tbuckley/cabot-search huggingface dataset:
Susceptibility and Resistance to Viral Leukemogenesis in the Mouse. I. Biologic Definition of the Virus&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Judith R. Tennant
Journal: JNCI Journal of the National Cancer Institute (1965)

A leukemogenic virus, BALB/Tennant-leukemia (B/T-L), previously isolated from a lymphoid leukemia occurring in a BALB mouse strain, was defined biologically by titration in sucklings of the BALB/cJ strain and by determination of its virulence for BALB/cJ mice of various ages and for sucklings and adults of a spectrum of 11 other strains. The virus was antigenic in guinea pigs as demonstrated by serum neutralization tests, but rabbits did not develop measurable neutralizing antibodies to the virus. In the fifth passage, at which level the virus was used throughout these studies, the titer of the virus was approximately 10−4 in the primary (BALB/c) strain. When inoculated within the first few days of life with a 10−1 dilution of virus, 100 percent of these mice died with lymphoid leukemia at an average age of 3.0 months. Leukemia induction decreased among those inoculated at a later age, or at a higher dilution of virus, as evidenced by a drop in percentage and a gradual lengthening of the latent period. The pattern of response to the virus in allogeneic hosts was examined for a possible direct correlation between the response of a given host strain to the virus and the histocompatibility-2 (H-2) allele carried by that strain. No direct correlation was found, but there were indications that the H-2 constitution of the host might play a significant role in susceptibility to the virus, and further studies are in progress. Potent leukemogenic viruses were recovered from spontaneous leukemias of the AKR/J and C58/J strains by cell-free passage in isogeneic sucklings. One of these C58 filtrates also induced mammary tumors which appeared in 6 of 7 C58 females at 3 months of age. Mammary tumors are rarely seen among mice of this strain.
Dysfunctional Microvasculature as a Consequence of <i>Shb</i> Gene Inactivation Causes Impaired Tumor Growth
Authors: Nina S. Funa, Vitezslav Kriz, Guangxiang Zang, Gabriela Calounova, Björn Åkerblom, Jaroslav Mares, Erik Larsson, Ying Sun, Christer Betsholtz, Michael Welsh
Journal: Cancer Research (2009)

Shb (Src homology 2 protein B) is an adapter protein downstream of the vascular endothelial growth factor receptor receptor-2 (VEGFR-2). Previous experiments have suggested a role for Shb in endothelial cell function. Recently, the Shb gene was inactivated and Shb null mice were obtained on a mixed genetic background, but not on C57Bl6 mice. The present study was performed to address endothelial function in the Shb knockout mouse and its relevance for tumor angiogenesis. Tumor growth was retarded in Shb mutant mice, and this correlated with decreased angiogenesis both in tumors and in Matrigel plugs. Shb null mice display an abnormal endothelial ultrastructure in liver sinusoids and heart capillaries with cytoplasmic extensions projecting toward the lumen. Shb null heart VE-cadherin staining was less distinct than that of control heart, exhibiting in the former case a wavy and punctuate pattern. Experiments on isolated endothelial cells suggest that these changes could partly reflect cytoskeletal abnormalities. Vascular permeability was increased in Shb null mice in heart, kidney, and skin, whereas VEGF-stimulated vascular permeability was reduced in Shb null mice. It is concluded that Shb plays an important role in maintaining a functional vasculature in adult mice, and that interference with Shb signaling may provide novel means to regulate tumor angiogenesis.
Human Vascular Smooth Muscle Cells Express a Urate Transporter
Authors: Karen L. Price, Yuri Y. Sautin, David A. Long, Li Zhang, Hiroki Miyazaki, Wei Mu, Hitoshi Endou, Richard J. Johnson
Journal: Journal of the American Society of Nephrology (2006)

An elevated serum uric acid is associated with the development of hypertension and renal disease. Renal regulation of urate excretion is largely controlled by URAT1 (SLC22A12), a member of the organic anion transporter superfamily. This study reports the specific expression of URAT1 on human aortic vascular smooth muscle cells, as assessed by reverse transcription-PCR and Western blot analysis. Expression of URAT1 was localized to the cell membrane. Evidence that the URAT1 transporter was functional was provided by the finding that uptake of 14C-urate was significantly inhibited in the presence of probenecid, an organic anion transporter inhibitor. It is proposed that URAT1 may provide a mechanism by which uric acid enters the human vascular smooth muscle cell, a finding that may be relevant to the role of uric acid in cardiovascular disease.
Representation is representation of similarities
Authors: Shimon Edelman
Journal: Behavioral and Brain Sciences (1998)

Advanced perceptual systems are faced with the problem of securing a principled (ideally, veridical) relationship between the world and its internal representation. I propose a unified approach to visual representation, addressing the need for superordinate and basic-level categorization and for the identification of specific instances of familiar categories. According to the proposed theory, a shape is represented internally by the responses of a small number of tuned modules, each broadly selective for some reference shape, whose similarity to the stimulus it measures. This amounts to embedding the stimulus in a low-dimensional proximal shape space spanned by the outputs of the active modules. This shape space supports representations of distal shape similarities that are veridical as Shepard's (1968) second-order isomorphisms (i.e., correspondence between distal and proximal similarities among shapes, rather than between distal shapes and their proximal representations). Representation in terms of similarities to reference shapes supports processing (e.g., discrimination) of shapes that are radically different from the reference ones, without the need for the computationally problematic decomposition into parts required by other theories. Furthermore, a general expression for similarity between two stimuli, based on comparisons to reference shapes, can be used to derive models of perceived similarity ranging from continuous, symmetric, and hierarchical ones, as in multidimensional scaling (Shepard 1980), to discrete and nonhierarchical ones, as in the general contrast models (Shepard & Arabie 1979; Tversky 1977).
What is the most appropriate treatment for patellar tendinopathy?
Authors: J L Cook, K M Khan
Journal: British Journal of Sports Medicine (2001)

LeadersThe medicolegal aspects of automatism in mild head injury Automatism or automatic behaviour was originally described in the Hippocratic corpus in relation to sleepwalking and other nocturnal behaviours. 1 Despite its long history, this area of automatism remains confused and imprecise in the medical and legal literature.Within English common law, it is a fundamental principle that the intent (mens rea) and the act (actus reus) must occur together to constitute the crime. 2As such, the absence of a mens rea means that the person at that point in time lacks the intent to commit a crime.In the legal view, post-traumatic automatism is a form of "sane" automatism because it results from an external factor, for example, a blow to the head, rather than from a disease of the mind (which is responsible for "insane" automatisms). 3 4As a legal defence under English law, if successful, post-traumatic automatism leads to acquittal rather than the judge deciding the disposal as in the case of insane automatism. 5 In recent years, a number of cases of footballers appearing before disciplinary tribunals for striking and other charges have claimed in their defence that they suVered a prior concussive injury and at the time of the alleged incident were suVering from a "post-traumatic automatism" and as a result were not responsible for their actions.In one celebrated case in Australian football, this defence was successful and resulted in the sport's administrative body developing specific guidelines to outlaw this potential defence.This topic of post-traumatic automatism has only a limited amount of published information to guide practitioners, players, administrators, and lawyers and this paper seeks to establish appropriate medical guidelines in this area.
Biochemical effects of 2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil and 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine in mouse leukemic cells sensitive and resistant to 1-beta-D-arabinofuranosylcytosine.
Authors: Ting-Chao Chou, Joseph H. Burchenal, Franz A. Schmid, Thomas J. Braun, Tsann-Long Su, Kyoichi A. Watanabe, Jack J. Fox, Frederick S. Philips
Journal: Cancer Research (1982)

Fluoro-5- methyl -1 -/A®-D-arabinofuranosyluracil(FMAU), like 2'-fluoro-5-iodo-1-/8-D-arabinofuranosylcytosine (FIAC), has potent antiviral activity, but unlike FIAC, It also has antileu- kemic effects. The two agents and 1-yS-o-arabinofuranosylcy- tosine (ara-C) are compared herein. Concentrations inhibiting thymidine (dThd) incorporation into DMA by 50% are for FMAU, FIAC, and ara-C, respectively, in L1210/0, 32, 353, and 0.2 fiM and in L1210/ara-C, 17, >10,000, and 3,900 JUM.Other FMAU analogs, 2'-fluoro-5-iodo-1-/S-D-arabinofuranosyluracil and 2'-fluoro-5-ethyl-1-yS-D-arabinofuranosyluracil, inhibit dThd incorporation equally in ara-C-sensitive and -resistant cells; however, their potencies are weaker than that of FMAU. Similar results are obtained when (3H)deoxyadenosine is used as a precursor of incorporation. In l_1210/0 cells, incorporation of (2-14C)FMAU radioactivity into DMA is competitively inhibited by dThd and deoxycytidine (dCyd), whereas the incorporation of (2-14C)FIAC radioactivity is competitively inhibited by dCyd but not appreciably by dThd. In L1210/ara-C cells, incorpo ration of (2-14C)FMAU is competitively inhibited by dThd but not by dCyd. In L1210/0 cells, FMAU has little inhibitory effect on the tritium release from (5-3H)deoxyuridine but markedly inhibits the incorporation of (2-14C)deoxyuridine into DMA. FIAC, by contrast, predominately inhibits the release of tritium from (5-3H)deoxyuridine but has little effect on subsequent incorporation into DNA. These results suggest that (a) FIAC, but not FMAU, is cross-resistant to ara-C; (b) FMAU is partic ularly effective against L1210/ara-C cells; (c) FIAC behaves metabolically like dCyd, and FMAU like dThd and dCyd; (d) dCyd and dThd may be used as chemotherapeutic modulators; and (e) FIAC predominately inhibits dThd kinase and/or thy midine monophosphate synthetase, whereas FMAU predomi nately inhibits DNA polymerase and/or nucleotide kinases. Similar conclusions were obtained when P815/0 and P815/ ara-C cells were used. The relative potencies of FIAC and FMAU in inhibiting dThd incorporation into DNA in leukemic sublines correlate with cytotoxicity in vitro and chemothera peutic effects in vivo.
Genes required for B cell development
Authors: Mary Ellen Conley
Journal: Journal of Clinical Investigation (2003)

Mutations in a variety of genes can cause congenital agammaglobulinemia and a failure of B cell development. The currently known genes encode components of the pre–B cell receptor or proteins that are activated by cross-linking of the pre–B cell receptor. Defects in these genes result in a block in B cell differentiation at the pro–B to pre–B cell transition. A patient with a translocation involving a previously unknown gene, LRRC8, demonstrated a block at exactly the same point in B cell differentiation (see the related article beginning on page 1707). It will be interesting to determine whether the protein encoded by this gene interacts with the pre–B cell receptor signal transduction pathway or is involved in a new pathway.
Serum Lipids and Lipoproteins in Chinese Men and Women
Authors: Wenying Yang, Jianzhong Xiao, Zhaojun Yang, Linong Ji, Weiping Jia, Jianping Weng, Juming Lu, Zhongyan Shan, Jie Liu, Haoming Tian, Qiuhe Ji, Dalong Zhu, Jiapu Ge, Lixiang Lin, Li Chen, Xiaohui Guo, Zhigang Zhao, Qiang Li, Zhiguang Zhou, Guangliang Shan, Jiang He
Journal: Circulation (2012)

Because of rapid change in lifestyle risk factors, cardiovascular disease has become the leading cause of death in China. We sought to estimate the national levels of serum lipids and lipoproteins among the Chinese adult population.We conducted a cross-sectional study in a nationally representative sample of 46 239 adults aged ≥20 years. Fasting serum total, high-density lipoprotein, and low-density lipoprotein cholesterol and triglycerides were measured by standard methods. The age-standardized estimates of total, high-density lipoprotein, and low-density lipoprotein cholesterol and triglycerides were 4.72 (95% confidence interval, 4.70-4.73), 1.30 (1.29-1.30), 2.68 (2.67-2.70), and 1.57 (1.55-1.58) mmol/L, respectively, in the Chinese adult population. In addition, 22.5% (21.8-23.3%) or 220.4 million (212.1-228.8) Chinese adults had borderline high total cholesterol (5.18-6.21 mmol/L), and 9.0% (8.5-9.5%) or 88.1 million (83.4-92.8) had high total cholesterol (≥6.22 mmol/L). The population estimates for borderline high (3.37-4.13 mmol/L), high (4.14-4.91 mmol/L), and very high (≥4.92 mmol/L) low-density lipoprotein cholesterol were 13.9% (13.3-14.5%) or 133.5 million (127.0-140.1), 3.5% (3.3-3.8%) or 33.8 million (31.2-36.5), and 3.0% (2.8-3.3%) or 29.0 million (26.3-31.8) persons, respectively. In addition, 22.3% (21.6-23.1%) or 214.9 million (207.0-222.8) persons had low high-density lipoprotein cholesterol (<1.04 mmol/L). The awareness, treatment, and control of borderline high or high total cholesterol were 11.0%, 5.1%, and 2.8%, respectively, in the Chinese adult population.Serum total and low-density lipoprotein cholesterol levels were high and increasing in the Chinese population. Without effective intervention, atherosclerotic cardiovascular diseases may soar in the near future in China.
Mental Stress–Induced Ischemia and All-Cause Mortality in Patients With Coronary Artery Disease
Authors: David S. Sheps, Robert P. McMahon, Lewis Becker, Robert M. Carney, Kenneth E. Freedland, Jerome D. Cohen, David Sheffield, A. David Goldberg, Mark W. Ketterer, Carl J. Pepine, James M. Raczynski, Kathleen Light, David S. Krantz, Peter H. Stone, Genell L. Knatterud, Peter G. Kaufmann
Journal: Circulation (2002)

Background — Ischemia during laboratory mental stress tests has been linked to significantly higher rates of adverse cardiac events. Previous studies have not been designed to detect differences in mortality rates. Methods and Results — To determine whether mental stress–induced ischemia predicts death, we evaluated 196 patients from the Psychophysiological Investigations of Myocardial Ischemia (PIMI) study who had documented coronary artery disease and exercise-induced ischemia. Participants underwent bicycle exercise and psychological stress testing with radionuclide imaging. Cardiac function data and psychological test results were collected. Vital status was ascertained by telephone and by querying Social Security records 3.5±0.4 years and 5.2±0.4 years later. Of the 17 participants who had died, new or worsened wall motion abnormalities during the speech test were present in 40% compared with 19% of survivors ( P =0.04) and significantly predicted death (rate ratio=3.0; 95% CI, 1.04 to 8.36; P =0.04). Ejection fraction changes during the speech test were similar in patients who died and in survivors ( P =0.9) and did not predict death even after adjusting for resting ejection fraction ( P =0.63), which was similar in both groups (mean, 56.4 versus 59.7; P =0.24). Other indicators of ischemia during the speech test (ST-segment depression, chest pain) did not predict death, nor did psychological traits, hemodynamic responses to the speech test, or markers of the presence and severity of ischemia during daily life and exercise. Conclusions — In patients with coronary artery disease and exercise-induced ischemia, the presence of mental stress–induced ischemia predicts subsequent death.
Inherited <i>NUDT15</i> Variant Is a Genetic Determinant of Mercaptopurine Intolerance in Children With Acute Lymphoblastic Leukemia
Authors: Jun J. Yang, Wendy Landier, Wenjian Yang, Chengcheng Liu, Lindsey Hageman, Cheng Cheng, Deqing Pei, Yanjun Chen, Kristine R. Crews, Nancy Kornegay, F. Lennie Wong, William E. Evans, Ching-Hon Pui, Smita Bhatia, Mary V. Relling
Journal: Journal of Clinical Oncology (2015)

Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL.The discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model.MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10(-9)) and rs116855232 in NUDT15 (P = 8.8 × 10(-9)), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others.We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.
Klotho Prevents Renal Calcium Loss
Authors: R. Todd Alexander, Titia E. Woudenberg-Vrenken, Jan Buurman, Henry Dijkman, Bram C. J. van der Eerden, Johannes P.T.M. van Leeuwen, René J. Bindels, Joost G. Hoenderop
Journal: Journal of the American Society of Nephrology (2009)

Disturbed calcium (Ca(2+)) homeostasis, which is implicit to the aging phenotype of klotho-deficient mice, has been attributed to altered vitamin D metabolism, but alternative possibilities exist. We hypothesized that failed tubular Ca(2+) absorption is primary, which causes increased urinary Ca(2+) excretion, leading to elevated 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and its sequelae. Here, we assessed intestinal Ca(2+) absorption, bone densitometry, renal Ca(2+) excretion, and renal morphology via energy-dispersive x-ray microanalysis in wild-type and klotho(-/-) mice. We observed elevated serum Ca(2+) and fractional excretion of Ca(2+) (FE(Ca)) in klotho(-/-) mice. Klotho(-/-) mice also showed intestinal Ca(2+) hyperabsorption, osteopenia, and renal precipitation of calcium-phosphate. Duodenal mRNA levels of transient receptor potential vanilloid 6 (TRPV6) and calbindin-D(9K) increased. In the kidney, klotho(-/-) mice exhibited increased expression of TRPV5 and decreased expression of the sodium/calcium exchanger (NCX1) and calbindin-D(28K), implying a failure to absorb Ca(2+) through the distal convoluted tubule/connecting tubule (DCT/CNT) via TRPV5. Gene and protein expression of the vitamin D receptor (VDR), 25-hydroxyvitamin D-1-alpha-hydroxylase (1alphaOHase), and calbindin-D(9K) excluded renal vitamin D resistance. By modulating the diet, we showed that the renal Ca(2+) wasting was not secondary to hypercalcemia and/or hypervitaminosis D. In summary, these findings illustrate a primary defect in tubular Ca(2+) handling that contributes to the precipitation of calcium-phosphate in DCT/CNT. This highlights the importance of klotho to the prevention of renal Ca(2+) loss, secondary hypervitaminosis D, osteopenia, and nephrocalcinosis.
Epithelioid Granulomas in Hodgkin Disease
Authors: Michael J. O'Connell
Journal: JAMA (1975)

Histologic sections of spleen and liver prepared from tissue obtained during exploratory laparotomy and splenectomy in 91 untreated patients with Hodgkin disease were reviewed to assess the incidence and possible implications of noncaseating, epitheliod, sarcoid-like granulomas. The 17 patients with granulomas and the 74 patients without granulomas did not differ appreciably with respect to pretreatment indexes. All patients were observed for at least 15 months following laparotomy or until the time of death (range, 15 to 67 months; median, 25 months). The 17 patients with granulomas tended to have fewer relapses, longer survival, and lower incidence of subsequent herpes zoster infection compared to the 74 without granulomas. The presence of epithelioid granulomas in association with Hodgkin disease may reflect a host response to the tumor with favorable prognostic implications.
Low-density lipoproteins generated during an oral fat load in mild hypertriglyceridemic and healthy subjects are smaller, denser, and have an increased low-density lipoprotein receptor binding affinity
Authors: Davide Noto, Manfredi Rizzo, Carlo Maria Barbagallo, Angelo Baldassare Cefalù, Alessia Lo Verde, Francesca Fayer, Alberto Notarbartolo, Maurizio Rocco Averna
Journal: Metabolism (2006)
<i>MRE11</i> Deficiency Increases Sensitivity to Poly(ADP-ribose) Polymerase Inhibition in Microsatellite Unstable Colorectal Cancers
Authors: Eduardo Vilar, Catherine M. Bartnik, Stephanie L. Stenzel, Leon Raskin, Jaeil Ahn, Victor Moreno, Bhramar Mukherjee, Maria D. Iniesta, Meredith A. Morgan, Gad Rennert, Stephen B. Gruber
Journal: Cancer Research (2011)

Microsatellite instability (MSI) is displayed by approximately 15% of colorectal cancers (CRC). Defective DNA mismatch repair generates mutations at repetitive DNA sequences such as those located in the double strand break (DSB) repair gene MRE11. We assessed the mutational status of MRE11 in a panel of 17 CRC cell lines and 46 primary tumors and found a strong correlation with MSI status in both cell lines and tumors. Therefore, we hypothesized that deficiency in MRE11 may sensitize CRC cells to poly(ADP-ribose) polymerase (PARP-1) inhibition based on the concept of synthetic lethality. We further assessed the activity of the PARP-1 inhibitor, ABT-888, in CRC cell lines and observed preferential cytotoxicity in those MSI cell lines harboring mutations in MRE11 compared with both wild-type cell lines and microsatellite stable (MSS) cell lines. A significant correlation between MRE11 expression levels and cytotoxicity to ABT-888 at 10 μM was observed (R² = 0.915, P < 0.001). Using two experimental approaches, including short hairpin RNA knocking down MRE11 in the wild-type and MSS cell line SW-480 and a second cell line model transfected with mutant MRE11, we experimentally tried to confirm the role of MRE11 in conferring sensitivity to PARP-1 inhibition. Both models led to changes in proliferation in response to ABT-888 at different concentrations, and a drug-response effect was not observed, suggesting a possible contribution of additional genes. We conclude that MSI colorectal tumors deficient in DSB repair secondary to mutation in MRE11 show a higher sensitivity to PARP-1 inhibition. Further clinical investigation of PARP-1 inhibitors is warranted in MSI CRCs.
Robot-Assisted Endoscopic Submucosal Dissection Is Effective in Treating Patients With Early-Stage Gastric Neoplasia
Authors: Soo Jay Phee, Nageshwar Reddy, Philip W.Y. Chiu, Pradeep Rebala, Guduru V. Rao, Zheng Wang, Zhenglong Sun, Jennie Y.Y. Wong, Khek–Yu Ho
Journal: Clinical Gastroenterology and Hepatology (2012)