Far infrared mapping of three Galactic star forming regions : W3(OH), S 209 & S 187

Three Galactic star forming regions associated with W3(OH), S209 and S187 have been simultaneously mapped in two trans-IRAS far infrared (FIR) bands centered at ~ 140 and 200 micron using the TIFR 100 cm balloon borne FIR telescope. These maps show extended FIR emission with structures. The HIRES processed IRAS maps of these regions at 12, 25, 60 & 100 micron have also been presented for comparison. Point-like sources have been extracted from the longest waveband TIFR maps and searched for associations in the other five bands. The diffuse emission from these regions have been quantified, which turns out to be a significant fraction of the total emission. The spatial distribution of cold dust (T < 30 K) for two of these sources (W3(OH) & S209), has been determined reliably from the maps in TIFR bands. The dust temperature and optical depth maps show complex morphology. In general the dust around S209 has been found to be warmer than that in W3(OH) region.Comment: Accepted for publication in Journal of Astrophysics and Astronomy (20 pages including 8 figures & 3 tables

Germline Analysis from Tumor–Germline Sequencing Dyads to Identify Clinically Actionable Secondary Findings

To evaluate germline variants in hereditary cancer susceptibility genes among unselected cancer patients undergoing tumor-germline sequencing

Somatic p16INK4a loss accelerates melanomagenesis

Loss of p16INK4a–RB and ARF–p53 tumor suppressor pathways, as well as activation of RAS–RAF signaling, is seen in a majority of human melanomas. Although heterozygous germline mutations of p16INK4a are associated with familial melanoma, most melanomas result from somatic genetic events: often p16INK4a loss and N-RAS or B-RAF mutational activation, with a minority possessing alternative genetic alterations such as activating mutations in K-RAS and/or p53 inactivation. To generate a murine model of melanoma featuring some of these somatic genetic events, we engineered a novel conditional p16INK4a-null allele and combined this allele with a melanocyte-specific, inducible CRE recombinase strain, a conditional p53-null allele and a loxP-stop-loxP activatable oncogenic K-Ras allele. We found potent synergy between melanocyte-specific activation of K-Ras and loss of p16INK4a and/or p53 in melanomagenesis. Mice harboring melanocyte-specific activated K-Ras and loss of p16INK4a and/or p53 developed invasive, unpigmented and nonmetastatic melanomas with short latency and high penetrance. In addition, the capacity of these somatic genetic events to rapidly induce melanomas in adult mice suggests that melanocytes remain susceptible to transformation throughout adulthood

Monitoring Tumorigenesis and Senescence In Vivo with a p16INK4a-Luciferase Model

Monitoring cancer and aging in vivo remains experimentally challenging. Here, we describe a luciferase knockin mouse (p16LUC), which faithfully reports expression of p16INK4a, a tumor suppressor and aging biomarker. Lifelong assessment of luminescence in p16+/LUC mice revealed an exponential increase with aging, which was highly variable in a cohort of contemporaneously housed, syngeneic mice. Expression of p16INK4a with aging did not predict cancer development, suggesting that the accumulation of senescent cells is not a principal determinant of cancer-related death. In 14 of 14 tested tumor models, expression of p16LUC was focally activated by early neoplastic events, enabling visualization of tumors with sensitivity exceeding other imaging modalities. Activation of p16INK4a was noted in the emerging neoplasm and surrounding stromal cells. This work suggests that p16INK4a activation is a characteristic of all emerging cancers, making the p16LUC allele a sensitive, unbiased reporter of neoplastic transformation

Monitoring Tumorigenesis and Senescence In Vivo with a p16INK4a-Luciferase Model

Monitoring cancer and aging in vivo remains experimentally challenging. Here, we describe a luciferase knockin mouse (p16LUC), which faithfully reports expression of p16INK4a, a tumor suppressor and aging biomarker. Lifelong assessment of luminescence in p16+/LUC mice revealed an exponential increase with aging, which was highly variable in a cohort of contemporaneously housed, syngeneic mice. Expression of p16INK4a with aging did not predict cancer development, suggesting that the accumulation of senescent cells is not a principal determinant of cancer-related death. In 14 of 14 tested tumor models, expression of p16LUC was focally activated by early neoplastic events, enabling visualization of tumors with sensitivity exceeding other imaging modalities. Activation of p16INK4a was noted in the emerging neoplasm and surrounding stromal cells. This work suggests that p16INK4a activation is a characteristic of all emerging cancers, making the p16LUC allele a sensitive, unbiased reporter of neoplastic transformation

p16INK4A Positively Regulates Cyclin D1 and E2F1 through Negative Control of AUF1

/pRB/E2F pathway, a key regulator of the critical G1 to S phase transition of the cell cycle, is universally disrupted in human cancer. However, the precise function of the different members of this pathway and their functional interplay are still not well defined. -dependent manner, and several of these genes are also members of the AUF1 and E2F1 regulons. We also present evidence that E2F1 mediates p16-dependent regulation of several pro- and anti-apoptotic proteins, and the consequent induction of spontaneous as well as doxorubicin-induced apoptosis. is also a modulator of transcription and apoptosis through controlling the expression of two major transcription regulators, AUF1 and E2F1

High resolution optical spectroscopy of an LBV-candidate inside the CygOB2 association

For the first time, we obtained the high-resolution (R=15000 and 60000) optical spectra for the extremely luminous star No.12, associated with the IR-source IRAS20308+4104, a member of the CygOB2 association. We have found about 200 spectral features in range 4552-7939AA, including the interstellar NaI, KI lines and numerous DIBs, which are the strongest absorption lines in the spectrum, along with the HeI, CII, and SiII lines. A two-dimensional spectral classification indicates that the spectral type is B5+/-0.5 Ia+. Our analysis of the Vr data shows the presence of a Vr gradient in the stellar atmosphere, caused by the infall of matter onto the star. The strong Halpha emission displays broad Thompson wings and time-variable core absorption, providing evidence that the stellar wind is inhomogeneous, and a slightly blue-shifted PCyg type absorption profile. We concluded that the wind is variable in time.Comment: 20 pages, 5 figures, 2 table

Somatic LKB1 Mutations Promote Cervical Cancer Progression

Human Papilloma Virus (HPV) is the etiologic agent for cervical cancer. Yet, infection with HPV is not sufficient to cause cervical cancer, because most infected women develop transient epithelial dysplasias that spontaneously regress. Progression to invasive cancer has been attributed to diverse host factors such as immune or hormonal status, as no recurrent genetic alterations have been identified in cervical cancers. Thus, the pressing question as to the biological basis of cervical cancer progression has remained unresolved, hampering the development of novel therapies and prognostic tests. Here we show that at least 20% of cervical cancers harbor somatically-acquired mutations in the LKB1 tumor suppressor. Approximately one-half of tumors with mutations harbored single nucleotide substitutions or microdeletions identifiable by exon sequencing, while the other half harbored larger monoallelic or biallelic deletions detectable by multiplex ligation probe amplification (MLPA). Biallelic mutations were identified in most cervical cancer cell lines; HeLa, the first human cell line, harbors a homozygous 25 kb deletion that occurred in vivo. LKB1 inactivation in primary tumors was associated with accelerated disease progression. Median survival was only 13 months for patients with LKB1-deficient tumors, but >100 months for patients with LKB1-wild type tumors (P = 0.015, log rank test; hazard ratio = 0.25, 95% CI = 0.083 to 0.77). LKB1 is thus a major cervical tumor suppressor, demonstrating that acquired genetic alterations drive progression of HPV-induced dysplasias to invasive, lethal cancers. Furthermore, LKB1 status can be exploited clinically to predict disease recurrence

A Novel Zinc Finger Protein Zfp277 Mediates Transcriptional Repression of the Ink4a/Arf Locus through Polycomb Repressive Complex 1

Polycomb group (PcG) proteins play a crucial role in cellular senescence as key transcriptional regulators of the Ink4a/Arf tumor suppressor gene locus. However, how PcG complexes target and contribute to stable gene silencing of the Ink4a/Arf locus remains little understood.We examined the function of Zinc finger domain-containing protein 277 (Zfp277), a novel zinc finger protein that interacts with the PcG protein Bmi1. Zfp277 binds to the Ink4a/Arf locus in a Bmi1-independent manner and interacts with polycomb repressor complex (PRC) 1 through direct interaction with Bmi1. Loss of Zfp277 in mouse embryonic fibroblasts (MEFs) caused dissociation of PcG proteins from the Ink4a/Arf locus, resulting in premature senescence associated with derepressed p16(Ink4a) and p19(Arf) expression. Levels of both Zfp277 and PcG proteins inversely correlated with those of reactive oxygen species (ROS) in senescing MEFs, but the treatment of Zfp277(-/-) MEFs with an antioxidant restored the binding of PRC2 but not PRC1 to the Ink4a/Arf locus. Notably, forced expression of Bmi1 in Zfp277(-/-) MEFs did not restore the binding of Bmi1 to the Ink4a/Arf locus and failed to bypass cellular senescence. A Zfp277 mutant that could not bind Bmi1 did not rescue Zfp277(-/-) MEFs from premature senescence.Our findings implicate Zfp277 in the transcriptional regulation of the Ink4a/Arf locus and suggest that the interaction of Zfp277 with Bmi1 is essential for the recruitment of PRC1 to the Ink4a/Arf locus. Our findings also highlight dynamic regulation of both Zfp277 and PcG proteins by the oxidative stress pathways

Identification of dissolved organic matter size components in freshwater and marine environments

Dissolved organic matter (DOM) in the transition zone from freshwater to marine systems was analyzed with a new approach for parameterizing the size distribution of organic compounds. We used size-exclusion chromatography for molecular size analysis and quantified colored DOM (CDOM) on samples from two coastal environments in the Baltic Sea (Roskilde Fjord, Denmark and Gulf of Gdansk, Poland). We applied a Gaussian decomposition method to identify peaks from the chromatograms, providing information beyond bulk size properties. This approach complements methods where DOM is separated into size classes with pre-defined filtering cutoffs, or methods where chromatograms are used only to infer average molecular weight. With this decomposition method, we extracted between three and five peaks from each chromatogram and clustered these into three size groups. To test the applicability of our method, we linked our decomposed peaks with salinity, a major environmental driver in the freshwater-marine continuum. Our results show that when moving from freshwater to low-salinity coastal waters, the observed steep decrease of apparent molecular weight is mostly due to loss of the high-molecular-weight fraction (HMW; >2 kDa) of CDOM. Furthermore, most of the CDOM absorbance in freshwater originates from HMW DOM, whereas the absorbing moieties are more equally distributed along the smaller size range (<2 kDa) in marine samples.Peer reviewe