tbuckley/cabot-search huggingface dataset:
Prolonged Adaptive Evolution of a Defensive Gene in the Solanaceae
Authors: Mark D. Rausher, Jie Huang
Journal: Molecular Biology and Evolution (2015)

Although plants and their natural enemies may coevolve for prolonged periods, little is known about how long individual plant defensive genes are involved in the coevolutionary process. We address this issue by examining patterns of selection on the defensive gene threonine deaminase (TD). Tomato (Solanum lycopersicum) has two copies of this gene. One performs the canonical housekeeping function in amino acid metabolism of catalyzing the first reaction in the conversion of threonine to isoleucine. The second copy functions as an antinutritive defense against lepidopteran herbivores by depleting threonine in the insect gut. Wild tobacco (Nicotiana attenuata) also contains a defensive copy. We show that a single copy of TD underwent two or three duplications near the base of the Solanaceae. One copy retains the housekeeping function, whereas a second copy evolved defensive functions. Positive selection occurred on the branch of the TD2 gene tree subtending the common ancestor of the Nicotianoideae and Solanoideae. It also occurred within the Solanoideae clade but not within the Nicotianoideae clade. Finally, it occurred on most branches leading from the common ancestor to S. lycopersicum. Based on recent calibrations of the Solanaceae phylogeny, TD2 experienced adaptive substitutions for a period of 30–50 My. We suggest that the most likely explanation for this result is fluctuating herbivore abundances: When herbivores are rare, relaxed selection increases the likelihood that slightly disadvantageous mutations will be fixed by drift; when herbivores are common, increased selection causes the evolution of compensatory adaptive mutations. Alternative explanations are also discussed.
Mesna: continuous or bolus infusion?
Authors: P H Willemse, E G de Vries
Journal: Journal of Clinical Oncology (1989)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1989.7.6.817 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 2497231 Mesna: continuous or bolus infusion? P H WillemsexP H WillemseSearch for articles by this author , E G de VriesxE G de VriesSearch for articles by this author https://doi.org/10.1200/JCO.1989.7.6.817 First Page PDF © 1989 by American Society of Clinical Oncology
Stepwise Functional Evolution in a Fungal Sugar Transporter Family
Authors: Carla Gonçalves, Marco A. Coelho, Madalena Salema-Oom, Paula Gonçalves
Journal: Molecular Biology and Evolution (2015)

Sugar transport is of the utmost importance for most cells and is central to a wide range of applied fields. However, despite the straightforward in silico assignment of many novel transporters, including sugar porters, to existing families, their exact biological role and evolutionary trajectory often remain unclear, mainly because biochemical characterization of membrane proteins is inherently challenging, but also owing to their uncommonly turbulent evolutionary histories. In addition, many important shifts in membrane carrier function are apparently ancient, which further limits our ability to reconstruct evolutionary trajectories in a reliable manner. Here, we circumvented some of these obstacles by examining the relatively recent emergence of a unique family of fungal sugar facilitators, related to drug antiporters. The former transporters, named Ffz, were previously shown to be required for fructophilic metabolism in yeasts. We first exploited the wealth of fungal genomic data available to define a comprehensive but well-delimited family of Ffz-like transporters, showing that they are only present in Dikarya. Subsequently, a combination of phylogenetic analyses and in vivo functional characterization was used to retrace important changes in function, while highlighting the evolutionary events that are most likely to have determined extant distribution of the gene, such as horizontal gene transfers (HGTs). One such HGT event is proposed to have set the stage for the onset of fructophilic metabolism in yeasts, a trait that according to our results may be the metabolic hallmark of close to 100 yeast species that thrive in sugar rich environments.
Alectinib in Crizotinib-Refractory <i>ALK-</i>Rearranged Non–Small-Cell Lung Cancer: A Phase II Global Study
Authors: Sai-Hong Ignatius Ou, Jin Seok Ahn, Luigi De Petris, Ramaswamy Govindan, James Chih-Hsin Yang, Brett Hughes, Hervé Lena, Denis Moro-Sibilot, Alessandra Bearz, Santiago Viteri Ramirez, Tarek Mekhail, Alexander Spira, Walter Bordogna, Bogdana Balas, Peter N. Morcos, Annabelle Monnet, Ali Zeaiter, Dong-Wan Kim
Journal: Journal of Clinical Oncology (2015)

Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC.Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC).Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2.Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.
Adult T cell leukemia with atypical surface phenotypes: clinical correlation.
Authors: Y Yamada, S Kamihira, T Amagasaki, K Kinoshita, M Kusano, S Chiyoda, E Yawo, S Ikeda, J Suzuyama, M Ichimaru
Journal: Journal of Clinical Oncology (1985)

The leukemic cells of 57 patients with adult T cell leukemia (ATL) were analyzed for their immunologic surface markers. Forty-four cases showed normal mature inducer/helper T cell phenotype (typical group: E-RFC+, Leu-1+, 2a-, 3a+ MASO36c-), but the other 13 cases showed unusual surface phenotypes (variant group) and could be subdivided into several groups (V1 to V5). Four cases had absent or low Leu-1 positivity (V1: E-RFC+, Leu-1-, 2a-, 3a+, MASO36c-), while two other cases with low Leu-1 positivity had both Leu-2a and 3a, a characteristic of cortical thymocytes, but were unreactive with MASO36c (V2: E-RFC+, Leu-1-, 2a+, 3a+, MASO36c-). Three cases lacked both Leu-2a and 3a despite having other T cell markers (V3: E-RFC+, Leu-1+, 2a-, 3a-, MASO36c-). The next three cases had low rosette-forming ability with sheep RBCs (V4: E-RFC-, Leu-1- approximately +, 2a- approximately +, 3a+, MASO36c-). Interestingly, one other case showed high reactivity against anti-Leu-7, which is believed to be one of the monoclonal antibodies directed against natural killer cells (V5: E-RFC+, Leu-1+, 2a-, 3a+, 7+, MASO36c-). Clinical and hematologic differences between the typical group and variant group were investigated, and it was found that the variant group (excluding V5) have statistically significant (P less than .002) higher serum lactic dehydrogenase (LDH) activity. The overall survival in the variant group was worse than in the typical group, but it was not quite statistically significant (P = .072). The median survival time was eight months for typical cases and only four months for variant cases; six cases died within two months. The V5 case was unusual not only because the patient's leukemic cells have Leu-7 antigen but also because she survived more than nine years after initial diagnosis. There seems to be some correlation between phenotypic diversity of ATL cells and prognosis.
Extracellular nucleotides as novel, underappreciated pro-metastatic factors that stimulate purinergic signaling in human lung cancer cells
Authors: Gabriela Schneider, Talita Glaser, Claudiana Lameu, Ahmed Abdelbaset-Ismail, Zachariah Payne Sellers, Marcin Moniuszko, Henning Ulrich, Mariusz Z. Ratajczak
Journal: Molecular Cancer (2015)

One of the challenging problems of current radio-chemotherapy is recurrence and metastasis of cancer cells that survive initial treatment. We propose that one of the unwanted effects of radiochemotherapy is the release from damaged ("leaky") cells of nucleotides such as ATP and UTP that exert pro-metastatic functions and can directly stimulate chemotaxis of cancer cells. To address this problem in a model of human lung cancer (LC), we employed several complementary in vitro and in vivo approaches to demonstrate the role of extracellular nucleotides (EXNs) in LC cell line metastasis and tumor progression. We measured concentrations of EXNs in several organs before and after radiochemotherapy. The purinergic receptor agonists and antagonists, inhibiting all or selected subtypes of receptors, were employed in in vitro and in vivo pro-metastatic assays. We found that EXNs accumulate in several organs in response to radiochemotherapy, and RT-PCR analysis revealed that most of the P1 and P2 receptor subtypes are expressed in human LC cells. EXNs were found to induce chemotaxis and adhesion of LC cells, and an autocrine loop was identified that promotes the proliferation of LC cells. Most importantly, metastasis of these cells could be inhibited in immunodeficient mice in the presence of specific small molecule inhibitors of purinergic receptors. Based on this result, EXNs are novel pro-metastatic factors released particularly during radiochemotherapy, and inhibition of their pro-metastatic effects via purinergic signaling could become an important part of anti-metastatic treatment.
Alcohol and Pregnancy: A Clinical Perspective
Authors: Henry L. Rosett, Lyn Weiner
Journal: Annual Review of Medicine (1985)

Exposure of the fetus at any gestational stage to high concentrations of alcohol can adversely affect growth, morphology, and neurophysiologic development. Sustained heavy drinking can result in the fetal alcohol syndrome. Cessation of heavy drinking during pregnancy will benefit both mother and child. Primary health care providers can effectively identify and treat women at risk.
Response to: ‘Role of nerve growth factor (NGF) and tropomyosin receptor kinase A (TrkA) in the pathogenesis of osteoarthritis. Might NGF be the link interwinding obesity and OA?’ by Iannone <i>et al</i>
Authors: Lilian N Nwosu, David A Walsh
Journal: Annals of the Rheumatic Diseases (2015)

Response to: 'Role of nerve growth factor (NGF) and tropomyosin receptor kinase A (TrkA) in the pathogenesis of osteoarthritis.Might NGF be the link interwinding obesity and OA?' by Iannone et alWe thank Dr Iannone 1 for his interest in our paper. 2We share his interest in possible non-neuronal effects of nerve growth factor (NGF).In addition to possible effects on inflammation, chondrocytes and adipocytes as highlighted by Iannone et al, 1 NGF might also contribute to angiogenesis 3 and bone turnover. 4Our data 2 suggest primary analgesic actions through reduction of sensitisation rather than through effects on inflammation, cartilage or bone turnover.However, although we did not observe structural disease-modifying effects of tropomyosin receptor kinase A (TrkA) inhibition, we cannot exclude small but clinically important effects.Non-neuronal effects of NGF or TrkA inhibition might be either beneficial or might contribute to adverse events, highlighting the importance not only of analgesic mechanisms, but also other possible roles of NGF-TrkA pathways.We agree that further investigation of the complex interactions between sensitisation, osteoarthritis structural damage, obesity and pain deserve further study.
SBI-0640756 Attenuates the Growth of Clinically Unresponsive Melanomas by Disrupting the eIF4F Translation Initiation Complex
Authors: Yongmei Feng, Anthony B. Pinkerton, Laura Hulea, Tongwu Zhang, Michael A. Davies, Stefan Grotegut, Yann Cheli, Hongwei Yin, Eric Lau, Hyungsoo Kim, Surya K. De, Elisa Barile, Maurizio Pellecchia, Marcus Bosenberg, Jian-Liang Li, Brian James, Christian A. Hassig, Kevin M. Brown, Ivan Topisirovic, Ze'ev A. Ronai
Journal: Cancer Research (2015)

Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex offers an appealing strategy to potentiate the effectiveness of existing cancer therapies and to overcome resistance to drugs such as BRAF inhibitors (BRAFi). Here, we identified and characterized the small molecule SBI-0640756 (SBI-756), a first-in-class inhibitor that targets eIF4G1 and disrupts the eIF4F complex. SBI-756 impaired the eIF4F complex assembly independently of mTOR and attenuated growth of BRAF-resistant and BRAF-independent melanomas. SBI-756 also suppressed AKT and NF-κB signaling, but small-molecule derivatives were identified that only marginally affected these pathways while still inhibiting eIF4F complex formation and melanoma growth, illustrating the potential for further structural and functional manipulation of SBI-756 as a drug lead. In the gene expression signature patterns elicited by SBI-756, DNA damage, and cell-cycle regulatory factors were prominent, with mutations in melanoma cells affecting these pathways conferring drug resistance. SBI-756 inhibited the growth of NRAS, BRAF, and NF1-mutant melanomas in vitro and delayed the onset and reduced the incidence of Nras/Ink4a melanomas in vivo. Furthermore, combining SBI-756 and a BRAFi attenuated the formation of BRAFi-resistant human tumors. Taken together, our findings show how SBI-756 abrogates the growth of BRAF-independent and BRAFi-resistant melanomas, offering a preclinical rationale to evaluate its antitumor effects in other cancers.
Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity
Authors: Deborah M. Siegal, John T. Curnutte, Stuart J. Connolly, Genmin Lu, Pamela B. Conley, Brian L. Wiens, Vandana S. Mathur, Janice Castillo, Michele D. Bronson, Janet M. Leeds, Florie A. Mar, Alex Gold, Mark A. Crowther
Journal: New England Journal of Medicine (2015)

Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors.Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant.Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported.Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).
Abstract 4204: The cellular hierarchy of intestinal tumors
Authors: Ryoji Yao, Tetsuo Noda
Journal: Cancer Research (2015)

Abstract Activation of the Wnt signaling is the initiating event in the majority of human colorectal cancers. In mouse models, disruption of the tumor suppressor gene, Apc, induces the adenomatous lesion. However, the analyses of initial events in animal models are hampered by difficulties to control the timing and the efficiency of introducing mutations. To overcome this problem, we used three dimensional organoid culture, which contain all epitherial components of intestinal cells with the defined organization of the crypt- and villus-like domains. In vitro 4-hydroxy-tamoxifen (4OHT) treatment of mouse organoids carrying Apc conditional mutation and CreERT2 allele led to the rapid and efficient gene aberration. Gene expression analysis revealed that the change in response to Apc inactivation was strikingly similar to those observed in the animal model. These observations demonstrated that the oragnoid culture is a useful tool to investigate the early cellular and molecular invents upon Apc inactivation. Recent analyses identified stem cells in normal intestine as well as cancer stem cells of human colorectal cancer. We found that Apc inactivation in the intestinal organoids led to the alteration in their expression profiles in a strikingly similar manner with those in animal models. The expression levels of tested stem cell markers were increased, except Aldh1. Immunofluorescence analysis demonstrated that their elevated epressions were caused by the increase of the stem cell population. Paneth cells, which provide the stem cell niche, consistently resided with the stem cells, indicating the accelerated growth of stem cells was accompanied by the differentiation process of the normal intestine. Notably, Aldh1 was exclusively expressed in the villus-like domains, which were decreased after 4OHT treatment. In the mouse intestine, it was expressed in the villi of normal intestine, and was not detected in the adenomatous lesion. These observations demonstrated that Apc inactivation led to the expansion of crypt-like domains by altering the proliferation and differentiation program of stem cells. Since the organoids share the features of the early response upon Apc inactivation with mouse models, they allowed detailed investigation of tumorigenesis. We have used the organoid culture system to elucidate the roles of oncogenic mutations as well as to evaluate the potential therapeutic targets. Citation Format: Ryoji Yao, Tetsuo Noda. The cellular hierarchy of intestinal tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4204. doi:10.1158/1538-7445.AM2015-4204
Staphylococcal Toxin Syndromes
Authors: J K Todd
Journal: Annual Review of Medicine (1985)

Staphylococcus aureus produces many extracellular products often referred to as toxins, some with definite disease-causing potential. The enterotoxins A through E are common causes of acute food poisoning characterized by a short incubation period after ingestion of performed toxin followed by nausea, vomiting, abdominal pain, and diarrhea. The epidermolytic toxins (A, B) are absorbed from a local site of colonization or infection and affect the granular cell layer of skin to cause the painful erythroderma and desquamation of the scalded skin syndrome. Other unique S. aureus strains produce one or more products that appear to be formed at sites of focal infection (wound infection, vagina during menstruation and tampon use) with systemic absorption and generalized effects resulting in toxic shock syndrome.
The Vacuolar H+-ATPase B1 Subunit Polymorphism p.E161K Associates with Impaired Urinary Acidification in Recurrent Stone Formers
Authors: Nasser A. Dhayat, Andre Schaller, Giuseppe Albano, John Poindexter, Carolyn Griffith, Andreas Pasch, Sabina Gallati, Bruno Vogt, Orson W. Moe, Daniel G. Fuster
Journal: Journal of the American Society of Nephrology (2015)

Mutations in the vacuolar-type H(+)-ATPase B1 subunit gene ATP6V1B1 cause autosomal-recessive distal renal tubular acidosis (dRTA). We previously identified a single-nucleotide polymorphism (SNP) in the human B1 subunit (c.481G>A; p.E161K) that causes greatly diminished pump function in vitro To investigate the effect of this SNP on urinary acidification, we conducted a genotype-phenotype analysis of recurrent stone formers in the Dallas and Bern kidney stone registries. Of 555 patients examined, 32 (5.8%) were heterozygous for the p.E161K SNP, and the remaining 523 (94.2%) carried two wild-type alleles. After adjustment for sex, age, body mass index, and dietary acid and alkali intake, p.E161K SNP carriers had a nonsignificant tendency to higher urinary pH on a random diet (6.31 versus 6.09; P=0.09). Under an instructed low-Ca and low-Na diet, urinary pH was higher in p.E161K SNP carriers (6.56 versus 6.01; P<0.01). Kidney stones of p.E161K carriers were more likely to contain calcium phosphate than stones of wild-type patients. In acute NH4Cl loading, p.E161K carriers displayed a higher trough urinary pH (5.34 versus 4.89; P=0.01) than wild-type patients. Overall, 14.6% of wild-type patients and 52.4% of p.E161K carriers were unable to acidify their urine below pH 5.3 and thus, can be considered to have incomplete dRTA. In summary, our data indicate that recurrent stone formers with the vacuolar H(+)-ATPase B1 subunit p.E161K SNP exhibit a urinary acidification deficit with an increased prevalence of calcium phosphate-containing kidney stones. The burden of E161K heterozygosity may be a forme fruste of dRTA.
Medical Treatment of Acromegaly
Authors: I D Goldfine
Journal: Annual Review of Medicine (1978)

ade­ noma of the pituitary gland, causes morbidity and mortality in affected patients by both local and peripheral physical changes (1-7). First, GR-secreting ade­ nomas, like other tumors of the pituitary, cause compression of surrounding neural and bony structures, among which are the normal pituitary tissues, the sphenoid and cavernous sinuses, optic nerves, and third ventricle. Second, the excess secretion of GR in acromegaly can lead to changes in the peripheral tissues, which result in gross disfigurement of the face, hands, and other parts of the body; crippling arthritis; carpal tunnel syndromes; heart disease; hyper­ tension; lung disease; a number of dermal changes; and carbohydrate and lipid abnormalities. Obviously, patients with acromegaly require therapeutic