tbuckley/cabot-search huggingface dataset:
Paediatric tuberculosis in Europe: lessons from Denmark and inclusive strategies to consider
Authors: Ben J. Marais, Marina Tadolini, Matteo Zignol, Giovanni Battista Migliori
Journal: European Respiratory Journal (2014)

Despite suffering high morbidity and mortality in tuberculosis (TB)-endemic areas, children with TB are generally less infectious than adult cases and are therefore low on the priority list of national tuberculosis control programmes [1]. Accurate disease burden assessment in children is hampered by diagnostic challenges [2], limited surveillance data and the poor quality of routinely collected programmatic data. In 2012, the World Health Organization (WHO) produced its first estimates of the TB disease burden suffered by children worldwide, which were updated in 2013: 530 000 cases and 74 000 child deaths were attributed to TB [3]. Many deficiencies were acknowledged and it probably is an underestimate given the conservative assumptions made [1]. However, it provided formal recognition of the plight of these children and supplemented the focus on paediatric TB during World TB Day commemorations in 2012. Despite improved awareness, pragmatic service delivery strategies are often lacking, with pronounced policy–practice gaps in TB-endemic areas with limited resources [3, 4].

This editorial puts recent paediatric TB trends in Denmark, as described by Hatleberg et al. [5] in this issue of the European Respiratory Journal , into perspective; it explores study findings that may seem counterintuitive, advises on the importance of consistent and accurate classification of clinical syndromes in order for reports to be more informative, and argues for new strategies to reduce TB transmission to a minimum in low-burden settings.

Relatively good data exist on the paediatric TB disease burden in Europe. A descriptive analysis of European Union/European Economic Area surveillance data from 2000 to 2009 reported 39 695 paediatric cases, accounting for 4.3% of all notified TB cases [6]. Overall TB incidence rates in children <15 years of age dropped from 5.5 per 100 …
Characterization of graft-versus-leukemia responses in patients treated for advanced chronic lymphocytic leukemia with donor lymphocyte infusions after in vitro T-cell depleted allogeneic stem cell transplantation following reduced-intensity conditioning
Authors: M Hoogendoorn, I Jedema, R M Y Barge, S A P van Luxemburg-Heijs, F Beaumont, E W A Marijt, R Willemze, J H F Falkenburg
Journal: Leukemia (2007)
IGF-IR determines the fates of BCR/ABL leukemia
Authors: Jingjing Xie, Xiaoli Chen, Junke Zheng, Chunling Li, Satomi Stacy, Martin Holzenberger, Xuemei Hu, Cheng Cheng Zhang
Journal: Journal of Hematology & Oncology (2015)

The tyrosine kinase receptor insulin-like growth factor 1 receptor (IGF-IR) contributes to the initiation and progression of many types of malignancies. We previously showed that IGF-2, which binds IGF-IR, is an extrinsic factor that supports the ex vivo expansion of hematopoietic stem cells (HSCs). We also demonstrated that IGF-IR is not required for HSC activity in vivo. Here we investigated the role of IGF-IR in chronic myeloid leukemia (CML) using the retroviral BCR/ABL transplantation mouse model. Existing antibodies against IGF-IR are not suitable for flow cytometry; therefore, we generated a fusion of the human IgG Fc fragment with mutant IGF-2 that can bind to IGF-IR. We used this fusion protein to evaluate mouse primary hematopoietic populations. Through transplantation assays with IGF-IR+ and IGF-IR− cells, we demonstrated that IGF-IR is expressed on all mouse HSCs. The expression of IGF-IR is much higher on CML cells than on acute lymphoblastic leukemia (ALL) cells. The depletion of IGF-IR expression in BCR/ABL+ cells led to the development of ALL (mostly T cell ALL) but not CML. Lack of IGF-IR resulted in decreased self-renewal of the BCR/ABL+ CML cells in the serial replating assay. IGF-IR regulates the cell fate determination of BCR/ABL+ leukemia cells and supports the self-renewal of CML cells.
Genomic profile analysis of diffuse-type gastric cancers
Authors: Yeon-Su Lee, Yun Sung Cho, Geon Kook Lee, Sunghoon Lee, Young-Woo Kim, Sungwoong Jho, Hak-Min Kim, Seung-Hyun Hong, Jung-Ah Hwang, Sook-young Kim, Dongwan Hong, Il Ju Choi, Byung Chul Kim, Byoung-Chul Kim, Chul Hong Kim, Hansol Choi, Youngju Kim, Kyung Wook Kim, Gu Kong, Hyung Lae Kim, Jong Bhak, Seung Hoon Lee, Jin Soo Lee
Journal: Genome biology (2014)

Abstract Background Stomach cancer is the third deadliest among all cancers worldwide. Although incidence of the intestinal-type gastric cancer has decreased, the incidence of diffuse-type is still increasing and its progression is notoriously aggressive. There is insufficient information on genome variations of diffuse-type gastric cancer because its cells are usually mixed with normal cells, and this low cellularity has made it difficult to analyze the genome. Results We analyze whole genomes and corresponding exomes of diffuse-type gastric cancer, using matched tumor and normal samples from 14 diffuse-type and five intestinal-type gastric cancer patients. Somatic variations found in the diffuse-type gastric cancer are compared to those of the intestinal-type and to previously reported variants. We determine the average exonic somatic mutation rate of the two types. We find associated candidate driver genes, and identify seven novel somatic mutations in CDH1 , which is a well-known gastric cancer-associated gene. Three-dimensional structure analysis of the mutated E-cadherin protein suggests that these new somatic mutations could cause significant functional perturbations of critical calcium-binding sites in the EC1-2 junction. Chromosomal instability analysis shows that the MDM2 gene is amplified. After thorough structural analysis, a novel fusion gene TSC2 - RNF216 is identified, which may simultaneously disrupt tumor-suppressive pathways and activate tumorigenesis. Conclusions We report the genomic profile of diffuse-type gastric cancers including new somatic variations, a novel fusion gene, and amplification and deletion of certain chromosomal regions that contain oncogenes and tumor suppressors.
Natural history of decompensated hepatitis C virus-related cirrhosis. A study of 200 patients
Authors: Ramon Planas, Belén Ballesté, Marco Antonio Álvarez, Monica Rivera, Silvia Montoliu, Josep Anton Galeras, Justiniano Santos, Susanna Coll, Rosa Maria Morillas, Ricard Solà
Journal: Journal of Hepatology (2004)
Staged miRNA re-regulation patterns during reprogramming
Authors: Christine M Henzler, Zhonghan Li, Jason Dang, Mary Luz Arcila, Hongjun Zhou, Jingya Liu, Kung-Yen Chang, Danielle S Bassett, Tariq M Rana, Kenneth S Kosik
Journal: Genome biology (2013)

Abstract Background MiRNAs often operate in feedback loops with transcription factors and represent a key mechanism for fine-tuning gene expression. In transcription factor-induced reprogramming, miRNAs play a critical role; however, detailed analyses of miRNA expression changes during reprogramming at the level of deep sequencing have not been previously reported. Results We use four factor reprogramming to induce pluripotent stem cells from mouse fibroblasts and isolate FACS-sorted Thy1- and SSEA1+ intermediates and Oct4-GFP+ induced pluripotent stem cells (iPSCs). Small RNAs from these cells, and two partial-iPSC lines, another iPSC line, and mouse embryonic stem cells (mES cells) were deep sequenced. A comprehensive resetting of the miRNA profile occurs during reprogramming; however, analysis of miRNA co-expression patterns yields only a few patterns of change. Dlk1-Dio3 region miRNAs dominate the large pool of miRNAs experiencing small but significant fold changes early in reprogramming. Overexpression of Dlk1-Dio3 miRNAs early in reprogramming reduces reprogramming efficiency, suggesting the observed downregulation of these miRNAs may contribute to reprogramming. As reprogramming progresses, fewer miRNAs show changes in expression, but those changes are generally of greater magnitude. Conclusions The broad resetting of the miRNA profile during reprogramming that we observe is due to small changes in gene expression in many miRNAs early in the process, and large changes in only a few miRNAs late in reprogramming. This corresponds with a previously observed transition from a stochastic to a more deterministic signal.
Observations on the Fate of Ingested Cholesterol in Man
Authors: M. W. BIGGS, D. KRITCHEVSKY, D. COLMAN, J. W. GOFMAN, H. B. JONES, F. T. LINDGREN, G. HYDE, T. P. LYON
Journal: Circulation (1952)

Tritium-labeled Cholesterol has been used to study several aspects of exogenous cholesterol metabolism in man. The rate and magnitude of the appearance of ingested cholesterol in the various blood compartments has been followed. Fecal excretion of the labeling material was measured. Cholesterol of dietary origin was demonstrated in a human atherosclerotic aorta.
Effects of glucose, Trolox-C, and glutathione disulphide on lipid peroxidation and cell death induced by oxidant stress in rat heart
Authors: C T Le, L Hollaar, E J M van der Valk, A van der Laarse
Journal: Cardiovascular Research (1992)

Objective: The aim was to find effective protection of myocytes against peroxide induced damage in terms of preservation of contractile activity, protection against lipid peroxidation, and protection against cell death. Methods: The components of the glutathione redox cycle, the production of malondialdehyde, cell contractions, and enzyme release from myocytes were measured in cultured neonatal rat heart cells before and after administration of cumene hydroperoxide, 80 μmol·litre−1. The protective action was tested of (1) glucose (10 mmol·litre) which stimulates the production of NADPH; (2) Trolox-C (0.16 mmol·litre−1) which is a water soluble analogue of a tocopherol and a scavenger of free radicals; and (3) GSSG (0.6 mmol·litre−1) which increases the intracellular concentrations of GSH and GSSG. Results: Although the three substances tested were equally effective in reducing the formation of malondialdehyde, exogenous GSSG afforded only slight protection against cumene hydroperoxide induced cell death, whereas glucose and Trolox-C were highly effective protectors. The depressant effect of cumene hydroperoxide on beating frequency was not influenced by preincubation with GSSG, nor by coadministration of glucose, but Trolox-C was able to diminish the negative chronotropic action of cumene hydroperoxide. Conclusions: Effective protection against cumene hydroperoxide induced lipid peroxidation is not associated per se with effective protection against cumene hydroperoxide induced loss of beating frequency and cell death.
A Novel Chemoimmunomodulating Property of Docetaxel: Suppression of Myeloid-Derived Suppressor Cells in Tumor Bearers
Authors: Krithika N. Kodumudi, Karrune Woan, Danielle L. Gilvary, Eva Sahakian, Sheng Wei, Julie Y. Djeu
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Myeloid-derived suppressor cells (MDSC) accumulate in tumor-bearing hosts and are associated with immune suppression. To date, there have only been few studies that evaluate the direct effect of chemotherapeutic agents on MDSCs. Agents that inhibit MDSCs may be useful in the treatment of patients with various cancers. Experimental Design: We investigated the in vivo effects of docetaxel on immune function in 4T1-Neu mammary tumor-bearing mice to examine if a favorable immunomodulatory effect accompanies tumor suppression. Primary focus was on the differentiation status of MDSCs and their ability to modulate T-cell responses. Results: Docetaxel administration significantly inhibited tumor growth in 4T1-Neu tumor-bearing mice and considerably decreased MDSC proportion in the spleen. The treatment also selectively increased CTL responses. Docetaxel-pretreated MDSCs cocultured with OT-II splenocytes in the presence of OVA323-339 showed OT-II–specific CD4 activation and expansion in vitro. In characterizing the phenotype of MDSCs for M1 (CCR7) and M2 [mannose receptor (CD206)] markers, MDSCs from untreated tumor bearers were primarily MR+ with few CCR7+ cells. Docetaxel treatment polarized MDSCs toward an M1-like phenotype, resulting in 40% of MDSCs expressing CCR7 in vivo and in vitro, and macrophage differentiation markers such as MHC class II, CD11c, and CD86 were upregulated. Interestingly, docetaxel induced cell death selectively in MR+ MDSCs while sparing the M1-like phenotype. Finally, inhibition of signal transducer and activator of transcription 3 may in part be responsible for the observed results. Conclusions: These findings suggest potential clinical benefit for the addition of docetaxel to current immunotherapeutic protocols. Clin Cancer Res; 16(18); 4583–94. ©2010 AACR.
Single fraction radiosurgery of epidural spinal cord compression: Tumor control and neurologic outcome
Authors: S. Ryu, J. Rock, R. Jain, S. Ellika, J. Jin, J. Anderson
Journal: Journal of Clinical Oncology (2007)

2041 Purpose: Spine radiosurgery improves the pain and quality of life in spine metastasis. Phase II study was performed to determine the clinical efficacy of radiosurgery for malignant epidural spinal cord compression. Method: Total 67 patients with 93 lesions of epidural spinal cord compression at the solitary spine level were accrued. All patients had pathology-proven malignancy and had epidural tumor seen on MRI or CT scan. For radiosurgery, grossly visible tumor including the involved spine was treated with single fraction radiosurgery dose of 14–20 Gy. Spinal cord dose constraint was 10 Gy to 10% partial volume of the cord. Followup included neurological exam and imaging studies every 2 months. Endpoints were radiographic tumor control and neurological outcome. Median followup time was 8 months (2–30 months). Results: Objective radiographic tumor response was seen in 82% of patients. At 2 months, complete response was in seen 27%, partial response in 30%, and minimal response in 23%, Epidural tumor progressed in 6% at or the adjacent spine level. Thecal sac patency (= decompression effect) seen on T2-weighted MR image was improved in 82% of the lesions. There was average 68% volumetric reduction of tumor at the level of most severe cord compression. This tumor reduction opened the thecal sac patency to average 75% following radiosurgery, compared to 45% before radisourgery (p&lt;0.05). Majority of patients with neurological deficit prior to radiosurgery were ambulatory with an improved neurological function or remained clinically stable. There was one case of likely long-term radiation-induced myelopathy 13 months after radiosurgery. Conclusion: Single fraction radiosurgery achieves significant tumor response and decompressive effect of spinal cord compression. Even minimal tumor response relieves the spinal cord compression and potential neurologic improvement. Spine radiosurgery can be a viable treatment option for spinal cord compression. No significant financial relationships to disclose.
Evolutionary origin and diversification of the mammalian CD1 antigen genes.
Authors: A L Hughes
Journal: Molecular Biology and Evolution (1991)

CD1 antigens are cell-surface glycoproteins which have a molecular structure which is similar (consisting of extracellular domains alpha 1, alpha 2, and alpha 3, a transmembrane portion, and a cytoplasmic tail) to that of class I MHC molecules. Phylogenetic analysis of mammalian CD1 DNA sequences revealed that these genes are more closely related to the class I major histocompatibility complex (MHC) than to the class II MHC and that mammalian genes are more closely related to avian class I MHC genes than they are to mammalian class I MHC genes. The CD1 genes form a multigene family with different numbers of genes in different species (five in human, eight in rabbit, and two in mouse). Known CD1 genes are grouped into the following three families, on the basis of evolutionary relationship: (1) the human HCD1B gene and a partial sequence from the domestic rabbit, (2) the human HCD1A and HCD1C genes, and (3) the human HCD1D and HCD1E genes plus the two mouse genes and a sequence from the cottontail rabbit. The alpha 1 and alpha 2 domains of CD1 are much less conserved at the amino acid level than are the corresponding domains of class I MHC molecules, but the alpha 3 domain of CD1 seems to be still more conserved than the well-conserved alpha 3 domain of class I MHC molecules. Furthermore, in the human CD1 gene family, interlocus exon exchange has homogenized alpha 3 domains of all CD1 genes except HCD1C.
Chronic Myeloid Leukemia: How Can Minimal Cytogenetic Response After 3 Months of Treatment Be Classified According to the New European LeukemiaNet Recommendations?
Authors: Antonio Jiménez-Velasco, Manuel Barrios, Magdalena Alcalá, Ana Isabel Heiniger
Journal: Journal of Clinical Oncology (2010)

TO THE EDITOR: Baccarani et al, on behalf of European LeukemiaNet, recently published the new recommendations for the management and monitoring of patients with chronic myeloid leukemia (CML). These recommendations, which are based mainly on the greater experience obtained during the past few years with tyrosine kinase inhibitors, update and improve the previous recommendations, published in 2006. One of the main proposals consists of the definition of optimal and suboptimal response and therapeutic failure after 3 months of imatinib treatment. The latest recommendations define the optimal response at 3 months as a complete hematologic response (CHR) with at least a minor cytogenetic response (CgR), which means that the number of Ph metaphases is equal to or lower than 65%. A suboptimal response is defined as a CHR associated with failure in the CgR (meaning that more than 95% of metaphases will be Ph ) and therapeutic failure is considered when CHR response is not achieved. Depending on the group in which the patient is included, subsequent clinical and therapeutic management will differ. However, these new recommendations result in a group of patients remaining unclassified. Patients with CHR and minimal CgR (between 66% and 95% Ph metaphases) at 3 months of imatinib treatment cannot be included in any of the three definitions mentioned (ie, optimal, suboptimal, or failure). Consequently, no recommendations currently exist for this group of patients with CML. The frequency of minimal CgR at 3 months becomes difficult to estimate, given that the IRIS (International Randomized IFN versus STI571) study did not publish results, though data suggest that the number of patients belonging to this group could be relevant. de Lavallade et al performed cytogenetic analyses on 203 patients at 3 months and found that 110 (54%) had between 36% and 95% Ph metaphases. Although this study did not distinguish between patients with minor or minimal CgR, the likelihood of the whole group obtaining a complete CgR at 5 years reached 96.4%. In contrast, Baccarani et al, in the previous European LeukemiaNet recommendations, showed that the group with minimal CgR at 3 months in combination with the group of null CgR could still obtain a complete CgR of 50% at 2 years. Unfortunately, neither of these studies analyzed separately the minimal CgR group, and the response or survival estimations therefore remain speculative. Given that the approach to the group in question could be very open, with several acceptable alternatives, we consider that the authors should clarify this point in order to manage more accurately and uniformly our patients with CML.
Further studies on the recovery of 2-acetylaminofluorene from rats following oral administration.
Authors: Helen M. Dyer, Helen E. Ross, Harold P. Morris
Journal: Cancer Research (1951)

The diazotization method of Westfall, with slight modifications, was used to determine the presence of 2-acetylaminofluorene (AAF), 2-aminofluorene (AF), or of closely related derivatives in acetone extracts of the tissues and in ether extracts of hydrolysates of protein and lipid fractions of the tissues of rats, following single doses of AAF by stomach tube or after repeated feeding of the carcinogen.

The method of analysis yields reliable recoveries of AAF from acetone extracts of tissues to which AAF is added before homogenization, but not more than 5 per cent of that which disappeared from the gastrointestinal tract during 5 to 23 hours of fasting could be recovered from the acetone extracts of the tissues and excreta of treated rats.

The recovery of 300 µg. of AAF added before the saponification of fat was excellent, but saponification of extracts of lipid material from rats' tissues did not increase the amount recovered over that from unsaponified lipid extracts, except where large amounts of fat interfered with the glacial acetic acid solution of the carcinogen.

Moderate to large losses of AAF were encountered in control recovery experiments with the procedures used in the acid or alkaline hydrolyses of protein material. With 300 µg. of AAF added to the control tissues the poorest recovery, however, and that with only two fractions of tissues, was 75 µg. (25 per cent), whereas the hydrolysates of protein material from the experimental rats yielded completely negative results. Tryptic digests of protein material from the tissues of treated rats also failed to give any color in the test, although pilot control recovery tests demonstrated almost quantitative recovery.

It is concluded that orally administered AAF does not combine as such or as AF with the proteins or saponifiable lipids of the tissues, at least, in combinations that are reversible upon hydrolysis, or in amounts that represent significant fractions of that part of the administered AAF which cannot be recovered from acetone extracts of the tissues and excreta of the rats.

The experimental results indicate that much of the administered AAF is changed by the tissues of the rat into a nondiazotizable form.
ATTENTIONAL MODULATION OF VISUAL PROCESSING
Authors: John H. Reynolds, Leonardo Chelazzi
Journal: Annual Review of Neuroscience (2004)

▪ Abstract Single-unit recording studies in the macaque have carefully documented the modulatory effects of attention on the response properties of visual cortical neurons. Attention produces qualitatively different effects on firing rate, depending on whether a stimulus appears alone or accompanied by distracters. Studies of contrast gain control in anesthetized mammals have found parallel patterns of results when the luminance contrast of a stimulus increases. This finding suggests that attention has co-opted the circuits that mediate contrast gain control and that it operates by increasing the effective contrast of the attended stimulus. Consistent with this idea, microstimulation of the frontal eye fields, one of several areas that control the allocation of spatial attention, induces spatially local increases in sensitivity both at the behavioral level and among neurons in area V4, where endogenously generated attention increases contrast sensitivity. Studies in the slice have begun to explain how modulatory signals might cause such increases in sensitivity.
Injury to Tonsil
Authors: D. E. M. Brown
Journal: BMJ (1946)

MEDICAL MEMORANDA MEDICRATJUH 763 doing everything at top speed.His mind became choked with ideas, which occurred at all times of the day and night.While many of these never reached maturity, some of them resulted in the patient writing poems and creating new designs for houses and buildings.At times, too, he was seized with an uncontrollable desire to cry,