Potential Treatment Options After First‐Line Chemotherapy for Advanced NSCLC: Maintenance Treatment or Early Second‐Line?

Although substantial progress has been made in the therapeutic options currently available for patients with advanced non‐small cell lung cancer (NSCLC), the overall survival profile remains poor for most patients. One of the strategies currently under investigation with the aim of prolonging survival in NSCLC patients is maintenance treatment with either a chemotherapeutic agent or a molecularly targeted agent after first‐line chemotherapy. Moreover, this can consist of drugs included in the induction regimen or other noncrossresistant agents. With the currently available data, maintenance treatment with a different noncrossresistant agent (i.e., an early second‐line treatment) is perhaps the most promising strategy. The drug chosen for the early second‐line treatment should be a well‐tolerated agent, considering that patients have just completed a particularly toxic platinum‐based chemotherapy. Extending treatment with targeted agents rather than chemotherapy can provide longer progression‐free and overall survival times without increasing toxicity. However, at the moment, only progression‐free survival has been shown to be consistently superior with maintenance approaches; the evaluation of survival benefits is warranted before defining this strategy as a possible treatment option. Further studies are warranted to establish the role of maintenance chemotherapy in patients with advanced NSCLC.     

Structure-function analysis of a lupus anti-DNA autoantibody: central role of the heavy chain complementarity-determining region 3 Arg in binding of double- and single-stranded DNA

To determine the contribution of the somatic point mutations and that of the complementarity-determining region (CDR)3 Arg to DNA binding, we engineered the germline V(H) and V(kappa) gene revertant and site-mutagenized the CDR3 Arg residues of the mutated and "antigen-selected" mAb 412.67. This anti-DNA autoantibody was derived from B-1 cells of a lupus patient and bore two H-CDR3 Arg, Arg105 and Arg107, encoded by N segment additions, and one kappa-CDR3 Arg, Arg97, resulting from a point mutation (Kasaian et al. 1994. J. Immunol. 152: 3137-3151; Kasaian et al. 1995. Ann. N.Y Acad. Sci. 764: 410-423). The germ-line revertant bound double-stranded (ds) DNA and single-stranded (ss) DNA as effectively as its wild-type counterpart (relative avidity: 6.4x10(-7) and 9.9x10(-9) vs. 6.7x10(-7) and 9.1 x10(-9) g/microl), raising the possibility that an antigen other than DNA was responsible for the selection of the mAb 412.67 V(H) and V(kappa) point mutations. H-CDR3 Arg105 and Arg107 were both required for dsDNA binding, but either Arg105 or Arg107 was sufficient for ssDNA binding. The central role of Arg105 and Arg107 in DNA binding reflected their solvent-exposed orientation at the apex of the H-CDR3 main loop. Consistent with its inward orientation afar from the antigen-binding surface, the kappa-CDR3 Arg97 played no role in either dsDNA or ssDNA binding.     

Peak volume history and peak pressure-volume curve pressures independently affect the shape of the pressure-volume curve of the respiratory system

OBJECTIVE: To determine the specific effect of peak volume history pressure on the inflation limb of the pressure-volume curve and peak pressure-volume curve pressure on the deflation limb of the pressure-volume curve. DESIGN: Prospective assessment of pressure-volume curves in saline, lung lavage injured sheep. SETTING: Large animal laboratory of a university-affiliated hospital. SUBJECTS: Eight female Dorset sheep. INTERVENTIONS:: The effect of two volume history pressures (40 and 60 cm H2O) and three pressure-volume curve peak pressures (40, 50, and 60 cm H2O) were randomly compared. MEASUREMENTS AND MAIN RESULTS: Peak volume history pressure affected the inflation curve beyond the lower inflection point but did not affect the inflection point (Pflex). Peak pressure-volume curve pressure affected the deflation curve. Increased peak volume history pressure increased inflation compliance (p <.05). Increased peak pressure-volume curve pressure increased the point of maximum compliance change on the deflation limb and deflation compliance and decreased compliance between peak pressure and the point of maximum curvature on the deflation limb (p <.05). CONCLUSION: Peak volume history pressure must be considered when interpreting the inflation limb of the pressure-volume curve of the respiratory system beyond the inflection point. The peak pressure achieved during the pressure-volume curve is important during interpretation of deflation compliance and the point of maximum compliance change on the deflation limb.     

Evaluation of a semiautomatic 3D fusion technique applied to molecular imaging and MRI brain/frame volume data sets

A generally applicable 3D fusion method was evaluated using molecular imaging and MRI volumetric data sets from 15 brain tumor patients with stereotactic frames attached to their skull. Point pairs, placed on the frame only, were chosen, polynomial warping coefficients were generated to map voxels from one coordinate space to the other. The MRI frame was considered the reference structure and the standard for correct registration. An ANOVA test (p > 0.05) confirmed the point pair choice to be consistent. The 95% confidence interval for the t-test showed the measured distance difference between the registered volumes was within one MRI voxel. A further experiment was conducted to independently evaluate the brain registration based on testing for consistency of randomly selected interior/exterior points. A t-test result (p < 0.05)=" showed=" that=" the=" consistency=" (i.e.,=" both=" interior=" or=" both=" exterior)=" before=" and=" after=" volume=" registration=" were=" significantly=" different.=" this=" fusion=" method=" may=" be=" a=" viable=" alternative=" when=" other=" methods=">     

Brain mechanisms for emotional influences on perception and attention: What is magic and what is not

The rapid and efficient selection of emotionally salient or goal-relevant stimuli in the environment is crucial for flexible and adaptive behaviors. Converging data from neuroscience and psychology have accrued during the last decade to identify brain systems involved in emotion processing, selective attention, and their interaction, which together act to extract the emotional or motivational value of sensory events and respond appropriately. An important hub in these systems is the amygdala, which may not only monitor the emotional value of stimuli, but also readily project to several other areas and send feedback to sensory pathways (including striate and extrastriate visual cortex). This system generates saliency signals that modulate perceptual, motor, as well as memory processes, and thus in turn regulate behavior appropriately. Here, we review our current views on the function and properties of these brain systems, with an emphasis on their involvement in the rapid and/or preferential processing of threat-relevant stimuli. We suggest that emotion signals may enhance processing efficiency and competitive strength of emotionally significant events through gain control mechanisms similar to those of other (e.g. endogenous) attentional systems, but mediated by distinct neural mechanisms in amygdala and interconnected prefrontal areas. Alterations in these brain mechanisms might be associated with psychopathological conditions, such as anxiety or phobia. We conclude that attention selection and awareness are determined by multiple attention gain control systems that may operate in parallel and use different sensory cues but act on a common perceptual pathway.