tbuckley/cabot-search huggingface dataset:
Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in <i>LKB1</i>-Mutant Lung Cancer
Authors: Yan Liu, Kevin Marks, Glenn S. Cowley, Julian Carretero, Qingsong Liu, Thomas J.F. Nieland, Chunxiao Xu, Travis J. Cohoon, Peng Gao, Yong Zhang, Zhao Chen, Abigail B. Altabef, Jeremy H. Tchaicha, Xiaoxu Wang, Sung Choe, Edward M. Driggers, Jianming Zhang, Sean T. Bailey, Norman E. Sharpless, D. Neil Hayes, Nirali M. Patel, Pasi A. Janne, Nabeel Bardeesy, Jeffrey A. Engelman, Brendan D. Manning, Reuben J. Shaw, John M. Asara, Ralph Scully, Alec Kimmelman, Lauren A. Byers, Don L. Gibbons, Ignacio I. Wistuba, John V. Heymach, David J. Kwiatkowski, William Y. Kim, Andrew L. Kung, Nathanael S. Gray, David E. Root, Lewis C. Cantley, Kwok-Kin Wong
Journal: Cancer Discovery (2013)

The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase, which coordinates cell growth, polarity, motility, and metabolism. In non-small cell lung carcinoma, LKB1 is somatically inactivated in 25% to 30% of cases, often concurrently with activating KRAS mutations. Here, we used an integrative approach to define novel therapeutic targets in KRAS-driven LKB1-mutant lung cancers. High-throughput RNA interference screens in lung cancer cell lines from genetically engineered mouse models driven by activated KRAS with or without coincident Lkb1 deletion led to the identification of Dtymk, encoding deoxythymidylate kinase (DTYMK), which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 deficiency in mouse and human lung cancer lines. Global metabolite profiling showed that Lkb1-null cells had a striking decrease in multiple nucleotide metabolites as compared with the Lkb1-wild-type cells. Thus, LKB1-mutant lung cancers have deficits in nucleotide metabolism that confer hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors.
Hip pain in an adolescent after injury while playing football
Authors: J. T. Machin, D. R. Wordsworth, S. Raja, S. Burtt
Journal: BMJ (2012)

A 15 year old boy presented to the emergency department with left hip pain that first occurred while playing football. The exact mechanism of injury was unclear, but he thought that he may have “kicked the ground rather than the ball.” He was unable to continue playing because of pain on weight bearing, and he was forced to limp from the field with assistance. He arrived at hospital after a couple of hours. His developmental progress and medical history were normal, with no previous hip problems reported.

On examination he was constitutionally well. Tenderness of the left hemipelvis was noted on palpation. He was reluctant to perform any active movement of the hip or bear his weight, and he was unable to perform a straight leg raise. Passive movements (including rotation) caused generalised tenderness, with passive hip extension causing the most discomfort. Examinations of both his back and left knee were unremarkable. Anterioposterior radiography of the pelvis was performed (fig 1⇓).



Fig 1 Anterioposterior radiograph of the pelvis in a 15 year old boy





### 1 Given the history, what is the differential diagnosis?

#### Short answer

A simple muscular strain is the most likely diagnosis given the history. Hip dislocation, slipped capital femoral epiphysis, pelvic and femoral fractures, and infection are all potentially serious causes of pelvic pain in adolescents. Neoplastic and rheumatological disorders also merit consideration.

#### Long answer

All types of fracture pattern could present in this manner—growth plate injuries, apophyseal avulsion fractures, non-physeal fractures, pathological fractures, femoral neck fractures, and stress fractures. Dislocation of the hip is unlikely given the relatively innocuous mechanism of injury. Non-physeal injuries, such as femoral neck fracture, are usually caused by …
Platelet-Activating Factor Acetylhydrolase Is Mainly Associated With Electronegative Low-Density Lipoprotein Subfraction
Authors: Sonia Benítez, José Luis Sánchez-Quesada, Vicent Ribas, Oscar Jorba, Francisco Blanco-Vaca, Francesc González-Sastre, Jordi Ordóñez-Llanos
Journal: Circulation (2003)

Background— Electronegative LDL [LDL(−)], a modified subfraction of LDL present in plasma, induces the release of interleukin-8 and monocyte chemotactic protein-1 from cultured endothelial cells. Methods and Results— We demonstrate that platelet-activating factor acetylhydrolase (PAF-AH) is mainly associated with LDL(−). LDL(−) had 5-fold higher PAF-AH activity than the nonelectronegative LDL subfraction [LDL(+)] in both normolipemic and familial hypercholesterolemic subjects. Western blot analysis after SDS-PAGE confirmed these results, because a single band of 44 kDa corresponding to PAF-AH appeared in LDL(−) but not in LDL(+). Nondenaturing polyacrylamide gradient gel electrophoresis demonstrated that PAF-AH was bound to LDL(−) regardless of LDL size. In accordance with the above findings, nonesterified fatty acids, a cleavage product of PAF-AH, were increased in LDL(−) compared with LDL(+). Conclusions— The high PAF-AH activity observed in LDL(−) could be related to the proinflammatory activity of these lipoproteins toward cultured endothelial cells.
Activation of β-Catenin Signaling in Androgen Receptor–Negative Prostate Cancer Cells
Authors: Xinhai Wan, Jie Liu, Jing-Fang Lu, Vassiliki Tzelepi, Jun Yang, Michael W. Starbuck, Lixia Diao, Jing Wang, Eleni Efstathiou, Elba S. Vazquez, Patricia Troncoso, Sankar N. Maity, Nora M. Navone
Journal: Clinical Cancer Research (2012)

Abstract Purpose: To study Wnt/β-catenin in castrate-resistant prostate cancer (CRPC) and understand its function independently of the β-catenin–androgen receptor (AR) interaction. Experimental Design: We carried out β-catenin immunocytochemical analysis, evaluated TOP-flash reporter activity (a reporter of β-catenin–mediated transcription), and sequenced the β-catenin gene in MDA prostate cancer 118a, MDA prostate cancer 118b, MDA prostate cancer 2b, and PC-3 prostate cancer cells. We knocked down β-catenin in AR-negative MDA prostate cancer 118b cells and carried out comparative gene-array analysis. We also immunohistochemically analyzed β-catenin and AR in 27 bone metastases of human CRPCs. Results: β-Catenin nuclear accumulation and TOP-flash reporter activity were high in MDA prostate cancer 118b but not in MDA prostate cancer 2b or PC-3 cells. MDA prostate cancer 118a and MDA prostate cancer 118b cells carry a mutated β-catenin at codon 32 (D32G). Ten genes were expressed differently (false discovery rate, 0.05) in MDA prostate cancer 118b cells with downregulated β-catenin. One such gene, hyaluronan synthase 2 (HAS2), synthesizes hyaluronan, a core component of the extracellular matrix. We confirmed HAS2 upregulation in PC-3 cells transfected with D32G-mutant β-catenin. Finally, we found nuclear localization of β-catenin in 10 of 27 human tissue specimens; this localization was inversely associated with AR expression (P = 0.056, Fisher's exact test), suggesting that reduced AR expression enables Wnt/β-catenin signaling. Conclusion: We identified a previously unknown downstream target of β-catenin, HAS2, in prostate cancer, and found that high β-catenin nuclear localization and low or no AR expression may define a subpopulation of men with bone metastatic prostate cancer. These findings may guide physicians in managing these patients. Clin Cancer Res; 18(3); 726–36. ©2011 AACR.
BRAF and RAS oncogenes regulate Rho GTPase pathways to mediate migration and invasion properties in human colon cancer cells: a comparative study
Authors: Eleni Makrodouli, Eftychia Oikonomou, Michal Koc, Ladislav Andera, Takehiko Sasazuki, Senji Shirasawa, Alexander Pintzas
Journal: Molecular Cancer (2011)

Abstract Background Colorectal cancer is a common disease that involves genetic alterations, such as inactivation of tumour suppressor genes and activation of oncogenes. Among them are RAS and BRAF mutations, which rarely coexist in the same tumour. Individual members of the Rho (Ras homology) GTPases contribute with distinct roles in tumour cell morphology, invasion and metastasis. The aim of this study is to dissect cell migration and invasion pathways that are utilised by BRAF V600 E as compared to KRAS G12V and HRAS G12V oncoproteins. In particular, the role of RhoA (Ras homolog gene family, member A), Rac1 (Ras-related C3 botulinum toxin substrate 1) and Cdc42 (cell division cycle 42) in cancer progression induced by each of the three oncogenes is described. Methods Colon adenocarcinoma cells with endogenous as well as ectopically expressed or silenced oncogenic mutations of BRAF V600E , KRAS G12V and HRAS G12V were employed. Signalling pathways and Rho GTPases were inhibited with specific kinase inhibitors and siRNAs. Cell motility and invasion properties were correlated with cytoskeletal properties and Rho GTPase activities. Results Evidence presented here indicate that BRAF V600E significantly induces cell migration and invasion properties in vitro in colon cancer cells, at least in part through activation of RhoA GTPase. The relationship established between BRAF V600E and RhoA activation is mediated by the MEK-ERK pathway. In parallel, KRAS G12V enhances the ability of colon adenocarcinoma cells Caco-2 to migrate and invade through filopodia formation and PI3K-dependent Cdc42 activation. Ultimately increased cell migration and invasion, mediated by Rac1, along with the mesenchymal morphology obtained through the Epithelial-Mesenchymal Transition (EMT) were the main characteristics rendered by HRAS G12V in Caco-2 cells. Moreover, BRAF and KRAS oncogenes are shown to cooperate with the TGFβ-1 pathway to provide cells with additional transforming properties. Conclusion This study discriminates oncogene-specific cell migration and invasion pathways mediated by Rho GTPases in colon cancer cells and reveals potential new oncogene-specific characteristics for targeted therapeutics.
Population Proteomics: Quantitative Variation Within and Among Populations in Cardiac Protein Expression
Authors: B. B. Rees, T. Andacht, E. Skripnikova, D. L. Crawford
Journal: Molecular Biology and Evolution (2010)

Population analysis of gene expression is typically achieved by quantifying levels of mRNA; however, gene expression is also a function of protein translation and turnover. Therefore, a complete understanding of population variation in gene expression requires quantitative knowledge of protein expression within and among natural populations. We used two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) to quantitatively compare expression of heart ventricle proteins among 18 individuals in three populations of the teleost fish Fundulus. Among populations, expressions between orthologous proteins and mRNAs were generally positively correlated. Additionally, similar to the pattern of cardiac mRNA expression for the same populations, we found considerable variation in protein expression both within and among populations: Of 408 protein features in 2D gels, 34% are significantly different (P < 0.01) among individuals within a population, 9% differ between populations, and 12% have a pattern of expression that suggests they have evolved by natural selection. Although similar to mRNA expression, the frequency of significant differences among populations is larger for proteins. Similar to mRNA expressions, expressions of most proteins are correlated to the expressions of many other proteins. However, the correlations among proteins are more extensive than the correlation for similar RNAs. These correlations suggest a greater coordinate regulation of protein than mRNA expression. The larger frequency of significant differences among populations and the greater frequency of correlated expression among proteins versus among RNAs suggest that the molecular mechanisms affecting protein expression enhance the differences among populations, and these regulatory steps could be a source of variation for adaptation.
Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques.
Authors: A I Spira, P A Marx, B K Patterson, J Mahoney, R A Koup, S M Wolinsky, D D Ho
Journal: The Journal of Experimental Medicine (1996)

We used the simian immunodeficiency virus (SIV)/rhesus macaque model to study events that underlie sexual transmission of human immunodeficiency virus type 1 (HIV-1). Four female rhesus macaques were inoculated intravaginally with SIVmac251, and then killed 2, 5, 7, and 9 d later. A technique that detected polymerase chain reaction-amplified SIV in situ showed that the first cellular targets for SIV were in the lamina propria of the cervicovaginal mucosa, immediately subjacent to the epithelium. Phenotypic and localization studies demonstrated that many of the infected cells were likely to be dendritic cells. Within 2 d of inoculation, infected cells were identified in the paracortex and subcapsular sinus of the draining internal iliac lymph nodes. Subsequently, systemic dissemination of SIV was rapid, since culturable virus was detectable in the blood by day 5. From these results, we present a model for mucosal transmission of SIV and HIV-1.
Conceptual Objectives for a Model Course in Psychopharmacology in Psychiatric Education
Authors: FRITZ A. FREYHAN
Journal: American Journal of Psychiatry (1969)

Although pharmacotherapy has become the most widely used psychiatric treatment, psychiatric education reveals a striking neglect of clinical psychopharmacology. Our educational objective should be the development of knowledge in pharmacopsychiatry that is not limited to useful drugs but embodies interrelated aspects of clinical and experimental psychiatry. The author presents some ideas for a model course that attempts to integrate psychopharmacological topics with clinical psychopathology and psychiatric theory in general.
Treatment of Paget's disease of bone with single dose intravenous pamidronate.
Authors: R A Watts, S J Skingle, M M Bhambhani, G Pountain, A J Crisp
Journal: Annals of the Rheumatic Diseases (1993)

To assess the efficacy of a single intravenous infusion of pamidronate in Paget's disease of bone.Fourteen patients with active Paget's disease (raised serum alkaline phosphatase, bone pain or neurological involvement) were treated with a single intravenous infusion of 105 mg pamidronate. Patients were assessed for biochemical and clinical improvement for up to two years following treatment. A further infusion was given following symptomatic relapse (pain at a known site of pagetic involvement).Serum alkaline phosphatase fell following treatment, with a nadir 5.9 months after treatment. Bone pain was improved in nine of 12 patients after six months. Retreatment of four patients resulted in a similar response.Single dose intravenous pamidronate (105 mg) is a convenient and effective treatment for Paget's disease.
The clinical evaluation of respiratory tract infection caused by MRSA
Authors: Kei Nakashima, Yoshihito Otsuka, Haruki Kobayashi, Naoko Katsurada, Nobuhiro Asai, Hideki Makino, Masafumi Misawa, Yoshihiro Ohkuni, Norihiro Kaneko, Masahiro Aoshima
Journal: European Respiratory Journal (2012)

[Background]Most of the MRSA detected in respiratory specimens were colonization. However pneumonia due to MRSA becomes severe and improvement of outcomes were important.[Methods]Medical records of 11 MRSA pneumonia patients among 106 patients with MRSA detected in respiratory specimens from June 2010 to May 2011 at Kameda Medical Center were reviewed retrospectively. The following variables were studied: patient background, hospitalization, drug susceptibility, outcomes. [Results] Mean age was 73.5 y.o. Eight patients were male, 3 were female. Eight were HAP, 3 were NHCAP (Nursing and healthcare associated pneumonia). Four patients have Chronic kidney disease, 3 have neurological disorder and 2 were under steroid administration. Nine patients (81,8%) were detected through microbial substitution. Period from admission to detection was 41.9 days, period from antimicrobial initiation to detection was 23.1 days, numbers of antimicrobial agents were 2.1 on average. Nine patients (81.8%) have polymicrobial detection. P.aeruginosa, S.maltophilia, K.pneumonia were detected in 4, 3, 2 patients frequently. All of the anti MRSA agents administered were VCM. MIC of VCM were 1 with 2 patients, 0.5 with 1 patients, unexamined with 1 patients in the 4 patients after the introduction of broth microdilution method. Duation of administration was 12.8 days on average. In 9 patients (84.6%) beta-lactam agents were administered in combination. Duration of hospitalization was 124.8 days on average, 5 patients (45.5%) were died.[Conclusions]Most of the MRSA pneumonia were HAP and polymicrobial detection. MRSA caused the prolonged hospitalization and poor prognosis.
How Predictive Is a History of Penicillin Allergy?—Reply
Authors: Alan R. Salkind
Journal: JAMA (2001)

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GPR92/LPA5 lysophosphatidate receptor mediates megakaryocytic cell shape change induced by human atherosclerotic plaques
Authors: Anna L. Khandoga, Dharmendra Pandey, Ulrich Welsch, Richard Brandl, Wolfgang Siess
Journal: Cardiovascular Research (2010)

AimsOxidative processes and vascular inflammation underlying atherosclerosis lead to an accumulation of lysophosphatidic acid (LPA) molecules in the atheromatous intima. LPA, a platelet-activating component of human atherosclerotic plaques, possibly contributes to atherothrombus formation after plaque rupture. Human platelets express mRNA for the G protein-coupled receptors LPA1–7 that derive from megakaryocytes. The aim of our study was to identify the functional LPA receptor(s) in human platelets by silencing individual LPA receptors in megakaryocytic (MK) cells.
NFATc3-Induced Reductions in Voltage-Gated K <sup>+</sup> Currents After Myocardial Infarction
Authors: Charles F. Rossow, Elina Minami, Eric G. Chase, Charles E. Murry, L.F. Santana
Journal: Circulation Research (2004)

Reductions in voltage-activated K + (Kv) currents may underlie arrhythmias after myocardial infarction (MI). We investigated the role of β-adrenergic signaling and the calcineurin/NFAT pathway in mediating the reductions in Kv currents observed after MI in mouse ventricular myocytes. Kv currents were produced by the summation of 3 distinct currents: I to , I Kslow1 , and I Kslow2 . At 48 hours after MI, we found a 4-fold increase in NFAT activity, which coincided with a decrease in the amplitudes of I to , I Kslow1 , and I Kslow2 . Consistent with this, mRNA and protein levels of Kv1.5, 2.1, 4.2, and 4.3, which underlie I Kslow1 , I Kslow2 , and I to , were decreased after MI. Administration of the β-blocker metoprolol prevented the activation of NFAT and the reductions in I to , I Kslow1 , and I Kslow2 after MI. Cyclosporine, an inhibitor of calcineurin, also prevented the reductions in these currents after MI. Importantly, Kv currents did not change after MI in ventricular myocytes from NFATc3 knockout mice. Conversely, chronic β-adrenergic stimulation or expression of an activated NFATc3 decreased Kv currents to a similar extent as MI. Taken together, these data indicate that NFATc3 plays an essential role in the signaling pathway leading to reduced I to , I Kslow1 , and I Kslow2 after MI. We propose that increased β-adrenergic signaling after MI activates calcineurin and NFATc3, which decreases I to , I Kslow1 , and I Kslow2 via a reduction in Kv1.5, Kv2.1, Kv4.2, and Kv4.3 expression.
Tamoxifen Chemoprevention Treatment and Time to First Diagnosis of Estrogen Receptor-Negative Breast Cancer
Authors: Y. Shen, J. P. Costantino, J. Qin
Journal: JNCI Journal of the National Cancer Institute (2008)

Tamoxifen's effect of reducing the risk of estrogen receptor (ER)-positive breast cancer is well established. Its effect on the time to first diagnosis of breast cancer has not been reported. We used information from the randomized, placebo-controlled Breast Cancer Prevention Trial (BCPT) to make that evaluation.A total of 13,388 women enrolled in BCPT, of whom 174 were diagnosed with ER-positive tumors and 69 were diagnosed with ER-negative tumors. A flexible semiparametric cure rate model was used to assess the effects of tamoxifen vs placebo treatment on the time to disease diagnosis. Multivariable logistic regression, adjusted for age and tumor size at diagnosis, was used to assess the association between the mammography detection rate and treatment with tamoxifen. All statistical tests were two-sided.The median times to diagnosis of ER-positive tumors were similar in both treatment groups (43 months for the placebo arm and 51 months for the treatment arm). Times to diagnosis of ER-negative tumors, however, differed between treatment groups, with median times to diagnosis of 36 months in the placebo arm vs 24 months in the tamoxifen arm (difference = 12 months, 95% confidence interval [CI] = 3 to 17 months, P = .037). ER-negative breast cancers in the tamoxifen arm were more likely than those in the placebo arm to be detected by mammography than by clinical breast examination alone after adjustment for age and tumor size, but the increase was only marginally statistically significant (odds ratio for mammography detection = 4.68, 95% CI = 0.86 to 25.32, P = .073). No differences were found in the mammography detection rates for ER-positive tumors by treatment arm.Although tamoxifen treatment does not reduce the incidence of ER-negative breast cancer, it may have advanced detection of such tumors by approximately 1 year, compared with that in the placebo arm. The time to diagnosis of ER-positive breast cancer was similar in both treatment arms.