Gefitinib is often referred to as a "specific" or "selective" inhibitor of epidermal growth factor receptor. Studies demonstrate, however, that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal. Maximum plasma concentrations resulting from clinically relevant doses are 0.5-1 M or more, well within the IC 50 values of several tyrosine kinases. No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed throughout the body. Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces, with <4% of the dose in the urine. After daily oral administration, steady-state plasma levels are reached in 10 days and are 2-fold higher than those achieved after single doses. Gefitinib effectiveness was demonstrated in a randomized, double-blind, Phase II, multicenter trial comparing two oral doses of gefitinib (250 versus 500 mg/day). A total of 216 patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving 250 mg/day gefitinib and in 8% (6 of 76) of patients receiving 500 mg/day gefitinib. The overall objective response rate (RR) for both doses combined was 10.6% (15 of 142 patients; 95% confidence interval, 6.0 -16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6 -18.6؉ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV non-small cell lung cancer patients. Patients were randomized to receive gefitinib (250 or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n ‫؍‬ 1093) or carboplatin plus paclitaxel (n ‫؍‬ 1037). Results from this study showed no benefit (RR, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Interstitial lung disease has been observed in patients receiving gefitinib. Worldwide, the incidence of interstitial lung disease was about 1% (2% in the Japanese postmarketing experience and about 0.3% in a United States expanded access program). Approximately one-third of the cases have been fatal. Gefitinib was approved under accelerated approval regulations on the basis of a surrogate end point, RR. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in diseaserelated symptoms or incr...

BackgroundAdolescent risk-taking, including behaviors resulting in injury or death, has been attributed in part to maturational differences in mesolimbic incentive-motivational neurocircuitry, including ostensible oversensitivity of the nucleus accumbens (NAcc) to rewards.Methodology/Principal FindingsTo test whether adolescents showed increased NAcc activation by cues for rewards, or by delivery of rewards, we scanned 24 adolescents (age 12–17) and 24 adults age (22–42) with functional magnetic resonance imaging while they performed a monetary incentive delay (MID) task. The MID task was configured to temporally disentangle potential reward or potential loss anticipation-related brain signal from reward or loss notification-related signal. Subjects saw cues signaling opportunities to win or avoid losing $0, $.50, or $5 for responding quickly to a subsequent target. Subjects then viewed feedback of their trial success after a variable interval from cue presentation of between 6 to17 s. Adolescents showed reduced NAcc recruitment by reward-predictive cues compared to adult controls in a linear contrast with non-incentive cues, and in a volume-of-interest analysis of signal change in the NAcc. In contrast, adolescents showed little difference in striatal and frontocortical responsiveness to reward deliveries compared to adults.Conclusions/SignificanceIn light of divergent developmental difference findings between neuroimaging incentive paradigms (as well as at different stages within the same task), these data suggest that maturational differences in incentive-motivational neurocircuitry: 1) may be sensitive to nuances of incentive tasks or stimuli, such as behavioral or learning contingencies, and 2) may be specific to the component of the instrumental behavior (such as anticipation versus notification).

We investigated the local and remote vascular changes evoked by activation of the cerebellar parallel fibers (PFs). The PFs were stimulated (25-150 microA, 30 Hz) in halothane-anesthetized rats equipped with a cranial window. The changes in arteriolar and venular diameter produced by PF stimulation were measured with the use of a videomicroscopy system. Cerebellar blood flow (BFcrb) was monitored by laser Doppler flowmetry and the field potentials evoked by PF stimulation were recorded with the use of microelectrodes. PF stimulation increased the diameter of local arterioles (+26 +/- 1%, mean +/- SE) in the activated folium (n = 10, P < 0.05). The vasodilation was greatest in smaller arterioles (16.5 +/- 0.8 microm), was graded with the intensity of stimulation, and was less marked than the vasodilation produced by hypercapnia in comparably sized vessels (+58 +/- 5%, CO2 pressure = 50-60 mmHg, n = 8). In addition, the vasodilation was greatest along the horizontal beam of activated PFs and was reduced in arterioles located away from the stimulated site in a rostrocaudal direction. The increases in vascular diameter were associated with increases in BFcrb in the activated area (+55 +/- 4%, n = 5). PF stimulation increased vascular diameter (+10 +/- 0.5%, n = 10) also in larger arterioles (30-40 microm) located in the folium adjacent to that in which the PFs were stimulated. Higher-order branches of these arterioles supplied the activated area. No field potentials were evoked by PF stimulation in the area where these upstream vessels were located. The data suggest that increased synaptic activity in the PF system produces a "local" hemodynamic response mediated by synaptic release of vasoactive agents and a "remote" response that is propagated to upstream arterioles from vessels residing in the activated folium. These propagated vascular responses are important in the coordination of segmental vascular resistance that is required to increase flow effectively during functional brain hyperemia.

Tuberculosis (TB) remains one of the leading causes of mortality and morbidity worldwide, with approximately one-third of the world's population infected with latent TB. This is further aggravated by HIV coinfection and the emergence of multidrug- and extensively drug-resistant (MDR and XDR, respectively) TB; hence the quest for highly effective antitubercular drugs with novel modes of action is imperative. We report herein the discovery of an indole-2-carboxamide analogue, 3, as a highly potent antitubercular agent, and the subsequent chemical modifications aimed at establishing a preliminary body of structure-activity relationships (SARs). These efforts led to the identification of three molecules (12-14) possessing an exceptional activity in the low nanomolar range against actively replicating Mycobacterium tuberculosis , with minimum inhibitory concentration (MIC) values lower than those of the most prominent antitubercular agents currently in use. These compounds were also devoid of apparent toxicity to Vero cells. Importantly, compound 12 was found to be active against the tested XDR-TB strains and orally active in the serum inhibition titration assay.

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Development of effective therapeutic strategies to eliminate Cancer stem cells (CSCs), which play a major role in drug resistance and disease recurrence, is critical to improve cancer treatment outcomes. Our study showed that glioblastoma stem cells (GSCs) exhibited low mitochondrial respiration and high glycolytic activity. These GSCs were highly resistant to standard drugs such as carmustine and temozolomide, but showed high sensitivity to a glycolytic inhibitor 3-bromo-2-oxopropionate-1-propyl ester (3-BrOP), especially under hypoxic conditions. We further showed that combination of 3-BrOP with carmustine but not with temozolomide achieved a striking synergistic effect and effectively killed GSCs through a rapid depletion of cellular ATP and inhibition of carmustine-induced DNA repair. This drug combination significantly impaired the sphere formation ability of GSCs in vitro and tumor formation in vivo, leading to increase in the overall survival of mice bearing orthotopic inoculation of GSCs. Further mechanistic study showed that 3-BrOP and carmustine inhibited glyceraldehyde-3-phosphate dehydrogenase and caused a severe energy crisis in GSCs. Our study suggests that GSCs are highly glycolytic and that certain drug combination strategies can be used to effectively overcome their drug resistance based on their metabolic properties.

We have investigated how the nonclassical receptive field (nCRF) affects dynamic orientation selectivity of cells in the primary visual cortex (V1) in anaesthetized and paralysed cats using the reverse correlation method. We found that tuning to the orientation of the test stimulus depends on the size of the stimulation area. A significant sharpening of orientation tuning was induced by nCRF stimulation, with the magnitude of the effect increasing with the size of stimulation. The effect of the nCRF on the temporal dynamics of orientation tuning was also investigated by examining the tuning over a range of delays from stimulus onset. We found small but detectable changes in both the preferred orientation and the bandwidth of tuning over time when the classical receptive field (CRF) was stimulated alone. Stimulation in nCRF significantly increased the magnitude of these temporal changes. Thus, nCRF stimulation not only enhances the overall orientation selectivity, but also enriches the temporal dynamics of cortical neurones, which may increase the computational power of the visual cortex in information processing.

Human tumors, including gastric cancer, frequently express high levels of epidermal growth factor receptors (EGFRs), which are associated with a poor prognosis. Targeted delivery of anticancer drugs to cancerous tissues shows potential in sparing unaffected tissues. However, it has been a major challenge for drug penetration in solid tumor tissues due to the complicated tumor microenvironment. We have constructed a recombinant protein named anti-EGFR-iRGD consisting of an anti-EGFR VHH (the variable domain from the heavy chain of the antibody) fused to iRGD, a tumor-specific binding peptide with high permeability. Anti-EGFR-iRGD, which targets EGFR and αvβ3, spreads extensively throughout both the multicellular spheroids and the tumor mass. The recombinant protein anti-EGFR-iRGD also exhibited antitumor activity in tumor cell lines, multicellular spheroids, and mice. Moreover, anti-EGFR-iRGD could improve anticancer drugs, such as doxorubicin (DOX), bevacizumab, nanoparticle permeability and efficacy in multicellular spheroids. This study draws attention to the importance of iRGD peptide in the therapeutic approach of anti-EGFR-iRGD. As a consequence, anti-EGFR-iRGD could be a drug candidate for cancer treatment and a useful adjunct of other anticancer drugs.