Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma

BACKGROUND: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy. METHODS: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks (H3K14/9 ac, H3K27ac). We correlated significant differences in histone acetylation with gene expression in HDACi-resistant/sensitive CTCL. We extended these findings in additional CTCL patient cohorts (RNA-seq, microarray) and using ELISA in matched CTCL patient plasma. FINDINGS: Resistant CTCL exhibited high levels of histone acetylation, which correlated with increased expression of 338 genes (FDR \u3c 0·05), including some novel to CTCL: BIRC5 (anti-apoptotic); RRM2 (cell cycle); TXNDC5, GSTM1 (redox); and CXCR4, LAIR2 (cell adhesion/migration). Several of these, including LAIR2, were elevated pre-treatment in HDACi-resistant CTCL. In CTCL patient plasma (n = 6), LAIR2 protein was also elevated (p \u3c 0·01) compared to controls. INTERPRETATION: This study is the first to connect genome-wide differences in chromatin acetylation and gene expression to HDACi-resistance in primary CTCL. Our results identify novel markers with high pre-treatment expression, such as LAIR2, as potential prognostic and/or predictors of HDACi-resistance in CTCL. FUNDING: NIH:CA156690, CA188286; NCATS: WU-ICTS UL1 TR000448; Siteman Cancer Center: CA091842

A new and unusual LBV-like outburst from a Wolf–Rayet star in the outskirts of M33

MCA-1B (also called UIT003) is a luminous hot star in the western outskirts of M33, classified over 20 yr ago with a spectral type of Ofpe/WN9 and identified then as a candidate luminous blue variable (LBV). Palomar Transient Factory data reveal that this star brightened in 2010, with a light curve resembling that of the classic LBV star AF And in M31. Other Ofpe/WN9 stars have erupted as LBVs, but MCA-1B was unusual because it remained hot. It showed a WN-type spectrum throughout its eruption, whereas LBVs usually get much cooler. MCA-1B showed an almost four-fold increase in bolometric luminosity and a doubling of its radius, but its temperature stayed ≳29 kK. As it faded, it shifted to even hotter temperatures, exhibiting a WN7/WN8-type spectrum, and doubling its wind speed. MCA-1B is reminiscent of some supernova impostors, and its location resembles the isolated environment of SN 2009ip. It is most similar to HD 5980 (in the Small Magellanic Cloud) and GR 290 (also in M33). Whereas these two LBVs exhibited B-type spectra in eruption, MCA-1B is the first clear case where a Wolf–Rayet (WR) spectrum persisted at all times. Together, MCA-1B, HD 5980, and GR 290 constitute a class of WN-type LBVs, distinct from S Doradus LBVs. They are most interesting in the context of LBVs at low metallicity, a possible post-LBV/WR transition in binaries, and as likely Type Ibn supernova progenitors

Weight Status as a Mediator of the Association Between Preschool Extraversion and Adolescent Restrained Eating

Objectives To determine the longitudinal association between preschool extraversion and weight/dieting outcomes in adolescence. Methods Children (N = 180) were recruited as part of a longitudinal study, with child temperament assessed in preschool (age 5.25 years), weight assessed in 2nd grade and early adolescence, and eating outcomes assessed in early adolescence (mean age = 12.02 years). Results Preschoolers high in extraversion were significantly more likely to have higher body mass index z-scores (zBMI) and more restrained eating behaviors in adolescence. zBMI was found to mediate the relationship between extraversion and restrained eating, such that children with high levels of extraversion were more likely to have higher zBMI in adolescence and, owing to this higher weight status, to engage in more restrained eating. Conclusions Temperament is an important predictor of later maladaptive weight/dieting outcomes in adolescence, making it a potentially important early factor to consider in weight management interventions

SN2012ab: A Peculiar Type IIn Supernova with Aspherical Circumstellar Material

We present photometry, spectra, and spectropolarimetry of supernova (SN) 2012ab, mostly obtained over the course of $\sim 300$ days after discovery. SN 2012ab was a Type IIn (SN IIn) event discovered near the nucleus of spiral galaxy 2MASXJ12224762+0536247. While its light curve resembles that of SN 1998S, its spectral evolution does not. We see indications of CSM interaction in the strong intermediate-width emission features, the high luminosity (peak at absolute magnitude $M=-19.5$), and the lack of broad absorption features in the spectrum. The H$\alpha$ emission undergoes a peculiar transition. At early times it shows a broad blue emission wing out to $-14{,}000$ km $\mathrm{s^{-1}}$ and a truncated red wing. Then at late times ($>$ 100$\,$days) it shows a truncated blue wing and a very broad red emission wing out to roughly $+20{,}000$ km $\mathrm{s^{-1}}$. This late-time broad red wing probably arises in the reverse shock. Spectra also show an asymmetric intermediate-width H$\alpha$ component with stronger emission on the red side at late times. The evolution of the asymmetric profiles requires a density structure in the distant CSM that is highly aspherical. Our spectropolarimetric data also suggest asphericity with a strong continuum polarization of $\sim 1-3$% and depolarization in the H$\alpha$ line, indicating asphericity in the CSM at a level comparable to that in other SNe IIn. We estimate a mass-loss rate of $\dot{M} = 0.050\, {\rm M}_{\odot}\,\mathrm{yr^{-1}}$ for $v_{\rm pre} = 100$$\,$km$\,$$\mathrm{s^{-1}}$ extending back at least 75$\,$yr prior to the SN. The strong departure from axisymmetry in the CSM of SN 2012ab may suggest that the progenitor was an eccentric binary system undergoing eruptive mass loss.Comment: 18 pages, 12 figure

Executive Control Goes to School: Implications of Preschool Executive Performance for Observed Elementary Classroom Learning Engagement

The transition to elementary school is accompanied by increasing demands for children to regulate their attention and behavior within the classroom setting. Executive control (EC) may be critical for meeting these demands; however, few studies have rigorously examined the association between EC and observed classroom behavior. This study examined EC in preschool (age 5 years, 3 months) as a predictor of classroom learning engagement behaviors in first grade, using a battery of performance-based EC tasks and live classroom observations in a longitudinal sample of 313 children. Multilevel modeling results indicated that stronger EC predicted more focused engagement and fewer task management and competing responses, controlling for socioeconomic status, child sex, and age at observations. Results suggest that early EC may support subsequent classroom engagement behaviors that are critical for successful transition to elementary school and long-term learning trajectories

Detection and quantitation of HPV in genital and oral tissues and fluids by real time PCR

<p>Abstract</p> <p>Background</p> <p>Human papillomaviruses (HPVs) remain a serious world health problem due to their association with anogenital/oral cancers and warts. While over 100 HPV types have been identified, a subset is associated with malignancy. HPV16 and 18 are the most prevalent oncogenic types, while HPV6 and 11 are most commonly responsible for anogenital warts. While other quantitative PCR (qPCR) assays detect oncogenic HPV, there is no single tube assay distinguishing the most frequent oncogenic types and the most common types found in warts.</p> <p>Results</p> <p>A Sybr Green-based qPCR assay was developed utilizing degenerate primers to the highly conserved HPV E1 theoretically detecting any HPV type. A single tube multiplex qPCR assay was also developed using type-specific primer pairs and TaqMan probes that allowed for detection and quantitation of HPV6,11,16,18. Each HPV type was detected over a range from 2 × 10¹to 2 × 10⁶copies/reaction providing a reliable method of quantitating type-specific HPV in 140 anogenital/cutaneous/oral benign and malignant specimens. 35 oncogenic and low risk alpha genus HPV types were detected. Concordance was detected in previously typed specimens. Comparisons to the gold standard detected an overall sensitivity of 89% (95% CI: 77% - 96%) and specificity of 90% (95%CI: 52% - 98%).</p> <p>Conclusion</p> <p>There was good agreement between the ability of the qPCR assays described here to identify HPV types in malignancies previously typed using standard methods. These novel qPCR assays will allow rapid detection and quantitation of HPVs to assess their role in viral pathogenesis.</p

An ALMA Survey of H₂CO in Protoplanetary Disks

H₂CO is one of the most abundant organic molecules in protoplanetary disks and can serve as a precursor to more complex organic chemistry. We present an Atacama Large Millimeter/submillimeter Array survey of H₂CO toward 15 disks covering a range of stellar spectral types, stellar ages, and dust continuum morphologies. H₂CO is detected toward 13 disks and tentatively detected toward a fourteenth. We find both centrally peaked and centrally depressed emission morphologies, and half of the disks show ring-like structures at or beyond expected CO snowline locations. Together these morphologies suggest that H₂CO in disks is commonly produced through both gas-phase and CO-ice-regulated grain-surface chemistry. We extract disk-averaged and azimuthally-averaged H₂CO excitation temperatures and column densities for four disks with multiple H₂CO line detections. The temperatures are between 20–50 K, with the exception of colder temperatures in the DM Tau disk. These temperatures suggest that H₂CO emission in disks generally emerges from the warm molecular layer, with some contributions from the colder midplane. Applying the same H₂CO excitation temperatures to all disks in the survey, we find that H₂CO column densities span almost three orders of magnitude (~5 × 10¹¹–5 × 10¹⁴ cm⁻²). The column densities appear uncorrelated with disk size and stellar age, but Herbig Ae disks may have less H₂CO compared to T Tauri disks, possibly because of less CO freeze-out. More H₂CO observations toward Herbig Ae disks are needed to confirm this tentative trend, and to better constrain under which disk conditions H₂CO and other oxygen-bearing organics efficiently form during planet formation

Patient and Provider Perspectives on How Trust Influences Maternal Vaccine Acceptance Among Pregnant Women in Kenya

Background Pregnant women and newborns are at high risk for infectious diseases. Altered immunity status during pregnancy and challenges fully vaccinating newborns contribute to this medical reality. Maternal immunization is a strategy to protect pregnant women and their newborns. This study aimed to find out how patient-provider relationships affect maternal vaccine uptake, particularly in the context of a lower middle- income country where limited research in this area exists. Methods We conducted semi-structured, in-depth narrative interviews of both providers and pregnant women from four sites in Kenya: Siaya, Nairobi, Mombasa, and Marsabit. Interviews were conducted in either English or one of the local regional languages. Results We found that patient trust in health care providers (HCPs) is integral to vaccine acceptance among pregnant women in Kenya. The HCP-patient relationship is a fiduciary one, whereby the patients’ trusts is primarily rooted in the provider’s social position as a person who is highly educated in matters of health. Furthermore, patient health education and provider attitudes are crucial for reinstating and fostering that trust, especially in cases where trust was impeded by rumors, community myths and misperceptions, and religious and cultural factors. Conclusion Patient trust in providers is a strong facilitator contributing to vaccine acceptance among pregnant women in Kenya. To maintain and increase immunization trust, providers have a critical role in cultivating a positive environment that allows for favorable interactions and patient health education. This includes educating providers on maternal immunizations and enhancing knowledge of effective risk communication tactics in clinical encounters

Diet and Habitat of Mountain Woodland Caribou Inferred from Dung Preserved in 5000-year-old Alpine Ice in the Selwyn Mountains, Northwest Territories, Canada

Alpine ice patches are unique repositories of cryogenically preserved archaeological artefacts and biological specimens. Recent melting of ice in the Selwyn Mountains, Northwest Territories, Canada, has exposed layers of dung accumulated during seasonal use of ice patches by mountain woodland caribou of the ancestral Redstone population over the past ca. 5250 years. Although attempts to isolate the DNA of known caribou parasites were unsuccessful, the dung has yielded numerous well-preserved and diverse plant remains and palynomorphs. Plant remains preserved in dung suggest that the ancestral Redstone caribou population foraged on a variety of lichens (30%), bryophytes and lycopods (26.7%), shrubs (21.6%), grasses (10.5%), sedges (7.8%), and forbs (3.4%) during summer use of alpine ice. Dung palynomorph assemblages depict a mosaic of plant communities growing in the caribou’s summer habitat, including downslope boreal components and upslope floristically diverse herbaceous communities. Pollen and spore content of dung is only broadly similar to late Holocene assemblages preserved in lake sediments and peat in the study region, and differences are likely due to the influence of local vegetation and animal forage behaviour. The 5000-year legacy of summer use of alpine ice patches by mountain woodland caribou suggests that these small, long-lived features may be important for the health of caribou populations in the Selwyn/Mackenzie Mountain range.Les névés des régions alpines constituent des réserves uniques d’artefacts archéologiques et de spécimens biologiques préservés cryogéniquement. La fonte récente des glaces de la chaîne de Selwyn, dans les Territoires du Nord-Ouest, au Canada, a mis au jour des couches de déjections animales qui ont été accumulées lors de l’usage saisonnier des névés par le caribou des bois des montagnes de la population ancestrale de Redstone au cours des quelques 5 250 dernières années. Bien que les tentatives visant à isoler l’ADN des parasites connus du caribou aient échoué, les déjections ont permis de repérer de nombreux restes et palynomorphes de végétaux bien préservés et variés. Les restes de végétaux qui ont été conservés dans les déjections animales laissent croire que la population de caribou ancestrale de Redstone s’alimentait d’une variété de lichens (30 %), de bryophytes et de lycopodes (26,7 %), d’arbrisseaux (21,6 %), de graminées (10,5 %), de foin plat (7,8 %) et de plantes herbacées non graminoïdes (3,4 %) lorsqu’ils utilisaient la glace alpine pendant l’été. Les assemblages de palynomorphes provenant des déjections laissent entrevoir la croissance d’une mosaïque de peuplements végétaux au sein de l’habitat d’été du caribou, ce qui comprend des composantes boréales en pentes descendantes et des peuplements végétaux herbacés floristiquement variés en pentes ascendantes. La teneur en pollen et en spores des déjections animales est seulement largement similaire aux assemblages de l’Holocène tardif préservés dans les sédiments lacustres et dans la tourbe de la région visée par l’étude. Les différences sont vraisemblablement attribuables à l’influence de la végétation locale et au comportement alimentaire des animaux. L’utilisation estivale des névés des régions alpines par le caribou des bois des montagnes ces 5 000 dernières années laisse entrevoir que ces petites caractéristiques longévives pourraient revêtir de l’importance pour la santé des populations de caribou de la chaîne de Selwyn et des monts Mackenzie

PTF11iqb: Cool supergiant mass loss that bridges the gap between Type IIn and normal supernovae

PTF11iqb was initially classified as a TypeIIn event caught very early after explosion. It showed narrow Wolf-Rayet (WR) spectral features on day 2, but the narrow emission weakened quickly and the spectrum morphed to resemble those of Types II-L and II-P. At late times, Halpha emission exhibited a complex, multipeaked profile reminiscent of SN1998S. In terms of spectroscopic evolution, we find that PTF11iqb was a near twin of SN~1998S, although with weaker interaction with circumstellar material (CSM) at early times, and stronger CSM interaction at late times. We interpret the spectral changes as caused by early interaction with asymmetric CSM that is quickly (by day 20) enveloped by the expanding SN ejecta photosphere, but then revealed again after the end of the plateau when the photosphere recedes. The light curve can be matched with a simple model for weak CSM interaction added to the light curve of a normal SN~II-P. This plateau requires that the progenitor had an extended H envelope like a red supergiant, consistent with the slow progenitor wind speed indicated by narrow emission. The cool supergiant progenitor is significant because PTF11iqb showed WR features in its early spectrum --- meaning that the presence of such WR features in an early SN spectrum does not necessarily indicate a WR-like progenitor. [abridged] Overall, PTF11iqb bridges SNe~IIn with weaker pre-SN mass loss seen in SNe II-L and II-P, implying a continuum between these types.Comment: 21 pages, 12 figures, submitted to MNRA