Efficacy of lorlatinib in lung carcinomas carrying distinct ALK translocation variants: The results of a single-center study

BackgroundLorlatinib is a novel potent ALK inhibitor, with only a few studies reporting the results of its clinical use.MethodsThis study describes the outcomes of lorlatinib treatment for 35 non-small cell lung cancer patients with ALK rearrangements, who had 2 (n = 5), 1 (n = 26) or none (n = 4) prior tyrosine kinase inhibitors and received lorlatinib mainly within the compassionate use program.ResultsObjective tumor response (OR) and disease control (DC) were registered in 15/35 (43%) and 33/35 (94%) patients, respectively; brain metastases were particularly responsive to the treatment (OR: 22/27 (81%); DC: 27/27 (100%)). Median progression free survival (PFS) was estimated to be 21.8 months, and median overall survival (OS) approached to 70.1 months. Only 4 out of 35 patients experienced no adverse effects; two of them were the only subjects who had no clinical benefit from lorlatinib. PFS and OS in the no-adverse-events lorlatinib users were strikingly lower as compared to the remaining patients (1.1 months vs. 23.7 months and 10.5 months vs. not reached, respectively; p < 0.0001 for both comparisons). ALK translocation variants were known for 28 patients; there was no statistical difference between patients with V.1 and V.3 rearrangements with regard to the OS or PFS.ConclusionUse of lorlatinib results in excellent disease outcomes, however caution must be taken for patients experiencing no adverse effects from this drug.     

Mesozooplankton biomass,abundance and community composition in the Ross Sea and the Pacific sector of the Southern Ocean

Polar Biology - Due in part to its remote location, the zooplankton of the Ross Sea and adjacent waters is poorly characterized. Very little depth-integrated information exists for this region,...     

Statilia maculata (Thunberg, 1784) – the first invasive praying mantis (Mantodea,Mantidae) in the fauna of Russia

Summary

Recent years have seen an increasing number of alien praying mantis species being introduced and establishing populations across Europe. Here we add to this count, reporting a stable and spreading population of an Asian species, Statilia maculata (Thunberg, 1784), in Krasnodar Krai of Southern Russia. This is the first introduced praying mantis species in the Russian fauna and the first representative of the genus Statilia Stål, 1877 in Europe. We review what is known about biology of this species and provide diagnostic characters to distinguish nymphs, adults and oothecae from native and introduced European species of praying mantis. Our attempts at captive breeding identify humidity as one of the most important factors limiting possible spread of S. maculata. Invasion to neighbouring territories and other countries with a humid subtropical climate remains a very real possibility with an unknown outcome for local ecosystems.     

Time-series analysis of hydrological and biological variability on the Prince Edward Island (Southern Ocean) shelf

Eulerian time-series were completed at three sites on the south eastern shelf of the Sub-Antarctic Prince Edward Islands (PEI), from 9 to 27 April 2000, to investigate the spatial and temporal variability of mesozooplankton communities in relation to on-shelf hydrodynamics. Surface temperature and phytoplankton biomass were recorded daily at all three sites, while two Bongo net tows and vertical temperature profiles were collected daily at two sites. Contrary to predictions of on-shelf water retention at low ambient current velocities, cross-correlation analysis identified a northward advection of ∼8.23 cm s⁻¹ over the study area. Day to day changes in both physical and biological parameters were associated with cross-shelf advection. However, sea temperature had a narrow range of 6.2–7.4°C, while average between sample Bray–Curtis similarity in zooplankton communities was high, exceeding 75%. The relatively consistent average sample biomass amounted to ∼494 tonnes dry weight of mesozooplankton per day being advected onto the south eastern sector of the PEI shelf. We hypothesise that the observed stability of both physical and biological parameters was due to the Sub-Antarctic Front, with its high volume transport and steep physical gradients, being far to the north of the islands. Spatial and temporal variability of hydrodynamics on the PEI shelf, and particularly its relationship to shifting frontal positions, is highlighted as a future research area necessary to quantify the gross delivery of allochthonous biomass to the PEI ecosystem.     

microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration

The aggregation of Aβ42-peptides and the formation of drusen in age-related macular degeneration (AMD) are due in part to the inability of homeostatic phagocytic mechanisms to clear self-aggregating Aβ42-peptides from the extracellular space. The triggering receptor expressed in myeloid/microglial cells-2 (TREM2), a trans-membrane-spanning, sensor-receptor of the immune-globulin/lectin-like gene superfamily is a critical component of Aβ42-peptide clearance. Here we report a significant deficit in TREM2 in AMD retina and in cytokine- or oxidatively-stressed microglial (MG) cells. RT-PCR, miRNA-array, LED-Northern and Western blot studies indicated up-regulation of a microglial-enriched NF-кB-sensitive miRNA-34a coupled to a down-regulation of TREM2 in the same samples. Bioinformatics/transfection-luciferase reporter assays indicated that miRNA-34a targets the 299 nucleotide TREM2-mRNA-3’UTR, resulting in TREM2 down-regulation. C8B4-microglial cells challenged with Aβ42 were able to phagocytose these peptides, while miRNA-34a down-regulated both TREM2 and the ability of microglial-cells to phagocytose. Treatment of TNFα-stressed MG cells with phenyl-butyl nitrone (PBN), caffeic-acid phenethyl ester (CAPE), the NF-B-inhibitor/resveratrol analog CAY10512 or curcumin abrogated these responses. Incubation of anti-miRNA-34a (AM-34a) normalized miRNA-34a abundance and restored TREM2 back to homeostatic levels. These data support five novel observations: (i) that a ROS- and NF-B-sensitive, miRNA-34a-mediated modulation of TREM2 may in part regulate the phagocytic response; (ii) that gene products encoded on two different chromosomes (miRNA-34a at chr1q36.22 and TREM2 at chr6p21.1) orchestrate a phagocytic-Aβ42-peptide clearance-system; (iii) that this NF-kB-mediated-miRNA-34a-TREM2 mechanism is inducible from outside of the cell; (iv) that when operating normally, this pathway can clear Aβ42 peptide monomers from the extracellular medium; and (v) that anti-NF-kB and/or anti-miRNA (AM)-based therapeutic strategies may be useful against deficits in TREM-2 receptor-based-sensing and -phagocytic signaling that promote pathogenic amyloidogenesis.     

Spectroscopy on the wing: Naturally inspired SERS substrates for biochemical analysis

We show that naturally occurring chitinous nanostructures found on the wings of the Graphium butterfly can be used as substrates for surface‐enhanced Raman scattering when coated with a thin film of gold or silver. The substrates were found to exhibit excellent biocompatibility and sensitivity, making them ideal for protein assaying. An assay using avidin/biotin binding showed that the substrates could be used to quantify protein binding directly from changes in the surface‐enhanced Raman scattering (SERS) spectra and were sensitive over a concentration range comparable with a typical enzyme‐linked immunosorbent assays (ELISA) assay. A biomimetic version of the wing nanostructures produced using a highly reproducible, large‐scale fabrication process, yielded comparable enhancement factors and biocompatibility. The excellent biocompatibility of the wings and biomimetic substrates is unparalleled by other lithographically produced substrates, and this could pave the way for widespread application of ultrasensitive SERS‐based bioassays. (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

The first representative Pliocene assemblages of passerine birds in Asia (Northern Mongolia and Russian Transbaikalia)

Passerine birds from two late Pliocene localities, Shaamar in northern Mongolia and Beregovaya in Transbaikalia (East Russia), represent the first known Neogene fossil assemblages of perching birds from Asia. A total of 11 families and 15 taxa are recognized, including a new genus and species of bunting, Pliocalcarius orkhonensis, apparently related to the Longspurs, and new species within the genera Hirundo and Rhodospiza, which are described. The avifauna is composed of open land and bush dwellers; it contains a few arid species, representing the oldest finds of the corresponding genera or lineages. This may indicate that the living Asian arid avian complex originated in Central Asia in the Neogene. Several genera (Rhodospiza, Paradoxornis) are documented in this paper for the first time in pre-Pleistocene deposits. Report of Calcarius is the first pre-Holocene evidence of the occurrence of this genus in Asia, which together with the remains of Synaptomys lemmings at Shaamar, illustrates faunal interchanges between North America and Asia in the Pliocene.     

Properties of recombinant Rhizomucor miehei lipase with amino acid substitutions of Phe94 in the substrate binding domain

The chain length specificity of Rhizomucor miehei lipase was altered by substituting Phe94 in the protein groove which is responsible for accommodating the acyl chain of the substrate. Three recombinant enzymes, Phe94Arg, Phe94Glu and Phe94Gln, were expressed in Pichia pastoris, purified and their ability to hydrolyse p-nitrophenyl esters and triacylglycerols of different chain length was studied.     

Prediction of muscle fiber composition using multiple repetition testing

Direct determination of muscle fiber composition is invasive and expensive, with indirect methods also requiring specialist resources and expertise. Performing resistance exercises at 80% 1RM is suggested as a means of indirectly estimating muscle fiber composition, though this hypothesis has never been validated against a direct method. The aim of the study was to investigate the relationship between the number of completed repetitions at 80% 1RM of back squat exercise and muscle fiber composition. Thirty recreationally active participants’ (10 females, 20 males) 1RM back squat load was determined, before the number of consecutive repetitions at 80% 1RM was recorded. The relationship between the number of repetitions and the percentage of fast-twitch fibers from vastus lateralis was investigated. The number of completed repetitions ranged from 5 to 15 and was independent of sex, age, 1RM, training frequency, training type, training experience, BMI or muscle fiber cross-sectional area. The percentage of fast-twitch muscle fibers was inversely correlated with the number of repetitions completed (r = –0.38, P = 0.039). Participants achieving 5 to 8 repetitions (n = 10) had significantly more fast-twitch muscle fibers (57.5 ± 9.5 vs 44.4 ± 11.9%, P = 0.013) than those achieving 11–15 repetitions (n = 11). The remaining participants achieved 9 or 10 repetitions (n = 9) and on average had equal proportion of fast- and slow-twitch muscle fibers. In conclusion, the number of completed repetitions at 80% of 1RM is moderately correlated with muscle fiber composition.