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111.
Mani S Macapinlac M Goel S Verdier-Pinard D Fojo T Rothenberg M Colevas D 《Anti-cancer drugs》2004,15(6):553-558
Microtubule-stabilizing agents are increasingly studied for cancer treatment based largely on the prior success of paclitaxel and docetaxel. In this review, we focus on the clinical development of epothilones and discodermolide, and we discuss salient preclinical and clinical highlights of these two novel natural products. These agents are distinguished by their biochemical features making them poor P-glycoprotein substrates and capable of inducing cytotoxicity in cell lines or in vivo tumor models harboring mutations in tubulin. There is now considerable data regarding the efficacy of the epothilones in human beings and discodermolide holds such promise, as well. 相似文献
112.
Temporally irregular mnemonic persistent activity in prefrontal neurons of monkeys during a delayed response task 总被引:10,自引:0,他引:10
Compte A Constantinidis C Tegner J Raghavachari S Chafee MV Goldman-Rakic PS Wang XJ 《Journal of neurophysiology》2003,90(5):3441-3454
An important question in neuroscience is whether and how temporal patterns and fluctuations in neuronal spike trains contribute to information processing in the cortex. We have addressed this issue in the memory-related circuits of the prefrontal cortex by analyzing spike trains from a database of 229 neurons recorded in the dorsolateral prefrontal cortex of 4 macaque monkeys during the performance of an oculomotor delayed-response task. For each task epoch, we have estimated their power spectrum together with interspike interval histograms and autocorrelograms. We find that 1). the properties of most (about 60%) neurons approximated the characteristics of a Poisson process. For about 25% of cells, with characteristics typical of interneurons, the power spectrum showed a trough at low frequencies (<20 Hz) and the autocorrelogram a dip near zero time lag. About 15% of neurons had a peak at <20 Hz in the power spectrum, associated with the burstiness of the spike train; 2). a small but significant task dependency of spike-train temporal structure: delay responses to preferred locations were characterized not only by elevated firing, but also by suppressed power at low (<20 Hz) frequencies; and 3). the variability of interspike intervals is typically higher during the mnemonic delay period than during the fixation period, regardless of the remembered cue. The high irregularity of neural persistent activity during the delay period is likely to be a characteristic signature of recurrent prefrontal network dynamics underlying working memory. 相似文献
113.
Wenig BL Werner JA Castro DJ Sridhar KS Garewal HS Kehrl W Pluzanska A Arndt O Costantino PD Mills GM Dunphy FR Orenberg EK Leavitt RD 《Archives of otolaryngology--head & neck surgery》2002,128(8):880-885
OBJECTIVE: To determine the safety and efficacy of targeted antitumor therapy with cisplatin/epinephrine injectable gel in patients with advanced squamous cell carcinoma of the head and neck. DESIGN: Two prospective, double-blind, placebo-controlled phase III trials of identical design. Crossover from blinded to open-label phase was permitted for patients with disease progression. SETTING: Tertiary referral centers in North America and Europe. PATIENTS: One hundred seventy-nine intensively pretreated patients with recurrent or refractory squamous cell carcinoma of the head and neck. INTERVENTION: Cisplatin/epinephrine injectable or placebo gel was administered by direct intratumoral injection; up to 6 weekly treatments. Dose was 0.25 mL of active or placebo gel per cubic centimeter of tumor up to 10 mL total. Patient benefit after local tumor control of the most symptomatic tumor was assessed by patients and physicians using the Treatment Goals Questionnaire. MAIN OUTCOME MEASURES: Local tumor response and patient benefit attributable to improvements in tumor-related symptoms. RESULTS: Combined results for the 178 patients with evaluable data in the 2 trials confirmed objective tumor responses in 35 (29%) of 119 patients, including 23 (19%) complete responses achieved with cisplatin/epinephrine gel, vs 1 (2%) of 59 for placebo (P<.001). Tumor response and patient benefit were significantly correlated (P=.006): 47% (17/36) of patients with target tumor responses achieved a rigorously defined benefit based on a prospectively selected treatment goal vs 15% (22/142) of nonresponders. CONCLUSION: Cisplatin/epinephrine injectable gel reduces tumor burden, ameliorates tumor symptoms, and provides a new therapeutic option for treating patients with squamous cell carcinoma of the head and neck. 相似文献
114.
Neonatal spinal cord injury (SCI) is well described in the literature, though its diagnosis is often delayed or missed in the neonatal period. We present a neonate who was referred with upper gastrointestinal bleed and a diagnosis of spinal cord injury was subsequently made clinically and confirmed radiologically. 相似文献
115.
Rameshkumar N Veena A Ilavarasan R Adiraj M Shanmugapandiyan P Sridhar SK 《Biological & pharmaceutical bulletin》2003,26(2):188-193
In the present study, a new series of 2,6-diaryl-3-methyl-4-piperidones was synthesized by Mannich reaction (condensation) of ethyl-methyl ketone, substituted aromatic aldehydes and ammonium acetate. Oximes and thiosemicarbazone derivatives of 2,6-diaryl-3-methyl-4-piperidones were synthesized by reaction with hydroxylamine hydrochloride and thiosemicarbazide respectively. The chemical structures were confirmed by means of IR, 1H-, 13C-NMR and mass spectral data. The compounds were screened for acute toxicity, analgesic, local anaesthetic and antifungal activity. 2-(4-Methylphenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-one 2 exhibited the highest analgesic and local anaesthetic activity. The oximes and thiosemicarbazones were completely devoid of analgesic and local anaesthetic activity. 2-(4-Methylphenyl)-3-methyl-6-(4-hydroxyphenyl)-piperidin-4-oxime 21 and 2-(4-methoxyphenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-oxime 17 exhibited potent antifungal activity against Aspergillus niger. Antifungal activity against Candida albicans was observed only with 2-(4-dimethylaminophenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-oxime 20. 2,6-Diaryl-3-methyl-4-piperidones did not exhibit antifungal property. 相似文献
116.
Rameshkumar N Ashokkumar M Subramanian EH Ilavarasan R Sridhar SK 《European journal of medicinal chemistry》2003,38(11-12):1001-1004
In the present study, a series of 1-ethyl/benzyl-6-fluoro-7-(substituted piperazin-1-yl)1,4-dihydro-4-oxo-quinoline-3-carboxylic acid were synthesized and characterized by IR, 1H-NMR, mass spectral and elemental analysis. The in vitro antibacterial and antifungal activities of the compounds were evaluated by paper disc diffusion method. The minimum inhibitory concentrations (MIC) of the compounds were also determined by agar streak dilution method. The in vivo antibacterial activity of the compounds against Escherichia coli was also evaluated by mouse protection test. All the compounds exhibited significant antibacterial and weak antifungal activities. The in vivo antibacterial activity (ED50) against E. coli was 50-160 mg kg(-1) in the order of 7<9<8<10. 1-ethyl-6-fluoro-7-(2,5-dioxo-piperazin-1-yl)1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (7) was found to exhibit the most potent in vitro antimicrobial activity with MIC of 4.1, 3.1, 3.1, 2.4, 1, 1, 25 and >100 microg mL(-1) against Staphylococcus aureus, Staphylococcus epidermidis, Micrococcus luteus, Bacillus cereus, E. coli, Klebsiella pneumoniae, Candida albicans and Aspergillus niger. 相似文献
117.
Raez LE Cassileth PA Schlesselman JJ Padmanabhan S Fisher EZ Baldie PA Sridhar K Podack ER 《Cancer gene therapy》2003,10(11):850-858
Large tumor burdens in advanced non-small-cell lung carcinoma (NSCLC) are thought to be immunosuppressive. To determine whether CD8-mediated immune responses could be elicited in stage IIIB/IV NSCLC patients, 14 subjects were immunized several times with allogeneic NSCLC cells transfected with CD80 (B7.1) and HLA-A1 or A2. Patients enrolled were matched or unmatched at the HLA A1 or A2 locus and their immune response compared. Immunization significantly increased the frequencies of interferon-gamma secreting CD8 T cells in all but one patient in response to ex vivo challenge with NSCLC cells. The CD8 response of matched and unmatched patients was not statistically different. NSCLC reactive CD8 cells did not react to K562. Clinically, five of 14 patients responded to immunization with stable disease or partial tumor regression. The study demonstrates that CD8 Ifn-gamma responses against nonimmunogenic or immunosuppressive tumors can be evoked by cellular vaccines even at advanced stages of disease. The positive clinical outcome suggests that nonimmunogenic tumors may be highly susceptible to immune effector cells generated by immunization. 相似文献
118.
Surface,core, and X genes of hepatitis B virus in hepatocellular carcinoma: an in situ hybridization study 总被引:6,自引:0,他引:6
BACKGROUND: The incidence of hepatocellular carcinoma (HCC) and the seroprevalence of hepatitis B virus (HBV) in this disease state are significantly higher in South India than in North India. Because data on serologic studies do not project the actual association between the two parameters, this study was undertaken. METHODS: The prevalence of HBV genes in HCC patients was studied using nonisotopic in situ hybridization. Fifty patients from South India were diagnosed with HCC after performing ultrasound-guided fine-needle aspiration biopsies of liver lesions. The diagnosis was confirmed by cell block studies. Sections cut from paraffin-embedded cell blocks made out of the aspirates were probed with digoxigenin-labeled surface, core, and X regions of the viral genome. RESULTS: Nuclear integration of the surface gene was observed in 100% (50 of 50), the core gene was positive in 94% (47 of 50), and the X gene was present in 98% (49 of 50) of the cases. An episomal form of the virus was not found. Serum hepatitis B surface antigen was positive only in 48% (12 of 25) of the patients screened. CONCLUSIONS: We found molecular evidence that HBV is an important contributing factor in the etiology of HCC in South India. In HCC, the S gene of the virus was the most prevalent followed by the X and C genes. Only integrated forms of the viral DNA were observed. Nonisotopic in situ hybridization using multiple regions of the viral genome is a good technique for studying this association. It has an added advantage over polymerase chain reaction, of localization of signals in a tumor cell. Cell blocks made from fine-needle aspirates are ideal for in situ hybridization. 相似文献
119.
Wissner A Overbeek E Reich MF Floyd MB Johnson BD Mamuya N Rosfjord EC Discafani C Davis R Shi X Rabindran SK Gruber BC Ye F Hallett WA Nilakantan R Shen R Wang YF Greenberger LM Tsou HR 《Journal of medicinal chemistry》2003,46(1):49-63
A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer. 相似文献
120.
Overexpression of the epidermal growth factor receptor (EGFR) is correlated with a poor prognosis in several human malignancies. In addition, cancers overexpressing EGFR respond poorly to both chemotherapy and radiation therapy. Therefore, EGFR is a viable target for cancer therapy. This review will address how EGFR blockade modulates signal transduction, leading to alterations in the cell cycle progression with secondary inhibition of proliferation and differentiation of cancer cells. As a prototypical example, erlotinib (Tarceva), a reversible EGFR tyrosine kinase inhibitor will be discussed. This drug has demonstrated promising antitumor activity in Phase II trials in several solid tumors and definitive Phase III studies to demonstrate clinical benefit have completed accrual. 相似文献