Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331☆.

BACKGROUND: Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC. PATIENTS AND METHODS: CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS). RESULTS: Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus <1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%. CONCLUSION: Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

Growth of aluminum catalyzed AlGaAs nanowires on silicon substrate.

Aluminum catalyzed AlGaAs nanowires were fabricated on Si (111) substrates using metal-organic chemical vapor deposition (MOCVD) technique at a low growth temperature of 450 degrees C. Grown structures were characterized by field emission scanning electron microscope (FE-SEM), energy-dispersive X-ray spectroscopy (EDS) and photoluminescence (PL) techniques. Nanowire clusters were observed all over the substrate. Multiprong root-grown AlGaAs nanowire clusters as well as catalyst particle terminated growth was observed. The growth is explained by Vapor-Solid-Solid (VSS) and Vapor-Solid (VS) growth mechanisms using Al-Si binary phase diagram. EDS and PL measurement confirm the formation of AlGaAs nanowires.

Current status on manufacturing routes to produce metal matrix composites: State-of-the-art.

Owing to its excellent properties, Metal Matrix Composites (MMC) has gained popularity and finds application in aerospace, aircraft, shipbuilding, biomedical, biodegradable implant materials and many more. To serve the industrial needs, the manufactured MMC should have homogenous distribution along with minimum agglomeration of reinforcement particles, defect-free microstructure, superior mechanical, tribological and corrosive properties. The techniques implemented to manufacture MMC highly dominate the aforementioned characteristics. According to the physical state of the matrix, the techniques implemented for manufacturing MMC can be classified under two categories i.e. solid state processing and liquid state process. The present article attempts to review the current status of different manufacturing techniques covered under these two categories. The article elaborates on the working principles of state-of-the-art manufacturing techniques, the effect of dominating process parameters and the resulting characteristic of composites. Apart from this, the article does provide data regarding the range of dominating process parameters and resulting mechanical properties of different grades of manufactured MMC. Using this data along with the comparative study, various industries and academicians will be able to select the appropriate techniques for manufacturing MMC.

Room temperature ferromagnetism in Co-incorporated TiO2 thin films.

Observation of room temperature ferromagnetism (RTFM) in nano-crystalline Co-incorporated titanium dioxide [Ti(1-x)Co(x)O2(x = 0.05)] thin films prepared by spray pyrolysis technique is reported. While only the anatase phase was detected in as-deposited 5 at.% Co-incorporated TiO2 film, a small amount of rutile phase developed following its vacuum annealing. Besides, no X-ray diffraction peak corresponding to cobalt metal could be detected in any of the two films. SQUID magnetometry of both pristine and Co-doped thin films at room temperature elucidated distinct ferromagnetic behavior in 5 at.% Co-incorporated as-deposited film with saturation moment M(s) approximately 5.6 emu/cm3 which got enhanced up to 11.8 emu/cm3 on subsequent vacuum annealing. From the zero field cooled magnetization measurement we confirmed the absence of Co-metal clusters. The electrical resistivity was found to be greater than 108 omega-cm for the films. Based on the magnetic and electrical measurements the origin of RTFM has been attributed to the bound magnetic polaron (BMP) model.

Acquired factor VIII inhibitor in a patient with multiple sclerosis treated with interferon ß-1a.

Acquired Factor VIII inhibitor is a rare acquired clotting disorder which has been seen in the setting of particular medications, autoimmune disease, and malignancy. Reports of this disorder in patients receiving immunomodulatory therapies for multiple sclerosis are rare. We present a case of a 48 year-old woman with likely development of acquired Factor VIII inhibitor in the setting of interferon beta monotherapy for multiple sclerosis, and discuss the pathogenesis of this disorder which involves shifts in helper T cell populations and increased production of immunoglobulins.

Retention of delayed-alternation: effect of selective lesions of sulcus principalis.

Monkeys with bilateral lesions of the anterior, miiddle, or posterior thirds of the principal sulcus, of the periarcuate prefrontal region, or of the inferior parietal lobule were tested for retention of spatial delayed-alternation. Lesions limited to the middle third of sulcus principalis resulted in failure to relearn delayedalternation within 1000 trials; lesions elsewhere had little effect.

Thalamic and cortical afferents differentiate anterior from posterior cingulate cortex in the monkey.

The anterior cingulate cortex receives thalamic afferents mainly from the midline and intralaminar nuclei rather than the anterior thalamic nuclei. In contrast, the posterior cingulate cortex receives afferents primarily from the anterior thalamic nuclei and from extensive cortical areas in the frontal, parietal, and temporal lobes. These contrasting afferents may provide a structural basis for pain-related functions of the anterior cingulate cortex.

Cortical afferents to the entorhinal cortex of the Rhesus monkey.

Although the entorhinal cortex is a major contributor of afferents to the hippocampus and dentate gyrus, knowledge of its own afferents has been vague. Regions of both the frontal and temporal lobes were found to contribute afferents to this region of the brain. These afferents form probable multisynaptic links in pathways connecting the classical sensory areas of the cortex and the limbic system.

Electrophysiological evaluation of extracellular spermine and alkaline pH on synaptic human GABAA receptors.

Polyamines have fundamental roles in brain homeostasis as key modulators of cellular excitability. Several studies have suggested alterations in polyamine metabolism in stress related disorders, suicide, depression, and neurodegeneration, making the pharmacological modulation of polyamines a highly appealing therapeutic strategy. Polyamines are small aliphatic molecules that can modulate cationic channels involved in neuronal excitability. Previous indirect evidence has suggested that polyamines can modulate anionic GABAA receptors (GABAARs), which mediate inhibitory signaling and provide a direct route to reduce hyperexcitability. Here, we attempted to characterize the effect that spermine, the polyamine with the strongest reported effect on GABAARs, has on human postmortem native GABAARs. We microtransplanted human synaptic membranes from the dorsolateral prefrontal cortex of four cases with no history of mental or neurological disorders, and directly recorded spermine effects on ionic GABAARs responses on microtransplanted oocytes. We show that in human synapses, inhibition of GABAARs by spermine was better explained by alkalization of the extracellular solution. Additionally, spermine had no effect on the potentiation of GABA-currents by diazepam, indicating that even if diazepam binding is enhanced by spermine, it does not translate to changes in functional activity. Our results clearly demonstrate that while extracellular spermine does not have direct effects on human native synaptic GABAARs, spermine-mediated shifts of pH inhibit GABAARs. Potential spermine-mediated increase of pH in synapses in vivo may therefore participate in increased neuronal activity observed during physiological and pathological states, and during metabolic alterations that increase the release of spermine to the extracellular milieu.

NICU lactation consultant increases percentage of outborn versus inborn babies receiving human milk.

OBJECTIVE: To determine the effect of a dedicated lactation consultant (LC) on the percentage of neonates receiving any human milk in the neonatal intensive care unit (NICU) and at discharge over time. STUDY DESIGN: Retrospective chart review of three time periods of 3 months each; Time period 1 (before LC hire), Time period 2 (T2; after LC arrival) and Time period 3 (subsequent period after T2). RESULT: Percentage of infants receiving any HM during hospital stay and at discharge increased significantly over time after LC hire and with LC experience. Outborn (OB) infants receiving any HM in the NICU and at discharge increased over time, but there was no significant change for inborn infants, as the proportion receiving any HM remained consistently high over time. CONCLUSION: Addition of a dedicated LC to the NICU increased the percentage of neonates receiving any HM, specifically in the OB population.

Efferent association pathways originating in the caudal prefrontal cortex in the macaque monkey.

The efferent association fibers from the caudal part of the prefrontal cortex to posterior cortical areas course via several pathways: the three components of the superior longitudinal fasciculus (SLF I, SLF II, and SLF III), the arcuate fasciculus (AF), the fronto-occipital fasciculus (FOF), the cingulate fasciculus (CING F), and the extreme capsule (Extm C). Fibers from area 8Av course via FOF and SLF II, merging in the white matter of the inferior parietal lobule (IPL) and terminating in the caudal intraparietal sulcus (IPS). A group of these fibers turns ventrally to terminate in the caudal superior temporal sulcus (STS). Fibers from the rostral part of area 8Ad course via FOF and SLF II to the IPS and IPL and via the AF to the caudal superior temporal gyrus and STS. Some fibers from the rostral part of area 8Ad are conveyed to the medial parieto-occipital region via FOF, to the STS via Extm C, and to the caudal cingulate gyrus via CING F. Fibers from area 8B travel via SLF I to the supplementary motor area and area 31 in the caudal dorsal cingulate region and via the CING F to cingulate areas 24 and 23 and the cingulate motor areas. Fibers from area 9/46d course via SLF I to the superior parietal lobule and medial parieto-occipital region, via SLF II to the IPL. Fibers from area 9/46v travel via SLF III to the rostral IPL and the frontoparietal opercular region and via the CING F to the cingulate gyrus.

Study of Self-Induced Growth of AlGaAs Nanoneedles on Silicon Substrates Using Metal Organic Chemical Vapor Deposition Technique.

A simple catalyst free growth method was used for the growth of single crystalline AlGaAs nanoneedles on Si substrate by metal organic chemical vapor deposition (MOCVD) technique. The growth mechanism of catalyst free growth of nanoneedles was investigated. The effect of growth rate, growth temperature and V/III ratio was studied in detail. The growth of nanoneedles required a careful optimization of the growth conditions. The formation of well-faceted nanoneedles with hexagonal cross-section was found to be influenced by the growth parameters. Based on these studies, the growth mechanism has been explained using nucleation theory. The growth of nanoneedles was believed to proceed via Vapor-Solid (VS) growth mechanism after the initial AlGaAs cluster formation depending on the growth conditions.

Cytoarchitecture and cortical connections of the anterior insula and adjacent frontal motor fields in the rhesus monkey.

The cytoarchitecture and cortical connections of the ventral motor region are investigated using Nissl, and NeuN staining methods and the fluorescent retrograde tract tracing technique in the rhesus monkey. On the basis of gradual laminar differentiation, it is shown that the ventral motor region stems from the ventral proisocortical area (anterior insula and dorsal Sylvian opercular region). The cytoarchitecture of the ventral motor region is shown to progress in three lines, as we have recently shown for the dorsal motor region. Namely, root (anterior insular and dorsal Sylvian opercular area ProM), belt (ventral premotor cortex) and core (precentral motor cortex) lines. This stepwise architectonic organization is supported by the overall patterns of corticocortical connections. Areas in each line are sequentially interconnected (intralineal connections) and all lines are interconnected (interlinear connections). Moreover, root areas, as well as some of the belt areas of the ventral and dorsal trend are interconnected. The ventral motor region is also connected with the ventral somatosensory areas in a topographic manner. The root and belt areas of ventral motor region are connected with paralimbic, multimodal and prefrontal (outer belt) areas. In contrast, the core area has a comparatively more restricted pattern of corticocortical connections. This architectonic and connectional organization is consistent in part, with the functional organization of the ventral motor region as reported in behavioral and neuroimaging studies which include the mediation of facial expression and emotion, communication, phonic articulation, and language in human.

Corticostriatal connections of extrastriate visual areas in rhesus monkeys.

The striatal connections of extrastriate visual areas were examined by the autoradiographic technique in rhesus monkeys. The medial as well as the dorsolateral extrastriate regions project preferentially to dorsal and lateral portions of the head and of the body of the caudate nucleus, as well as to the caudodorsal sector of the putamen. The rostral portion of the annectant gyrus has connections to the caudal sector of the body and to the genu, whereas projections from the caudal portion of the lower bank of the superior temporal sulcus are directed to dorsal and central sectors of the head and the body, to the genu and the tail, as well as to the caudal putamen. The ventrolateral extrastriate region is related mainly to the ventral sector of the body, to the genu and the tail, and to the caudal putamen. In contrast, the striatal projections of the ventromedial extrastriate cortex resemble those of the medial and dorsolateral regions. The caudal inferotemporal cortex is related strongly to the tail of the caudate nucleus and to the ventral putamen. The differential corticostriatal connectivity of the various extrastriate regions may contribute to the specific functional roles of these cortices. Thus, the connections from the dorsomedial, dorsolateral, and ventromedial areas to dorsal portions of the caudate nucleus and of the putamen may serve a visuospatial function. In contrast, the connections from the ventrolateral extrastriate and inferotemporal regions to the tail of the caudate nucleus and to the ventral putamen may have a role in visual object-related processes.

Parietal, temporal, and occipital projections to cortex of the superior temporal sulcus in the rhesus monkey: a retrograde tracer study.

The afferent cortical connections of individual cytoarchitectonic areas within the superior temporal sulcus (STS) of the rhesus monkey were studied by retrograde tracer techniques, including double tracer experiments. Rostral superior temporal polysensory (STP) cortex (area TPO-1) receives input from the rostral superior temporal gyrus (STG), cortex of the circular sulcus, and parahippocampal gyrus (PHG) (areas 35, TF, and TL). Mid-STP cortex (areas TPO-2 and -3) has input from the mid-STG, cortex of the mid-circular sulcus, caudal inferior parietal lobule (IPL), cingulate gyrus (areas, 23, 24, retrosplenial cortex), and mid-PHG (areas 28, TF, TH, and TL). Caudal STP cortex (area TPO-4) has afferent connections with the caudal STG, cortex of the caudal insula and caudal circular sulcus, caudal IPL, lower bank of the intraparietal sulcus (IPS), medial parietal lobe, cingulate gyrus, and mid- and caudal PHG (areas TF, TH, TL; prostriate area). The most rostral cortex of the lower bank of the STS (areas TEa and TEm), a presumed visual association area, receives input from the rostral inferotemporal (IT) region; more caudal portions of areas TEa and TEm have afferent connections with the caudal IT region, PHG, preoccipital gyrus, and cortex of the lower bank of the IPS.

Prelunate, occipitotemporal, and parahippocampal projections to the basis pontis in rhesus monkey.

We used tritiated amino acids to study projections to the basilar pons from prestriate cortices in 18 rhesus monkeys to determine how connectional and functional heterogeneity of these regions are reflected in corticopontine circuitry. Fibers travelled with those from other parasensory associative cortices before terminating in the pontine nuclei. Prelunate projections were derived from area 19 (OA) at the medial convexity (including areas V3 and PO) and from the lateral convexity dorsal to the caudal tip of the Sylvian fissure (including areas DP and the dorsal part of area V4d). Pontine projections also arose from area 19 (OA), and areas TF, TL, and TH in the posterior aspect of the parahippocampal gyrus. No pontine projections arose from the prelunate convexity ventral to the caudal tip of the Sylvian fissure (ventral part of area V4d and area V4v), area TEO, the inferior temporal gyrus, or the lateral ventral temporal region. Terminations in the pons were distributed in the dorsolateral and lateral nuclei, and the lateral part of the peripeduncular nucleus. Medial convexity injections produced more extensive rostrocaudal pontine labeling, as well as terminations in the extreme dorsolateral nucleus and the nucleus reticularis tegmenti pontis. Dorsal prelunate injections had additional terminations in the ventral pontine nucleus. Posterior parahippocampal gyrus injections resulted in discrete label in the lateral and dorsolateral nuclei. Corticopontine projections destined for the cerebellum appear to be derived from extrastriate areas concerned mainly with visual spatial parameters, visual motion, and the peripheral field of vision, but not from areas subserving visual object identification and the central field of vision. Pontine afferents from the posterior parahippocampal gyrus may facilitate a cerebellar contribution to visual spatial memory, particularly when invested with motivational valence.

Prefrontal projections to the mediodorsal nucleus of the thalamus in the rhesus monkey.

The corticothalamic projections to the prefrontal cortex have been shown to be topographically organized. However, the underlying basis for this topography as it relates to the organization of the different architectonically defined areas of the prefrontal cortex has not been systematically studied. In the present investigation we have reassessed the thalamic projections from the different architectonic areas of the prefrontal cortex by using the technique of autoradiography in the rhesus monkey. The results show that the prefronto-mediodorsal projections are organized according to the architectonic differentiation of the prefrontal cortices. Thus architectonically less differentiated medial and orbital prefrontal regions project to the medial sector of the mediodorsal nucleus, the magnocellular subdivision. In contrast, highly differentiated prefrontal area 8 projects to the most lateral sector of the mediodorsal nucleus, the multiformis subdivision. Lateral prefrontal areas with intermediate architectonic features project to the central parvocellular sector of the mediodorsal nucleus. Additionally, these projections also reveal a dorsoventral topography. Thus areas in the medial and dorsolateral cortices project to the dorsal part of the mediodorsal nucleus. In contrast, areas in orbital and ventrolateral cortices project to the ventral part of the mediodorsal nucleus. The topographic organization of the corticothalamic connections described in this study corresponds to the progressive elaboration and differentiation of the architectonic features of the different prefrontal areas. This successive and dichotomous organization of prefrontothalamic connections may provide the basis for the observed differential functions of the prefrontal cortex and the mediodorsal nucleus.

Post-rolandic cortical projections of the superior temporal sulcus in the rhesus monkey.

The efferent connections of different cytoarchitectonic areas of the superior temporal sulcus (STS) in the rhesus monkey with parieto-temporo-occipital cortex were investigated using autoradiographic methods. Four rostral-to-caudal subdivisions of cortex (area TPO) in the upper bank of the STS have distinct projection patterns. Rostral sectors (areas TPO-1 and -2) project to the rostral superior temporal gyrus (areas Ts1, Ts2, and Ts3), insula of the Sylvian fissure, and parahippocampal gyrus (perirhinal and prorhinal cortexes, areas TF, TH, and TL); caudal sectors (TPO-3 and -4) project to the caudal superior temporal gyrus (areas paAlt and Tpt), supratemporal plane (area paAc), circular sulcus of the Sylvian fissure (area reIt), as well as medial paralimbic (areas 23, 24, and retrosplenial cortex) and extrastriate (areas 18 and 19) cortexes. Area TPO-1 does not project to the parietal lobe; area TPO-2 projects to the inferior parietal lobule; area TPO-3 to the lower bank of the intraparietal sulcus (IPS) (area POa); and area TPO-4 to medial parietal cortex (area PGm). Vision-related cortex (area TEa) in the rostral lower bank of the STS sends fibers to the rostral inferotemporal region (areas TE1, -2, and -3) and parahippocampal gyrus (perirhinal cortex, areas TF and TL). Visual zones in the caudal lower bank and depth of the sulcus (area OAa, or MT and FST) project to the caudal inferotemporal region (areas TE3 and TEO), lateral preoccipital region (area V4), and lower bank of the IPS (area POa). A zone in the rostral depth of the STS (area IPa) projects to the rostral inferotemporal region, parahippocampal gyrus, insula of the Sylvian fissure, parietal operculum, and lower rim of the IPS (area PG). STS projections to parieto-temporo-occipital cortex have "feedforward," "feedbackward," and "side-to-side" laminar patterns of termination similar to those of other cortical sensory systems. The differential connectivity supports the cytoarchitectonic parcellation of the STS and suggests functional heterogeneity.