We study some mechanisms responsible for synchronous oscillations and loss of synchrony at physiologically relevant frequencies (10-200 Hz) in a network of heterogeneous inhibitory neurons. We focus ...on the factors that determine the level of synchrony and frequency of the network response, as well as the effects of mild heterogeneity on network dynamics. With mild heterogeneity, synchrony is never perfect and is relatively fragile. In addition, the effects of inhibition are more complex in mildly heterogeneous networks than in homogeneous ones. In the former, synchrony is broken in two distinct ways, depending on the ratio of the synaptic decay time to the period of repetitive action potentials (tau s/T), where T can be determined either from the network or from a single, self-inhibiting neuron. With tau s/T > 2, corresponding to large applied current, small synaptic strength or large synaptic decay time, the effects of inhibition are largely tonic and heterogeneous neurons spike relatively independently. With tau s/T < 1, synchrony breaks when faster cells begin to suppress their less excitable neighbors; cells that fire remain nearly synchronous. We show numerically that the behavior of mildly heterogeneous networks can be related to the behavior of single, self-inhibiting cells, which can be studied analytically.
It is well established that 4-Hydroxynonenal (HNE) plays a major role in oxidative stress-induced signaling and the toxicity of oxidants. Surprisingly our recent studies also demonstrate that low ...levels of HNE generated during oxidative stress promote cell survival mechanisms and proliferation. Since the expression and secretion of VEGF is known to be affected by Oxidative stress, during present studies, we have examined dose dependent effect of HNE on VEGF expression and secretion in a model of Retinal Pigment Epithelial (RPE) cells in culture. Results of these studies showed that while inclusion of 0.1μM HNE in the medium caused increased secretion of VEGF, its secretion and expression was significantly suppressed in the presence of >5 μM HNE in the media. These concentration dependent hormetic effects of HNE on VEGF secretion could be blocked by the over expression of GSTA4-4 indicating that these effects were specifically attributed to HNE and regulated by GSTA4-4. VEGF secreted in to the media showed angiogenic properties as indicated by increased migration and tube formation of HUVEC in matrigel when grown in media from RPE cells treated with 1 μM HNE. The corresponding media from GSTA4-4 over expressing RPE cells had no effect on migration and tube formation of HUVEC in matrigel. These results are consistent with earlier studies showing that at low concentrations, HNE promotes proliferative mechanisms and suggest that HNE induces VEGF secretion from RPE cells that acts in a paracrine fashion to induce angiogenic signaling mechanism in the endothelial cells. These findings may suggest a role of HNE and GSTA4-4 in oxidative stress induced proliferative retinopathies.
A series of N,O‐ketimine supported gallium and digallane complexes have been synthesized and structurally characterized. The mono(ketiminate) gallium dichloride OCMeCHCMeN(Dipp)GaCl2, 2 ...(Dipp=2,6‐iPr2C6H3) and bis(ketiminate) gallium chloride OCMeCHCMeN(Dipp)2GaCl, 3 were isolated from the reaction of GaCl3 with 1 and 2 equivalents of lithiated ketimine, OCMeCHCMeN(Dipp)Li, 1 respectively. Treatment of 1 with ‘‘GaI’’ yielded diiodobis(ketiminate) digallane complex OCMeCHCMeN‐(Dipp)2Ga2I2, 4. To the best of our knowledge, compound 4 is the first report on N,O‐ketiminate ligand supported stable heteroleptic digallane(II) complex. The frontier molecular orbital analysis and a high Wiberg Bond Index (WBI) values support the strong interaction between the gallium centers in 4. In an attempt to synthesize alkyl substituted Ga complexes, we carried out the reaction of ketimine ligand with GatBu2Cl (1:1 ratio) that generated the adduct OCMeCHCMeN(H)(Dipp)GatBu2Cl, 5. In a similar fashion, dialkyl gallium complex OCMeCHCMeN(Dipp)GatBu2, 6 was obtained from the reaction of 1 with GatBu2Cl. All the compounds have been charecterized by 1H, 13C NMR and mass spectroscopy. The molecular structures of complexes 2–5 have also been determined by single crystal X‐ray diffraction analysis.
A serious of N,O‐ketimine supported gallium and digallane complexes have been synthesized. The mono(ketiminate) gallium dichloride OCMeCHCMeN(Dipp)GaCl2, 2 (Dipp=2,6‐iPr2C6H3) and bis(ketiminate) gallium chloride OCMeCHCMeN(Dipp)2GaCl, 3 were isolated from the reaction of GaCl3 with 1 and 2 equivalents of lithiated ketimine, OCMeCHCMeN(Dipp)Li, 1 respectively. Treatment of 1 with ‘‘GaI’’ yielded diiodobis(ketiminate) digallane complex OCMeCHCMeN‐(Dipp)2Ga2I2, 4. All the compounds have been charecterized by 1H/13C NMR, mass spectrometry and single crystal X‐ray diffraction analysis.
The thyroid lesions comprise developmental, degenerative, cystic, non-neoplastic, and neoplastic etiology. Among cystic lesions of thyroid colloid cyst, papillary carcinoma of thyroid, thyroglossal ...cyst, and rarely epidermal cyst can be present. Epidermal inclusion cyst, though a common entity, is extremely rare in the thyroid gland and thought to arise from foci of squamous metaplasia. We report a rare case of inclusion epidermal cyst diagnosed on cytology and confirmed by histopathology.
Targeting p53-null neuroblastomas through RLIP76 Singhal, Jyotsana; Yadav, Sushma; Nagaprashantha, Lokesh Dalasanur ...
Cancer prevention research (Philadelphia, Pa.),
06/2011, Letnik:
4, Številka:
6
Journal Article
Recenzirano
Odprti dostop
The search for p53-independent mechanism of cancer cell killing is highly relevant to pediatric neuroblastomas, where successful therapy is limited by its transformation into p53-mutant and a highly ...drug-resistant neoplasm. Our studies on the drug-resistant p53-mutant as compared with drug-resistant p53 wild-type neuroblastoma revealed a novel mechanism for resistance to apoptosis: a direct role of p53 in regulating the cellular concentration of proapoptotic alkenals by functioning as a specific and saturable allosteric inhibitor of the alkenal-glutathione conjugate transporter, RLIP76. The RLIP76-p53 complex was showed by both immunoprecipitation analyses of purified proteins and immunofluorescence analysis. Drug transport studies revealed that p53 inhibited both basal and PKCα-stimulated transport of glutathione conjugates of 4HNE (GSHNE) and doxorubicin. Drug resistance was significantly greater for p53-mutant as compared with p53 wild-type neuroblastoma cell lines, but both were susceptible to depletion of RLIP76 by antisense alone. In addition, inhibition of RLIP76 significantly enhanced the cytotoxicity of cisplatin. Taken together, these studies provide powerful evidence for a novel mechanism for drug and apoptosis resistance in p53-mutant neuroblastoma, based on a model of regulation of p53-induced apoptosis by RLIP76, where p53 is a saturable and specific allosteric inhibitor of RLIP76, and p53 loss results in overexpression of RLIP76; thus, in the absence of p53, the drug and glutathione-conjugate transport activities of RLIP76 are enhanced. Most importantly, our findings strongly indicate RLIP76 as a novel target for therapy of drug-resistant and p53-mutant neuroblastoma.
Lung cancer is still a major cause of cancer deaths in spite of considerable efforts in its systemic therapy. Chemotherapy, along with local irradiation is frequently employed but as a palliative ...therapy. Inherent and acquired resistance in NSCLC and SCLC towards chemotherapeutic agents further makes chemotherapy an incommodious problem. The resistance mechanisms responsible for inherent DOX-resistance of NSCLC and acquired DOX-resistance in SCLC have been the subject of numerous investigations. This review will focus on the recent studies done for understanding the mechanism(s) of inherent and acquired resistance in NSCLC and SCLC and how these can be exploited for the future development of more effective novel biologic agents for the treatment of lung cancer.
Proton computed tomography (pCT) has recently seen considerable research interest as a means of reducing range uncertainties in proton therapy, by reconstructing directly relative stopping power to ...water (RSP). Recent detector developments have permitted the development of two list-mode pCT scanner prototypes based on broad (passively scattered) proton beam delivery 1,2. In this Monte Carlo (MC) simulation study, the application of fluence field modulated computed tomography (FFMCT), initially developed for X-ray CT 3, to pCT is presented. Fluence modulated pCT (FMpCT) scans can be acquired by utilizing pencil beam (PB) scanning and can achieve variable image quality in a pCT image. Dose calculation accuracy may thus be simultaneously preserved in the beam path in parallel with imaging dose reduction.
Using MC simulations of an ideal list-mode pCT scanner, a uniform cylinder and two patients were studied. Regions of interests (ROI) were selected for high image quality and only PBs intercepting them preserved full fluence (FF). Image quality was investigated in terms of accuracy and noise of the reconstructed RSP. Dose calculation accuracy on FMpCT images was evaluated in terms of dose volume histograms (DVH), range difference (RD) for beam-eye-view (BEV) dose profiles and gamma evaluation. Furthermore, the concept of FMpCT was tested on experimental data by creating pseudo FMpCT scans from broad beam scans acquired with a pCT prototype.
For the virtual phantoms, FMpCT noise in ROIs at 1% of FF was equivalent to that of FF images. Integral imaging dose reduction up to 56% was achieved for the two patients for that modulation. Corresponding proton dose calculations on FMpCT images agreed to those from reference images. Applying FMpCT to preliminary experimental data showed that low noise levels and accuracy could be preserved in a ROI.
Singultus (hiccups lasting longer than 48 hours) is a described complication following epidural steroid injections, sacroiliac joint injections, and facet joint injections. The underlying etiology is ...not completely understood, but it is a condition that can be distressing to patients. Our case presentation involves a 62-year-old male presenting for cervical epidural steroid injection. He subsequently developed persistent hiccups that resolved after medical therapy. When approaching these patients, it is critical to evaluate for potentially life-threatening etiologies before progressing down a treatment algorithm.
In this case report we describe a case of propofol infusion syndrome in an adult after a short-term infusion of large-dose propofol during a neurosurgical procedure. Large-dose propofol (9 ...mg.kg(-1).h(-1)) was given for only 3 h during surgery and was followed by a small-dose infusion (2.3 mg.kg(-1).h(-1)) for 20 h postoperatively. The patient had also received large doses of methylprednisolone. He developed a marked lactic acidosis with mild biological signs of renal impairment and rhabdomyolysis but no cardiocirculatory failure. There were no other evident causes of lactic acidosis as documented by laboratory data. We believe this is the first report of reversible lactic acidosis associated with a short duration of large-dose propofol anesthesia.
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