Immune Reactivity and Pseudoprogression or Tumor Flare in a Serially Biopsied Neuroendocrine Patient Treated with the Epigenetic Agent RRx-001.

Neuroendocrine tumors (NETs) are grouped together as a single class on the basis of histologic appearance, immunoreactivity for the neuroendocrine markers chromogranin A and synaptophysin, and potential secretion of hormones, neurotransmitters, neuromodulators and neuropeptides. Nevertheless, despite these common characteristics, NETs differ widely in terms of their natural histories: high-grade NETs are clinically aggressive and, like small cell lung cancer, which they most closely resemble, tend to respond to cisplatin and etoposide. In contrast, low-grade NETs, which as a rule progress and behave indolently, do not. In either case, the treatment strategy, apart from potentially curative surgical resection, is very poorly defined. This report describes the case of a 28-year-old white male with a diagnosis of high-grade NET of undetermined primary site metastatic to the lymph nodes, skin and paraspinal soft tissues, treated with the experimental anticancer agent RRx-001, in the context of a phase II clinical trial called TRIPLE THREAT (NCT02489903); serial sampling of tumor material through repeat biopsies demonstrated an intratumoral inflammatory response, including the amplification of infiltrating T cells, which correlated with clinical and symptomatic benefit. This case suggests that pseudoprogression or RRx-001-induced enlargement of tumor lesions, which has been previously described for several RRx-001-treated patients, is the result of tumoral lymphocyte infiltration

Author Correction: Probiotics and prebiotics in intestinal health and disease: from biology to the clinic (Nature Reviews Gastroenterology & Hepatology, (2019), 16, 10, (605-616), 10.1038/s41575-019-0173-3)

© 2019, Springer Nature Limited. In the original article published online, the Competing Interests statement was incorrect and should have stated the following: M.E.S. declares personal fees related to probiotics from the following entities: California Dairy Research Foundation, Clorox, Danone, Danone USA, Dutch Mill, General Mills, JHeimbach, Kelley Drye & Warren, Kellogg, Kerry, Medscape, Nestle, New Chapter, Pepsico, Pfizer, Pharmavite, Probi, Procter & Gamble, Trouw Nutrition, Visalia Dairy Company, Williams Mullen, Winclove Probiotics and Yakult. D.J.M. declares personal fees for consulting for Bayer and Pharmavite. G.R. declares that he helped develop and commercialize probiotic strains GR-1 and RC-14, but has had no financial interest in them for over 10 years. He is Chief Scientific Officer for Seed, a company producing probiotic products. Over the past 3 years, he has consulted on probiotics with Acerus Pharmaceuticals, Altmann, Chr. Hansen, Danone, KGK Science, Kimberly-Clark, Metagenics and Seed. G.R.G. and R.A.R. declare no competing interests. This error has been corrected in the HTML and PDF versions of the article

Probiotics and prebiotics in intestinal health and disease: from biology to the clinic

Probiotics and prebiotics are microbiota-management tools for improving host health. They target gastrointestinal effects via the gut, although direct application to other sites such as the oral cavity, vaginal tract and skin is being explored. Here, we describe gut-derived effects in humans. In the past decade, research on the gut microbiome has rapidly accumulated and has been accompanied by increased interest in probiotics and prebiotics as a means to modulate the gut microbiota. Given the importance of these approaches for public health, it is timely to reiterate factual and supporting information on their clinical application and use. In this Review, we discuss scientific evidence on probiotics and prebiotics, including mechanistic insights into health effects. Strains of Lactobacillus, Bifidobacterium and Saccharomyces have a long history of safe and effective use as probiotics, but Roseburia spp., Akkermansia spp., Propionibacterium spp. and Faecalibacterium spp. show promise for the future. For prebiotics, glucans and fructans are well proven, and evidence is building on the prebiotic effects of other substances (for example, oligomers of mannose, glucose, xylose, pectin, starches, human milk and polyphenols)

The deubiquitinating enzyme Doa4p protects cells from DNA topoisomerase I poisons

DNA topoisomerase I (Top1p) catalyzes changes in DNA topology via the formation of an enzyme-DNA covalent complex that is reversibly stabilized by the antitumor drug, camptothecin (CPT). During S-phase, collisions with replication forks convert these complexes into cytotoxic DNA lesions that trigger cell cycle arrest and cell death. To investigate cellular responses to CPT-induced DNA damage, a yeast genetic screen identified conditional tah mutants with enhanced sensitivity to self-poisoning DNA topoisomerase I mutant (Top1T722Ap), which mimics the action of CPT. Mutant alleles of three genes, DOA4, SLA1 and SLA2, were recovered. A nonsense mutation in DOA4 eliminated the catalytic residues of the Doa4p deubiquitinating enzyme, yet retained the rhodanase domain. At 36 degrees C, this doa4-10 mutant exhibited increased sensitivity to CPT, osmotic stress, and hydroxyurea, and a reversible petite phenotype. However, the accumulation of pre-vacuolar class E vesicles that was observed in doa4Delta cells was not detected in the doa4-10 mutant. Mutations in SLA1 or SLA2, which alter actin cytoskeleton architecture, induced a conditional synthetic lethal phenotype in combination with doa4-10 in the absence of DNA damage. Here actin cytoskeleton defects coincided with the enhanced fragility of large-budded cells. In contrast, the enhanced sensitivity of doa4-10 mutant cells to Top1T722Ap was unrelated to alterations in endocytosis and was selectively suppressed by increased dosage of the ribonucleotide reductase inhibitor Sml1p. Additional studies suggest a role for Doa4p in the Rad9p checkpoint response to Top1p poisons. These findings indicate a functional link between ubiquitin-mediated proteolysis and cellular resistance to CPT-induced DNA damage

Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL.

A subset of individuals diagnosed with cerebral palsy will have an underlying genetic diagnosis. Previously, a missense variant in GAD1 was described as a candidate mutation in a single family diagnosed with autosomal recessive spastic cerebral palsy-1 (CPSQ1; OMIM 603513). Following the ascertainment of a further branch of the CPSQ1 kindred, we found that the previously reported GAD1 variant did not segregate with the neurological disease phenotype in the recently ascertained branch of the kindred. Following genetic linkage studies to map autozygous regions and whole-exome sequencing, a missense variant (c.527 T > C; p. Leu176Pro, rs773333490) in the HPDL gene was detected and found to segregate with disease status in both branches of the kindred. HPDL encodes a 371-amino acid protein (4-Hydroxyphenylpyruvate Dioxygenase Like) that localizes to mitochondria but whose function is uncertain. Recently, biallelic loss of function variants and missense substitution-causing variants in HPDL were reported to cause a childhood onset progressive spastic movement disorder with a variable presentation. These findings suggest that HPDL-related neurological disease may mimic spastic cerebral palsy and that GAD1 should not be included in diagnostic gene panels for inherited cerebral palsy.NIH

Quiescent Radio Emission from Southern Late-type M Dwarfs and a Spectacular Radio Flare from the M8 Dwarf DENIS 1048-3956

We report the results of a radio monitoring program conducted at the Australia Telescope Compact Array to search for quiescent and flaring emission from seven nearby Southern late-type M and L dwarfs. Two late-type M dwarfs, the M7 V LHS 3003 and the M8 V DENIS 1048-3956, were detected in quiescent emission at 4.80 GHz. The observed emission is consistent with optically thin gyrosynchrotron emission from mildly relativistic (~1-10 keV) electrons with source densities n_e ~ 10 G magnetic fields. DENIS 1048-3956 was also detected in two spectacular, short-lived flares, one at 4.80 GHz (peak f_nu = 6.0+/-0.8 mJy) and one at 8.64 GHz (peak f_nu = 29.6+/-1.0 mJy) approximately 10 minutes later. The high brightness temperature (T_B >~ 10^13 K), short emission period (~4-5 minutes), high circular polarization (~100%), and apparently narrow spectral bandwidth of these events imply a coherent emission process in a region of high electron density (n_e ~ 10^11-10^12 cm^-3) and magnetic field strength (B ~ 1 kG). If the two flare events are related, the apparent frequency drift in the emission suggests that the emitting source either moved into regions of higher electron or magnetic flux density; or was compressed, e.g., by twisting field lines or gas motions. The quiescent fluxes from the radio-emitting M dwarfs violate the Gudel-Benz empirical radio/X-ray relations, confirming a trend previously noted by Berger et al. (abridged)Comment: 28 pages, 8 figures, accepted for publication in Ap

Entrances and exits: changing perceptions of primary teaching as a career for men

Original article can be found at: http://www.informaworld.com/smpp/title~content=t713640830~db=all Copyright Informa / Taylor and Francis. DOI: 10.1080/03004430802352087The number of men in teaching has always been small, particularly in early childhood, but those that do come into teaching usually do so for the same reasons as women, namely enjoyment of working with children, of wanting to teach and wanting to make a difference to children's lives. However, in two separate studies, the authors have shown that on beginning teacher training in 1998, and at the point of leaving the profession in 2005, men and women tend to emphasise different concerns. This article will explore those differences and seek possible explanations for how men's views of teaching might be changing over time.Peer reviewe

Cruciferous vegetable intake is inversely associated with lung cancer risk among smokers: a case-control study

<p>Abstract</p> <p>Background</p> <p>Inverse associations between cruciferous vegetable intake and lung cancer risk have been consistently reported. However, associations within smoking status subgroups have not been consistently addressed.</p> <p>Methods</p> <p>We conducted a hospital-based case-control study with lung cancer cases and controls matched on smoking status, and further adjusted for smoking status, duration, and intensity in the multivariate models. A total of 948 cases and 1743 controls were included in the analysis.</p> <p>Results</p> <p>Inverse linear trends were observed between intake of fruits, total vegetables, and cruciferous vegetables and risk of lung cancer (ORs ranged from 0.53-0.70, with P for trend < 0.05). Interestingly, significant associations were observed for intake of fruits and total vegetables with lung cancer among never smokers. Conversely, significant inverse associations with cruciferous vegetable intake were observed primarily among smokers, in particular former smokers, although significant interactions were not detected between smoking and intake of any food group. Of four lung cancer histological subtypes, significant inverse associations were observed primarily among patients with squamous or small cell carcinoma - the two subtypes more strongly associated with heavy smoking.</p> <p>Conclusions</p> <p>Our findings are consistent with the smoking-related carcinogen-modulating effect of isothiocyanates, a group of phytochemicals uniquely present in cruciferous vegetables. Our data support consumption of a diet rich in cruciferous vegetables may reduce the risk of lung cancer among smokers.</p

Prolonged history of silicic peralkaline volcanism in the eastern Pacific Ocean

Socorro Island, Mexico, is an alkaline and peralkaline volcanic island located in the eastern Pacific Ocean on a mid-ocean ridge spreading center that was abandoned at ∼3.5 Ma. Silicic peralkaline rocks comprise up to 80% of the surface of the island, rendering Socorro virtually unique in the Pacific Ocean. Precise, replicate 40Ar/39Ar ages of 21 peralkaline trachytes and rhyolites reveal a history of episodic volcanic activity from ∼540 to 370 ka that may have culminated with caldera formation; repose periods between these episodes may have had maximum duration of ∼30 kyr. After up to 200 kyr of quiescence, 40Ar/39Ar ages indicate that postcaldera silicic peralkaline activity commenced by 180 ka, forming the Cerro Evermann Formation. Postcaldera mafic alkaline lavas of the Lomas Coloradas Formation erupted dominantly between 70 and 150 ka based upon relative age relations. The dominant lithology of precaldera and syncaldera silicic peralkaline deposits on Socorro is nonfragmental and nonvesicular and lacks lithic fragments and fiamme; despite this, numerous lines of evidence including welding zonation, presence of a proximal ignimbrite or co-ignimbrite deposit, association with a caldera, and compositional heterogeneity within eruptive units suggest that they are dominantly ash flow tuffs. A change in eruptive style, from predominantly explosive to predominantly effusive, followed caldera formation and suggests that a change in the efficacy of magma degassing may be linked to caldera formation. On the basis of the presence of a caldera, the magma chamber associated with Socorro Island is shallow and probably resides within the upper oceanic crust or the edifice. This together with a prolonged history of silicic magmatism indicates that intrusion of mafic magma maintained thermal viability of the magmatic plumbing system. The minimum calculated growth rate for the entire volcanic edifice (7 × 10−4 km3/yr) exceeds those of nonhotspot off-axis volcanoes in the Pacific by almost an order of magnitude. Eruption rates for subaerial phases on Socorro may be several orders of magnitude smaller than this growth rate and are comparable to subaerial eruption rates of isolated ocean islands related to mantle plumes