free/pharmacology , Dose-Response Relationship, Drug , Down-Regulation , Glutamic Acid/metabolism , Glutamic Acid/pharmacology , Hippocampus/cytology , Hippocampus/drug effects , N-Methylaspartate/metabolism , N-Methylaspartate/pharmacology , Neuroglia/cytology , Neuroglia/metabolism , Neurons/cytology , Neurons/drug effects , Patch-Clamp Techniques , Pyramidal Cells/cytology , Pyramidal Cells/drug effects , Pyramidal Cells/metabolism , RNA, Messenger/metabolism , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Receptors, Calcitriol/metabolism
4.
J Comp Physiol A ; 182(4): 509-19, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9530839

ABSTRACT

In crayfish stimulation of abdominal positioning interneurons (APIs) recruits other interneurons producing various abdominal movements. We investigated whether: (1) the same API from different preparations activated a similar number or group of interneurons, (2) different APIs activated different groups, and (3) repeated stimulation of an API consistently affected a similar set of interneurons. To quantify the similarities and differences of the recruited interneuronal groups we compared the number of interneurons affected, their firing frequencies, and motor outputs. Three types of APIs (Curly Q, L and T) were identified and each type was stimulated in three preparations. Our results showed that for the Curly Q and L cells, each cell type activated interneuronal groups that were statistically similar in number and firing frequency. The T cell activated interneuronal groups that were more variable. Some APIs generally provided a repeatable motor output; all did not. The interneuronal groups activated by the Curly Q, L and T cells were very different from each other. Repeated stimulation of one Curly Q cell affected similar although not identical sets of interneurons. These data suggest that repeated motor outputs could be produced by a similar but not identical group of cells.


Subject(s)
Astacoidea/physiology , Interneurons/physiology , Neural Pathways/growth & development , Neural Pathways/physiology , Action Potentials/physiology , Animals , Electric Stimulation , Female , Ganglia, Invertebrate/cytology , Ganglia, Invertebrate/physiology , Male , Neural Pathways/cytology
6.
J Exp Zool ; 278(3): 119-32, 1997 Jun 15.
Article in English | MEDLINE | ID: mdl-9181692

ABSTRACT

Quantitative studies were made of a large population of interneurons that controls postural flexion and extension of the crayfish abdomen. The number of interneurons needed to produce a motor program was estimated by stimulating a single abdominal positioning interneuron and recording interneuronal activity that was evoked from rostral and caudal connectives in an isolated abdominal nerve cord. We also examined the role that these functional groups have in producing a stronger motor output in either a rostral or caudal direction and thus specifying various abdominal geometrics. The average number of interneurons responding to stimulation of a single abdominal positioning interneuron was 32 (range: 3-50; n = 27). The average number of interneurons that decreased activity was 10 (range: 2-32). Of 653 activated interneurons from 20 preparations, approximately 43% fired between 2 and 5 Hz, 33% fired between 6 and 15 Hz, and 25% fired > 15 Hz. The size of a recruited group was usually but not always correlated with the strength of its motor response or with the direction of motor bias. Therefore, the contribution of a group may depend upon the number of active elements as well as synaptic efficacy.


Subject(s)
Abdomen/innervation , Astacoidea/physiology , Behavior, Animal/physiology , Interneurons/physiology , Movement/physiology , Action Potentials , Animals , Female , Ganglia, Invertebrate/physiology , Interneurons/cytology , Male , Neural Conduction/physiology , Synapses/physiology , Synaptic Transmission/physiology
7.
Transfusion ; 34(7): 562-9, 1994 Jul.
Article in English | MEDLINE | ID: mdl-8053036

ABSTRACT

BACKGROUND: Alloimmunization to red cell antigens is a significant risk in chronically transfused patients with sickle cell disease. Antigen matching, by decreasing the likelihood of alloantibody development, may significantly facilitate long-term management while decreasing morbidity. STUDY DESIGN AND METHODS: The transfusion records of 86 patients who underwent chronic transfusion for sickle cell disease at a tertiary-care medical center were reviewed retrospectively to determine the efficacy of an antigen-matching program in the prevention of alloimmunization to clinically significant red cell antigens. Recipients were phenotyped and given units matched for the K, C, E, S, and Fya or Fyb antigens. RESULTS: None (0%) of the 40 patients who received antigen-matched transfusions showed any evidence of alloimmunization, while 16 (34.8%) of the 46 patients who received both antigen-matched and non-antigen-matched transfusions developed clinically significant alloantibodies. The cost was 1.8 to 1.5 times that for a standard transfusion protocol. CONCLUSION: On the basis of this experience, it is recommended that transfusion centers engaged in the management of chronically transfused sickle cell anemia patients consider providing antigen-matched units for such patients. This is recommended not only because it prevents alloimmunization but also because such a program provides additional clinical benefits to the patient that may outweigh the higher costs of the process.


Subject(s)
Anemia, Sickle Cell/therapy , Blood Donors , Blood Grouping and Crossmatching , Blood Transfusion , Female , Humans , Isoantibodies/blood , Male , Retrospective Studies
8.
J Androl ; 12(4): 264-72, 1991.
Article in English | MEDLINE | ID: mdl-1917693

ABSTRACT

While investigating the coordinate regulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and farnesyl pyrophosphate synthetase, the authors observed that rat testes contained high levels of a farnesyl pyrophosphate synthetase mRNA that was larger than that found in most other tissues. This mRNA contains upstream AUG codons that may alter its rate of translation. The developmental and hormonal regulation of this testicular mRNA were investigated. Testicular levels of farnesyl pyrophosphate synthetase mRNA increased in rats between 30 and 40 days of age and remained elevated. Significant increases in serum testosterone concentrations and secondary sexual organ weights first occurred at 50 days of age. Hypophysectomy resulted in nearly undetectable levels of testicular farnesyl pyrophosphate synthetase mRNA. Treatment of hypophysectomized rats with gonadotropins increased the levels of this mRNA toward normal. These data indicate that an increase in farnesyl pyrophosphate synthetase mRNA takes place in testes just before the onset of puberty. This may be induced by the peripubertal rise in follicle-stimulating hormone.


Subject(s)
Dimethylallyltranstransferase/genetics , Gene Expression Regulation, Enzymologic , Pituitary Gland/physiology , Testis/enzymology , Animals , Follicle Stimulating Hormone/blood , Hypophysectomy , Male , Organ Size , RNA, Messenger/metabolism , Radioimmunoassay , Rats , Rats, Inbred Strains , Sexual Maturation , Testis/growth & development , Testosterone/blood
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