Mithramycin and Analogs for Overcoming Cisplatin Resistance in Ovarian Cancer

Ovarian cancer is a highly deadly malignancy in which recurrence is considered incurable. Resistance to platinum-based chemotherapy bodes a particularly abysmal prognosis, underscoring the need for novel therapeutic agents and strategies. The use of mithramycin, an antineoplastic antibiotic, has been previously limited by its narrow therapeutic window. Recent advances in semisynthetic methods have led to mithramycin analogs with improved pharmacological profiles. Mithramycin inhibits the activity of the transcription factor Sp1, which is closely linked with ovarian tumorigenesis and platinum-resistance. This article summarizes recent clinical developments related to mithramycin and postulates a role for the use of mithramycin, or its analog, in the treatment of platinum-resistant ovarian cancer

Elastic electron scattering from 3-hydroxytetrahydrofuran: experimental and theoretical studies

We report the results of measurements and calculations for elastic electron scattering from 3-hydroxytetrahydrofuran (C4H8O2). The measurements are performed with a crossed electron-target beam apparatus and the absolute cross-sections are determined using the relative flow technique. The calculations are carried out using the Schwinger multichannel method in the static-exchange plus polarization (SEP) approximation. A set of angular differential cross-sections (DCS) is provided at five incident energies (6.5, 8, 10, 15 and 20 eV) over an angular range of 20–130°, and the energy dependence of the elastic DCS at a scattering angle of 120° is also presented. Integral elastic and elastic momentum transfer cross-sections have also been derived and calculated. The results are compared with those of recent measurements and calculations for the structurally similar molecule tetrahydrofuran (C4H8O)

Meta-analysis of effect of nintedanib on reducing FVC decline across interstitial lung diseases

INTRODUCTION: The effect of nintedanib on slowing the rate of decline in forced vital capacity (FVC) has been investigated in randomized placebo-controlled trials in subjects with idiopathic pulmonary fibrosis (IPF), other progressive fibrosing interstitial lung diseases (ILDs), and ILD associated with systemic sclerosis (SSc-ILD). We assessed the consistency of the effect of nintedanib on the rate of decline in FVC over 52 weeks across four placebo-controlled phase III trials. METHODS: We used data on FVC decline from the INPULSIS-1 and INPULSIS-2 trials in subjects with IPF, the INBUILD trial in subjects with progressing fibrosing ILDs other than IPF, and the SENSCIS trial in subjects with SSc-ILD. In each trial, the primary endpoint was the annual rate of decline in FVC (mL/year) assessed over 52 weeks. We performed fixed effect and random effects meta-analyses based on the relative treatment effect of nintedanib versus placebo on the rate of decline in FVC (mL/year) over 52 weeks. Heterogeneity of the relative treatment effect of nintedanib across populations was assessed using the I2 statistic, τ2 and corresponding p value from a Q test for heterogeneity. RESULTS: The combined analysis comprised 1257 subjects treated with nintedanib and 1042 subjects who received placebo. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks by 51.0% (95% CI 39.1, 63.0) compared with placebo. The relative effect (95% CI) was the same using the fixed effect and random effects models. There was no evidence of heterogeneity in the relative treatment effect of nintedanib across the populations studied (I2 = 0%, τ2 = 0, p = 0.93). CONCLUSIONS: A meta-analysis of data from four placebo-controlled trials demonstrated that nintedanib approximately halved the rate of decline in FVC over 52 weeks across subjects with different forms of pulmonary fibrosis, with no evidence of heterogeneity in its relative treatment effect across patient populations

\u3cem\u3ePhaeophleospora vochysiae\u3c/em\u3e Savi & Glienke sp. nov. Isolated from \u3cem\u3eVochysia divergens\u3c/em\u3e Found in the Pantanal, Brazil, Produces Bioactive Secondary Metabolites

Microorganisms associated with plants are highly diverse and can produce a large number of secondary metabolites, with antimicrobial, anti-parasitic and cytotoxic activities. We are particularly interested in exploring endophytes from medicinal plants found in the Pantanal, a unique and widely unexplored wetland in Brazil. In a bio-prospecting study, strains LGMF1213 and LGMF1215 were isolated as endophytes from Vochysia divergens, and by morphological and molecular phylogenetic analyses were characterized as Phaeophleospora vochysiae sp. nov. The chemical assessment of this species reveals three major compounds with high biological activity, cercoscosporin (1), isocercosporin (2) and the new compound 3-(sec-butyl)-6-ethyl-4,5-dihydroxy-2-methoxy-6-methylcyclohex-2-enone (3). Besides the isolation of P. vochysiae as endophyte, the production of cercosporin compounds suggest that under specific conditions this species causes leaf spots, and may turn into a pathogen, since leaf spots are commonly caused by species of Cercospora that produce related compounds. In addition, the new compound 3-(sec-butyl)-6-ethyl-4,5-dihydroxy-2-methoxy-6-methylcyclohex-2-enone showed considerable antimicrobial activity and low cytotoxicity, which needs further exploration

The Green Bank Northern Celestial Cap Pulsar Survey - I: Survey Description, Data Analysis, and Initial Results

We describe an ongoing search for pulsars and dispersed pulses of radio emission, such as those from rotating radio transients (RRATs) and fast radio bursts (FRBs), at 350 MHz using the Green Bank Telescope. With the Green Bank Ultimate Pulsar Processing Instrument, we record 100 MHz of bandwidth divided into 4,096 channels every 81.92 $\mu s$. This survey will cover the entire sky visible to the Green Bank Telescope ($\delta > -40^\circ$, or 82% of the sky) and outside of the Galactic Plane will be sensitive enough to detect slow pulsars and low dispersion measure ($<$30 $\mathrm{pc\,cm^{-3}}$) millisecond pulsars (MSPs) with a 0.08 duty cycle down to 1.1 mJy. For pulsars with a spectral index of $-$1.6, we will be 2.5 times more sensitive than previous and ongoing surveys over much of our survey region. Here we describe the survey, the data analysis pipeline, initial discovery parameters for 62 pulsars, and timing solutions for 5 new pulsars. PSR J0214$+$5222 is an MSP in a long-period (512 days) orbit and has an optical counterpart identified in archival data. PSR J0636$+$5129 is an MSP in a very short-period (96 minutes) orbit with a very low mass companion (8 $M_\mathrm{J}$). PSR J0645$+$5158 is an isolated MSP with a timing residual RMS of 500 ns and has been added to pulsar timing array experiments. PSR J1434$+$7257 is an isolated, intermediate-period pulsar that has been partially recycled. PSR J1816$+$4510 is an eclipsing MSP in a short-period orbit (8.7 hours) and may have recently completed its spin-up phase.Comment: 18 pages, 10 figures, 5 tables, accepted by Ap

The Green Bank Northern Celestial Cap Pulsar Survey II: The Discovery and Timing of Ten Pulsars

We present timing solutions for ten pulsars discovered in 350 MHz searches with the Green Bank Telescope. Nine of these were discovered in the Green Bank Northern Celestial Cap survey and one was discovered by students in the Pulsar Search Collaboratory program in analysis of drift-scan data. Following discovery and confirmation with the Green Bank Telescope, timing has yielded phase-connected solutions with high precision measurements of rotational and astrometric parameters. Eight of the pulsars are slow and isolated, including PSR J0930$-$2301, a pulsar with nulling fraction lower limit of $\sim$30\% and nulling timescale of seconds to minutes. This pulsar also shows evidence of mode changing. The remaining two pulsars have undergone recycling, accreting material from binary companions, resulting in higher spin frequencies. PSR J0557$-$2948 is an isolated, 44 \rm{ms} pulsar that has been partially recycled and is likely a former member of a binary system which was disrupted by a second supernova. The paucity of such so-called `disrupted binary pulsars' (DRPs) compared to double neutron star (DNS) binaries can be used to test current evolutionary scenarios, especially the kicks imparted on the neutron stars in the second supernova. There is some evidence that DRPs have larger space velocities, which could explain their small numbers. PSR J1806+2819 is a 15 \rm{ms} pulsar in a 44 day orbit with a low mass white dwarf companion. We did not detect the companion in archival optical data, indicating that it must be older than 1200 Myr.Comment: 9 pages, 5 figure

The Green Bank North Celestial Cap Pulsar Survey. IV: Four New Timing Solutions

We present timing solutions for four pulsars discovered in the Green Bank Northern Celestial Cap (GBNCC) survey. All four pulsars are isolated with spin periods between 0.26$\,$s and 1.84$\,$s. PSR J0038$-$2501 has a 0.26$\,$s period and a period derivative of ${7.6} \times {10}^{-19}\,{\rm s\,s}^{-1}$, which is unusually low for isolated pulsars with similar periods. This low period derivative may be simply an extreme value for an isolated pulsar or it could indicate an unusual evolution path for PSR J0038$-$2501, such as a disrupted recycled pulsar (DRP) from a binary system or an orphaned central compact object (CCO). Correcting the observed spin-down rate for the Shklovskii effect suggests that this pulsar may have an unusually low space velocity, which is consistent with expectations for DRPs. There is no X-ray emission detected from PSR J0038$-$2501 in an archival swift observation, which suggests that it is not a young orphaned CCO. The high dispersion measure of PSR J1949+3426 suggests a distance of 12.3$\,$kpc. This distance indicates that PSR J1949+3426 is among the most distant 7% of Galactic field pulsars, and is one of the most luminous pulsars.Comment: 7 pages, 5 figure

Water Chemisorption and Reconstruction of the MgO Surface

The observed reactivity of MgO with water is in apparent conflict with theoretical calculations which show that molecular dissociation does not occur on a perfect (001) surface. We have performed ab-initio total energy calculations which show that a chemisorption reaction involving a reconstruction to form a (111) hydroxyl surface is strongly preferred with Delta E = -90.2kJ/mol. We conclude that protonation stabilizes the otherwise unstable (111) surface and that this, not the bare (001), is the most stable surface of MgO under ambient conditions.Comment: RevTeX, 4 pages, 1 Encapsulated Postscript Figur

Novel GC-rich DNA-binding compound produced by a genetically engineered mutant of the mithramycin producer Streptomyces argillaceus exhibits improved transcriptional repressor activity: implications for cancer therapy

The aureolic acid antibiotic mithramycin (MTM) binds selectively to GC-rich DNA sequences and blocks preferentially binding of proteins, like Sp1 transcription factors, to GC-rich elements in gene promoters. Genetic approaches can be applied to alter the MTM biosynthetic pathway in the producing microorganism and obtain new products with improved pharmacological properties. Here, we report on a new analog, MTM SDK, obtained by targeted gene inactivation of the ketoreductase MtmW catalyzing the last step in MTM biosynthesis. SDK exhibited greater activity as transcriptional inhibitor compared to MTM. SDK was a potent inhibitor of Sp1-dependent reporter activity and interfered minimally with reporters of other transcription factors, indicating that it retained a high degree of selectivity toward GC-rich DNA-binding transcription factors. RT–PCR and microarray analysis showed that SDK repressed transcription of multiple genes implicated in critical aspects of cancer development and progression, including cell cycle, apoptosis, migration, invasion and angiogenesis, consistent with the pleiotropic role of Sp1 family transcription factors. SDK inhibited proliferation and was a potent inducer of apoptosis in ovarian cancer cells while it had minimal effects on viability of normal cells. The new MTM derivative SDK could be an effective agent for treatment of cancer and other diseases with abnormal expression or activity of GC-rich DNA-binding transcription factors