tbuckley/cabot-search huggingface dataset:
Development of a standardised tool to survey MDR-/XDR-TB case management in Europe
Authors: G Sotgiu, R Centis, L D’ambrosio, S De Lorenzo, M D’arcy Richardson, C. Lange, D. Manissero, G.B. Migliori
Journal: European Respiratory Journal (2010)

To the Editors:

The emergence of multidrug-resistant tuberculosis (MDR-TB, defined as in vitro resistance to isoniazid and rifampicin) 1–5 and extensively drug-resistant TB (XDR-TB, defined as in vitro drug resistance to isoniazid and rifampicin plus any fluoroquinolone and at least one of the injectable drugs: capreomycin, kanamycin or amikacin) represents a major threat to TB control at the global level 1–5.

In 2007, the World Health Organization (WHO) estimated a prevalence of 511,000 MDR-TB cases (with 150,000 deaths) and 50,000 XDR-TB cases (and 30,000 deaths) 1; 14 out of 19 high-MDR-TB burden territories are located in Former Soviet Union (FSU) countries 1.

XDR-TB is a manmade product, resulting, in essence, from clinical mismanagement of newly diagnosed pan-susceptible TB cases as well as MDR-TB cases 1, 2. There is evidence that suboptimal TB case management in parts of Europe contributes to the development of resistance to the XDR-TB defining drugs 4–7.

In spite of the growing amount of public awareness about TB drug resistance, the essential variables necessary to fully understand MDR-TB and XDR-TB are unfortunately not systematically collected, analysed and reported in published studies 2, 8. Although the international community is providing a rapid response to XDR-TB (formulation of an emergency plan 9; development of an instrument to support implementation and scale-up of national strategies and to assess programmatic needs 10), no standardised and comprehensive tool is available to survey the key factor responsible for the emergence of MDR-/XDR-TB: inappropriate TB case management.

The aim of this letter is to describe the process undertaken by the Tuberculosis Network European Trialsgroup (TBNET) in collaboration with the European Centre for Disease Prevention and Control (ECDC) to develop a standardised tool to survey MDR-/XDR-TB case management in the …
Phase I and Pharmacokinetic Study of Sequential Paclitaxel and Trabectedin Every 2 Weeks in Patients with Advanced Solid Tumors
Authors: Quincy Chu, Alain Mita, Bahram Forouzesh, Anthony W. Tolcher, Gary Schwartz, Antonio Nieto, Arturo Soto-Matos, Vicente Alfaro, Claudia Lebedinsky, Eric K. Rowinsky
Journal: Clinical Cancer Research (2010)

Abstract Purpose: This phase I study evaluated the feasibility, safety, pharmacokinetics (PK), and preliminary evidence of anticancer activity of the sequential administration of paclitaxel and trabectedin on an every-2-week schedule in patients with refractory solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) level on this schedule, as well as to recommend doses for disease-directed studies. Experimental Design: Twenty-seven patients were treated with paclitaxel (80-120 mg/m2; 1-hour i.v. infusion, day 1) and trabectedin (0.525-0.775 mg/m2; 3-hour i.v. infusion, day 2) with doses increased in successive cohorts. Blood sampling for PK and drug-drug interaction studies was done. Results: Neutropenia, which resulted in treatment delay exceeding 1 week, was the principal dose-limiting toxicity for this paclitaxel-trabectedin regimen and precluded dose escalation above 120 mg/m2 paclitaxel and 0.650 mg/m2 trabectedin. At the MTD (120 mg/m2 paclitaxel and 0.650 mg/m2 trabectedin), the safety profile was favorable in patients receiving cumulative treatment. Relevant drug-drug PK interactions between paclitaxel and trabectedin were not identified. A patient with soft tissue sarcoma had a complete response and several patients with various refractory solid malignancies showed protracted stable disease as their best response. Conclusions: The MTD level of sequential paclitaxel 1-hour infusion (day 1) and trabectedin 3-hour infusion (day 2) administered every 2 weeks is 120 and 0.650 mg/m2, respectively. The manageable toxicities at the MTD, preliminary evidence of antitumor activity, and lack of notable PK drug-drug interactions warrant further disease-directed studies of this regimen in relevant tumor types and settings. Clin Cancer Res; 16(9); 2656–65. ©2010 AACR.
Antibody Targeting of Long-Circulating Lipidic Nanoparticles Does Not Increase Tumor Localization but Does Increase Internalization in Animal Models
Authors: Dmitri B. Kirpotin, Daryl C. Drummond, Yi Shao, M. Refaat Shalaby, Keelung Hong, Ulrik B. Nielsen, James D. Marks, Christopher C. Benz, John W. Park
Journal: Cancer Research (2006)

We describe evidence for a novel mechanism of monoclonal antibody (MAb)-directed nanoparticle (immunoliposome) targeting to solid tumors in vivo. Long-circulating immunoliposomes targeted to HER2 (ErbB2, Neu) were prepared by the conjugation of anti-HER2 MAb fragments (Fab' or single chain Fv) to liposome-grafted polyethylene glycol chains. MAb fragment conjugation did not affect the biodistribution or long-circulating properties of i.v.-administered liposomes. However, antibody-directed targeting also did not increase the tumor localization of immunoliposomes, as both targeted and nontargeted liposomes achieved similarly high levels (7-8% injected dose/g tumor tissue) of tumor tissue accumulation in HER2-overexpressing breast cancer xenografts (BT-474). Studies using colloidal gold-labeled liposomes showed the accumulation of anti-HER2 immunoliposomes within cancer cells, whereas matched nontargeted liposomes were located predominantly in extracellular stroma or within macrophages. A similar pattern of stromal accumulation without cancer cell internalization was observed for anti-HER2 immunoliposomes in non-HER2-overexpressing breast cancer xenografts (MCF-7). Flow cytometry of disaggregated tumors posttreatment with either liposomes or immunoliposomes showed up to 6-fold greater intracellular uptake in cancer cells due to targeting. Thus, in contrast to nontargeted liposomes, anti-HER2 immunoliposomes achieved intracellular drug delivery via MAb-mediated endocytosis, and this, rather than increased uptake in tumor tissue, was correlated with superior antitumor activity. Immunoliposomes capable of selective internalization in cancer cells in vivo may provide new opportunities for drug delivery.
Modern social and clinical characteristics of miliary tuberculosis
Authors: Liudmila Pankratova, Natalia Kazimirova
Journal: European Respiratory Journal (2014)

Aim- to study the modern pathomorphism of miliary tuberculosis (MT)–an acute form of TB inherent in periods of epidemiologic disadvantage.  We examined 44 patients in Saratov hospitals (Russia) in 2008–2013: 33 men and 11 women aged 20-62. 75.9% were under 40. 68.2% were unemployed. Only 25.0% were married; 43.6%-alcoholics, 33.3%- drugusers. 81.8% were HIV-infected–but only 58.3% were registered in AIDS centers.  81.8% were newly identified; 18.2% relapsed. 38.6% had generalized lesions: meningitis-25.0%, TB of larynx-4.5%, pleurisy-6.8%, gonitis-1.3%.  Only 21.0% had had an apparent TB contact. The onset was always gradual: over 2 weeks-16.7%, 1 month-56.7%, 2-26.7%. Intoxication was mild: weakness-75.0%, but only in 15.4% it was severe. High temperature was in 62.8%: subfebrile-29.9%, febrile-37.2%, only 4.6% reached 39-40°C. Decreased appetite and weight loss were observed in 55.8%, which could also be attributed to HIV. Except for cases of meningitis, no mental disoders were observed. Respiratory syndrome was scarce: dry cough-48.8%, scanty sputum-27.9%. Dyspnea on exertion in 20.9%, at rest-20.9%. General condition was satisfactory in 16.1%, moderate-48.4%, grave-25.8%, and extremely severe-9.7%. Respiration was rough in 48.7%, weakened-38.5%, wheezing -only 16.6%. 47.5% were bacillary. Anemia in 45.0%. WBC count was usually normal, low-30% and high-2.5% only. WBC formula left shift-80%. Lymphopenia in 32.3%. Accelerated ESR in 67.7%.  All patients received TB treatment. 50.0% of HIV-infected received HAART. 37.5% of patients recovered, a positive trend in 12.5%, 32.5% died, 17.5% continued treatment.  Conclusions: The disease has subtle clinical manifestations, frequent HIV coinfection, and adverse outcomes.
Role of SREBP-1 in the Development of Parasympathetic Dysfunction in the Hearts of Type 1 Diabetic Akita Mice
Authors: Ho-Jin Park, Yali Zhang, Chuang Du, C. Michael Welzig, Christopher Madias, Mark J. Aronovitz, Serban P. Georgescu, Isaac Naggar, Bo Wang, Young-Bum Kim, Robert O. Blaustein, Richard H. Karas, Ronglih Liao, Clayton E. Mathews, Jonas B. Galper
Journal: Circulation Research (2009)

Diabetic autonomic neuropathy (DAN), a major complication of diabetes mellitus, is characterized, in part, by impaired cardiac parasympathetic responsiveness. Parasympathetic stimulation of the heart involves activation of an acetylcholine-gated K+ current, I(KAch), via a (GIRK1)2/(GIRK4)2 K+ channel. Sterol regulatory element binding protein-1 (SREBP-1) is a lipid-sensitive transcription factor.We describe a unique SREBP-1-dependent mechanism for insulin regulation of cardiac parasympathetic response in a mouse model for DAN.Using implantable EKG transmitters, we demonstrated that compared with wild-type, Ins2(Akita) type I diabetic mice demonstrated a decrease in the negative chronotropic response to carbamylcholine characterized by a 2.4-fold decrease in the duration of bradycardia, a 52+/-8% decrease in atrial expression of GIRK1 (P<0.01), and a 31.3+/-2.1% decrease in SREBP-1 (P<0.05). Whole-cell patch-clamp studies of atrial myocytes from Akita mice exhibited a markedly decreased carbamylcholine stimulation of I(KAch) with a peak value of -181+/-31 pA/pF compared with -451+/-62 pA/pF (P<0.01) in cells from wild-type mice. Western blot analysis of extracts of Akita mice demonstrated that insulin treatment increased the expression of GIRK1, SREBP-1, and I(KAch) activity in atrial myocytes from these mice to levels in wild-type mice. Insulin treatment of cultured atrial myocytes stimulated GIRK1 expression 2.68+/-0.12-fold (P<0.01), which was reversed by overexpression of dominant negative SREBP-1. Finally, adenoviral expression of SREBP-1 in Akita atrial myocytes reversed the impaired I(KAch) to levels in cells from wild-type mice.These results support a unique molecular mechanism for insulin regulation of GIRK1 expression and parasympathetic response via SREBP-1, which might play a role in the pathogenesis of DAN in response to insulin deficiency in the diabetic heart.
Synergistic upregulation of low-density lipoprotein receptor activity by tamoxifen and lovastatin
Authors: Y SUAREZ, C FERNANDEZ, D GOMEZCORONADO, A FERRUELO, A DAVALOS, J MARTINEZBOTAS, M LASUNCION
Journal: Cardiovascular Research (2004)

To study the mechanism involved in the cholesterol-lowering activity of tamoxifen, an estrogen receptor (ER) modulator widely used in breast cancer therapy.We used MOLT-4 cells, which do not express estrogen receptors and require important amounts of cholesterol for proliferation. We firstly confirmed that tamoxifen reduced cholesterol biosynthesis by inhibiting sterol Delta(8,7)-isomerase and Delta(24)-reductase activities, which resulted in the accumulation of zymosterol. In cells incubated in the presence of low-density lipoprotein (LDL) (120 microg cholesterol/ml), tamoxifen stimulated LDL receptor activity and expression in a dose-dependent manner, as determined by 1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarbocyanineperchlorate (DiI)-labeled LDL uptake, LDL receptor expression on the cell surface and LDL receptor mRNA levels. Furthermore, tamoxifen, but not lovastatin, inhibited the egress of LDL-derived cholesterol from lysosomes, as ascertained by filipin staining in both MOLT-4 and HepG2 cells. When studied in combination, especially at relatively high LDL concentrations in the medium, tamoxifen and lovastatin stimulated LDL receptor activity synergistically, which is attributed to the different mechanism of action these drugs exhibit.The present study demonstrates the stimulation of the LDL receptor by tamoxifen. These results explain the long-known hypolipidemic effect of tamoxifen and support its use, or that of other intracellular cholesterol trafficking inhibitors, in combination with statins for the reduction of plasma LDL cholesterol levels.
Whole-genome sequencing and analysis of the Malaysian cynomolgus macaque (Macaca fascicularis) genome
Authors: Atsunori Higashino, Ryuichi Sakate, Yosuke Kameoka, Ichiro Takahashi, Makoto Hirata, Reiko Tanuma, Tohru Masui, Yasuhiro Yasutomi, Naoki Osada
Journal: Genome biology (2012)

The genetic background of the cynomolgus macaque (Macaca fascicularis) is made complex by the high genetic diversity, population structure, and gene introgression from the closely related rhesus macaque (Macaca mulatta). Herein we report the whole-genome sequence of a Malaysian cynomolgus macaque male with more than 40-fold coverage, which was determined using a resequencing method based on the Indian rhesus macaque genome.We identified approximately 9.7 million single nucleotide variants (SNVs) between the Malaysian cynomolgus and the Indian rhesus macaque genomes. Compared with humans, a smaller nonsynonymous/synonymous SNV ratio in the cynomolgus macaque suggests more effective removal of slightly deleterious mutations. Comparison of two cynomolgus (Malaysian and Vietnamese) and two rhesus (Indian and Chinese) macaque genomes, including previously published macaque genomes, suggests that Indochinese cynomolgus macaques have been more affected by gene introgression from rhesus macaques. We further identified 60 nonsynonymous SNVs that completely differentiated the cynomolgus and rhesus macaque genomes, and that could be important candidate variants for determining species-specific responses to drugs and pathogens. The demographic inference using the genome sequence data revealed that Malaysian cynomolgus macaques have experienced at least three population bottlenecks.This list of whole-genome SNVs will be useful for many future applications, such as an array-based genotyping system for macaque individuals. High-quality whole-genome sequencing of the cynomolgus macaque genome may aid studies on finding genetic differences that are responsible for phenotypic diversity in macaques and may help control genetic backgrounds among individuals.
Phylogenetic relationships of artiodactyls and cetaceans as deduced from the comparison of cytochrome b and 12S rRNA mitochondrial sequences
Authors: C Montgelard, F M Catzeflis, E Douzery
Journal: Molecular Biology and Evolution (1997)

A data set of complete mitochondrial cytochrome b and 12S rDNA sequences is presented here for 17 representatives of Artiodactyla and Cetacea, together with potential outgroups (two Perissodactyla, two Carnivora, two Tethytheria, four Rodentia, and two Marsupialia). We include seven sequences not previously published from Hippopotamidae (Ancodonta) and Camelidae (Tylopoda), yielding a total of nearly 2.1 kb for both genes combined. Distance and parsimony analyses of each gene indicate that 11 clades are well supported, including the artiodactyl taxa Pecora, Ruminantia (with low 12S rRNA support), Tylopoda, Suina, and Ancodonta, as well as Cetacea, Perissodactyla, Carnivora, Tethytheria, Muridae, and Caviomorpha. Neither the cytochrome b nor the 12S rDNA genes resolve the relationships between these major clades. The combined analysis of the two genes suggests a monophyletic Cetacea +Artiodactyla clade (defined as "Cetartiodactyla"), whereas Perissodactyla, Carnivora, and Tethytheria fall outside this clade. Perissodactyla could represent the sister taxon of Cetartiodactyla, as deduced from resampling studies among outgroup lineages. Cetartiodactyla includes five major lineages: Ruminantia, Tylopoda, Suina, Ancodonta, and Cetacea, among which the phylogenetic relationships are not resolved. Thus, Suiformes do not appear to be monophyletic, justifying their split into the Suina and Ancodonta infraorders. An association between Cetacea and Hippopotamidae is supported by the cytochrome b gene but not by the 12S rRNA gene. Calculation of divergence dates suggests that the Cetartiodactyla could have diverged from other Ferungulata about 60 MYA.
Productivity and exponence
Authors: James P. Blevins
Journal: Behavioral and Brain Sciences (1999)

The experimental results reported in Clahsen's target article clearly distinguish regular from irregular processes and suggest a basic difference between items that are productively formed and items which are stored in the lexicon. However, these results do not directly implicate any particular combinatory operation (such as affixation), nor do they distinguish inflectional items from other productive formations.
Equally Potent Inhibition of c-Src and Abl by Compounds that Recognize Inactive Kinase Conformations
Authors: Markus A. Seeliger, Pratistha Ranjitkar, Corynn Kasap, Yibing Shan, David E. Shaw, Neil P. Shah, John Kuriyan, Dustin J. Maly
Journal: Cancer Research (2009)

Abstract Imatinib is an inhibitor of the Abl tyrosine kinase domain that is effective in the treatment of chronic myelogenic leukemia. Although imatinib binds tightly to the Abl kinase domain, its affinity for the closely related kinase domain of c-Src is at least 2,000-fold lower. Imatinib recognition requires a specific inactive conformation of the kinase domain, in which a conserved Asp-Phe-Gly (DFG) motif is flipped with respect to the active conformation. The inability of c-Src to readily adopt this flipped DFG conformation was thought to underlie the selectivity of imatinib for Abl over c-Src. Here, we present a series of inhibitors (DSA compounds) that are based on the core scaffold of imatinib but which bind with equally high potency to c-Src and Abl. The DSA compounds bind to c-Src in the DFG-flipped conformation, as confirmed by crystal structures and kinetic analysis. The origin of the high affinity of these compounds for c-Src is suggested by the fact that they also inhibit clinically relevant Abl variants bearing mutations in a structural element, the P-loop, that normally interacts with the phosphate groups of ATP but is folded over a substructure of imatinib in Abl. Importantly, several of the DSA compounds block the growth of Ba/F3 cells harboring imatinib-resistant BCR-ABL mutants, including the Thr315Ile “gatekeeper” mutation, but do not suppress the growth of parental Ba/F3 cells. [Cancer Res 2009;69(6):2384–92
Intestinal infarction caused by paroxysmal nocturnal hemoglobinuria
Authors: Michael A. Doukas, Paul E. Dilorenzo, Daniel N. Mohler
Journal: American Journal of Hematology (1984)

Abstract A patient with paroxysmal nocturnal hemoglobinuria of 14 years duration presented with severe abdominal pain and fever. On admission, his hematocrit had fallen to 19% from his usual level of approximately 30%, and stools were positive for occult blood. Dilated loops of small bowel with air fluid levels were noted on radiographs, and sonography revealed free intraperitoneal fluid. Several sections of gangrenous jejunum and ileum were resected at exploratory laparotomy, and mesenteric venous thromboses were present. This is the second report of pathologically proven intestinal infarction in a patient with paroxysmal nocturnal hemoglobinuria who has survived this abdominal emergency with surgical intervention. Although abdominal pain in patients with paroxysmal nocturnal hemoglobinuria has frequently been attributed to mesenteric venous thromboses, this has rarely been documented either during life or at autopsy.
Toll-like receptor-4 signalling is specifically tak1-independent in synovial fibroblasts
Authors: B. T. van den Brand, S. Abdollahi-Roodsaz, O. J. Arntz, M. Kracht, J. Geurts, W. B. van den Berg, F. A. J. van de Loo
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background and objective</h3> Activated synovial fibroblasts are key players in the pathogenesis of rheumatoid arthritis (RA) by driving inflammation and joint destruction. Numerous molecules including cytokines and toll-like receptor (TLR) ligands induce pro-inflammatory signalling and gene expression through a hierarchical network of kinases. Upstream mitogen-activated protein kinase kinase kinases (MAP3Ks) represent an attractive target for RA treatment. In this study the authors sought to determine the role of the MAP3K transforming growth factor β activated kinase1 (TAK1) in cytokine and TLR-mediated signalling. <h3>Materials and methods</h3> TAK1 activity was inhibited using either a small molecule inhibitor 5Z-7-oxozeaenol or lentivirally overexpressed kinase-inactive TAK1-K63W mutant in murine embryonic and human dermal and synovial fibroblasts. Fibroblasts were stimulated with interleukin 1 (IL-1), tumour necrosis factor (TNF), TLR2 or TLR4 agonists and responses were evaluated using transcriptional reporters and analysis of gene expression of collagenases (matrix metalloproteinases (MMP3, MMP13)), cytokines (IL-1β, IL-6) and chemokines (IL-8, MCP-1). <h3>Results</h3> TAK1 inhibition abrogated cytokine- and TLR-induced activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and <i>Saa3</i>-promoter reporters in mouse and human dermal fibroblasts. In synovial fibroblasts, TAK1 crucially regulated IL-1 and TNF mediated NF-κB, but not <i>Saa3</i>-promoter activation. Furthermore, TAK1 was required for inducible mRNA expression of IL-1β, IL-6, IL-8, MMP3 and MMP13, but not MCP-1, in response to IL-1, TNF and TLR2 agonist. Unexpectedly, TLR4-induced NF-κB activation and gene expression was fully TAK1-independent as found using the TAK1 inhibitor or kinase inactive mutant. Western blots demonstrated IL-1-inducible p38 and p65 phosphorylation and inhibition by the TAK1 inhibitor 5Z-7-oxozeaenol, whereas no effect of TAK1 inhibitor on lipopolysaccharides signalling in RA-SF. <h3>Conclusions</h3> In general, TAK1 plays a prominent role in regulation of IL-1- and TNF mediated signalling in fibroblasts. Interestingly, TLR4 signalling is specifically TAK1-independent in synovial fibroblasts. Consequently, therapeutic TAK1 inhibition in arthropaties may not dampen the damage-associated molecular pattern-mediated TLR4 activation of synovial fibroblasts.
Temozolomide in Malignant Gliomas of Childhood: A United Kingdom Children’s Cancer Study Group and French Society for Pediatric Oncology Intergroup Study
Authors: L. S. Lashford, P. Thiesse, A. Jouvet, T. Jaspan, D. Couanet, P. D. Griffiths, F. Doz, J. Ironside, K. Robson, R. Hobson, M. Dugan, A. D.J. Pearson, G. Vassal, D. Frappaz
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To determine the response rate of the malignant gliomas of childhood to an oral, daily schedule of temozolomide. PATIENTS AND METHODS: A multicenter, phase II evaluation of an oral, daily schedule of temozolomide (200 mg/m 2 on 5 consecutive days) was undertaken in children with relapsed or progressive, biopsy-proven, high-grade glioma (arm A) and progressive, diffuse, intrinsic brainstem glioma (arm B). Evidence of activity was defined by radiologic evidence of a sustained reduction in tumor size on serial magnetic resonance imaging scans. RESULTS: Fifty-five patients were recruited (34 to arm A and 21 to arm B) and received 215 cycles of chemotherapy. Grade 3/4 thrombocytopenia was the most frequent toxic event (7% of cycles). Prolonged myelosuppression resulted in significant treatment delays and dose reductions (17% and 22% of cycles, respectively). Two toxic deaths were documented and were related to myelosuppression and sepsis in one patient and pneumonia in a second. The overall (best) response rate was 12% for arm A (95% confidence interval [CI], 3 to 28 in the study cohort, and 2 to 31 for eligible patients) and 5% and 6%, respectively, for arm B (95% CI, 0 to 26 in the study cohort, and 0 to 27 for eligible patients). Stabilization of disease was also documented and was most noteworthy for brainstem gliomas, where two patients achieved both radiologic static disease and discontinued steroid medication. CONCLUSION: Despite moderate toxicity, objective response rates to temozolomide have been low, indicating that temozolomide has minimal activity in the high-grade gliomas of childhood.