tbuckley/cabot-search huggingface dataset:
Molecular basis for incomplete penetrance of familial retinoblastoma
Authors: Yoonsoo Park, Akihito Kubo, Takefumi Komiya, Amy Coxon, Frederic Kaye
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2777 

We previously showed that kindreds with low penetrant (lp) retinoblastoma carry unique mutant RB alleles which are null for E2F1 binding but retain partial tumor suppressor activity. To define the molecular basis for incomplete penetrance, we now show that three common lp alleles representing single codon alterations (R661W, C712R, and del480) exhibit >50% wildtype RB activity as measured by i) site-specific cyclin-mediated phosphorylation at key regulatory serine residues, ii) by transcriptional activation in mammalian cells, and iii) by ‘flat cell’ differentiation in mammalian cells in vivo. These data demonstrate that these lp alleles, present in 30 different lp kindreds, retain substantially greater functional activity than previously suggested using in vitro GST-based binding assays. We, therefore, hypothesize that the molecular basis for incomplete penetrance associated with partially active RB alleles may result from the need for an additional genetic/epigenetic event for tumorigenesis that is not required for null RB alleles. Retinoblastoma and small-cell carcinoma are the only tumors that are commonly associated (>90%) with mutational inactivation of RB. Although retinoblastoma tumors from lp families were not available for this analysis, we have studied a small-cell tumor that is homozygous for a common lp RB allele. Genetic analysis of this tumor has allowed us to test several predictions about the molecular basis of incomplete penetrance and has identified candidate pathways for this phenotype.
Abstract 14809: Out of Proportion Pulmonary Hypertension Has the Long-Term Prognostic Significance in Patients Admitted With Acute Decompensated Heart Failure, Regardless of Reduced or Preserve Left Ventricular Ejection Fraction
Authors: Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Kentaro Ozu, Takumi Kondo, Kaoruko Sengoku, Hironori Yamomoto, Tsutomu Kawai, Satoshi Takahashi, Masashi Ishimi, Hideyuki Hakui, Masatake Fukunami
Journal: Circulation (2013)

Backgroud: Pulmonary hypertension (PH) in patients with heart failure, which is associated with a greater mortality rate, is classified as reactive (out of proportion) and passive PH. However, ther...
Abstract 1861: S100P is a potential biomarker in distinguishing mucinous from non-mucinous pancreatic cysts and predicting invasive adenocarcinoma
Authors: Wenyi Mi, David L. Diehl, Jianhi Shi, Joseph Blansfield, Marie Hunsinger, Wannian Yang, Fan Lin
Journal: Cancer Research (2014)

Abstract Introduction. Our previous publications demonstrated that S100P was a highly sensitive biomarker in identifying pancreatic mucinous neoplasms (PMNs) and invasive ductal adenocarcinomas (ADCs) on both cytological and surgical specimens. When working on pancreatic cystic lesions, there are two important undertakings: 1) distinguishing mucinous neoplasms from non-mucinous cysts and 2) predicting the presence of invasive adenocarcinomas. In this study, we investigated the potential utility of S100P for these purposes. Design. Thirty pancreatic cystic fluid samples obtained by EUS-FNA biopsy were retrieved from Geisinger Biospecimen Bank. Diagnosis was based on definitive cytological diagnosis in all cases and additional surgical pathology confirmation in 11 cases. These 30 samples included 7 benign cysts in Group 1, 14 PMNs in Group 2, and 9 ADCs in Group 3. The S100P protein level of each sample was quantitatively measured by enzyme-linked immunoassay (ELISA) (CircuLex S100P ELISA kit, MBL International Corporation) according to the vendor's protocol. Results. The results are summarized in Table 1. Marked elevation of S100P was seen in 6 of 9 ADCs (2129.81 + 1834.34 ng/ml), in contrast to the moderate increase in Group 2 (666.67 + 1439.91 ng/ml) and the minimal increase in Group 1 (22.27 + 18.62 ng/ml). Using 50 ng/ml as a cutoff value to differentiate a PMN/ADC (Group 2 and Group 3) from a benign cyst (Group 1), the sensitivity, specificity, positive predictive value and negative predictive value for identifying a PMN/ADC were 60.9%, 100%, 100%, and 43.8%, respectively. Conclusion. These preliminary data suggest that S100P is a useful biomarker in identifying invasive adenocarcinomas and in distinguishing mucinous neoplasms from non-mucinous cysts. Caution should be taken since some ADCs may show only mildly increased S100P levels, similar to some PMNs and non-mucinous cysts. Additional study in a large series of cases is needed to substantiate the current findings. Table 1.Summary of S100P protein level (ng/ml) in 30 pancreatic cysts by ELISACase #Benign CystsMucinous NeoplasmsAdenocarcinomas12.515.4812.6722.596.6413.2135.0410.8544.07428.0918.371849.20530.6219.802162.98643.2929.402831.67743.75120.483076.958137.954441.439158.684736.0810221.7711285.6012290.78133385.19144628.37 Citation Format: Wenyi Mi, David L. Diehl, Jianhi Shi, Joseph Blansfield, Marie Hunsinger, Wannian Yang, Fan Lin. S100P is a potential biomarker in distinguishing mucinous from non-mucinous pancreatic cysts and predicting invasive adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1861. doi:10.1158/1538-7445.AM2014-1861
Abstract 10406: The Development of Negative T Waves After Initial ST-Segment Elevation Differs Between Takotsubo Cardiomyopathy and Reperfused Anterior Acute Myocardial Infarction
Authors: Masami Kosuge, Toshiaki Ebina, Kiyoshi Hibi, Satoshi Morita, Noriaki Iwahashi, Mitsuaki Endo, Nobuhiko Maejima, Kengo Tsukahara, Kazuaki Uchino, Toshiyuki Ishikawa, Satoshi Umemura, Kazuo Kimura
Journal: Circulation (2010)

In takotsubo cardiomyopathy (TC), negative T waves (Neg T) with QT interval prolongation commonly appear after resolution of ST-segment elevation (ST↑) in precordial leads, but also occur in reperf...
Early cytotoxic lymphocyte expansion contributes to a deep molecular response to dasatinib in patients with newly diagnosed chronic myeloid leukemia in the chronic phase: results of the D‐first study
Authors: Noriyoshi Iriyama, Shin Fujisawa, Chikashi Yoshida, Hisashi Wakita, Shigeru Chiba, Shinichiro Okamoto, Kimihiro Kawakami, Naoki Takezako, Takashi Kumagai, Koiti Inokuchi, Kazuma Ohyashiki, Jun Taguchi, Shingo Yano, Tadahiko Igarashi, Yasuji Kouzai, Satoshi Morita, Junichi Sakamoto, Hisashi Sakamaki
Journal: American Journal of Hematology (2015)

Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study (ClinicalTrials.gov NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100 mg day(-1) ) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/μL for NK cells and 347/μL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP.
Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation
Authors: Kristian Wachtell, Björn Hornestam, Mika Lehto, David J. Slotwiner, Eva Gerdts, Michael H. Olsen, Peter Aurup, Björn Dahlöf, Hans Ibsen, Stevo Julius, Sverre E. Kjeldsen, Lars H. Lindholm, Markku S. Nieminen, Jens Rokkedal, Richard B. Devereux
Journal: Journal of the American College of Cardiology (2005)
Abstract 15759: Arrhythmic Risk Stratification in Patients With Idiopathic Dilated Cardiomyopathy and No Conventional Indications for Implantable Cardiac Defibrillator
Authors: Marco Merlo, Fabrizio Pirozzi, Davide Stolfo, D’Angelo Gianluca, Marco Alonge, Marta Gigli, Giulia Barbati, Massimo Zecchin, Gianfranco Sinagra
Journal: Circulation (2014)

Background: Primary prevention of major ventricular arrhythmias (MVA) in patients with idiopathic dilated cardiomyopathy (IDCM) is primarily based on left ventricular ejection fraction (LVEF) assessment. Nonetheless, unexpected MVA still affect patients considered at low-risk (LR), attesting the limitation of the current risk stratification. We sought to identify the clinical predictors of MVA in patients with IDCM and no conventional indications for implantable cardioverter defibrillator (ICD). Methods: In this retrospective, case-control study, among 922 patients enrolled in the Heart Muscle Disease Registry of Trieste from 1988 to 2013, we analyzed 414 IDCM patients considered at LR according to the following criteria: LVEF≥36% and no previous episodes of MVA (sustained ventricular tachycardia/non-fatal ventricular fibrillation (SVT/VF), appropriate ICD intervention and sudden cardiac death (SD)). Data were recorded at the last available medical examination before the index event. Patients were optimally treated at the time of index evaluation (87% and 84% of ACE-inhibitors/sartans and beta-blockers, respectively). Results: Over a median follow-up of 43 (IQR 16-116) months, 45 patients (11 % of patients at LR; 31% of the all MVA in whole IDCM population) experienced MVA. The mean age at the time of event was 51±14 years. They were characterized by a previous history of syncope in 10 patients (22%), LVEF of 42±6% with a normal value (&gt;50%) in 10 patients (22%), significant LV dilation (VTDi&gt;90ml/m 2 ) in 16 patients (35%) and left bundle branch block 12 patients (27%). Independent risk factors for MVA in LR subgroup were previous history of syncope (OR 3.41, 1.45-8.03, p=0.004), larger left ventricular dilation (OR 2.62, 1.72-3.99, p&lt;0.0001) and longer duration of disease (OR 1.39, 1.42-2.63, p&lt;0.0001). Conclusions: in a large cohort of IDCM patients nearly one-third of the MVA occurred in a population apparently at LR of events. History of syncope, larger LV dilatation and significant duration of disease emerged as strong predictors of MVA and should be considered in the arrhythmic risk stratification of patients without conventional criteria for SD primary protection.
The case for involuntary hospitalization of the mentally ill
Authors: Paul Chodoff
Journal: American Journal of Psychiatry (1976)

The author examines three points of view on the question of society's right to involuntarily hospitalize a mentally ill individual. The "abolitionists" oppose involuntary hospitalization entirely; the medical model psychiatrists support the need for commitment under certain circumstances and so do the civil liberties lawyers, but by different standards. The author believes that with the current overreliance on the dangerousness standard, we are witnessing a pendular swing in which the rights of the mentally ill to be treated and protected are being set aside in the rush to give them their freedom. He favors a return to the use of medical criteria by psychiatrists, albeit with constructive legal safeguards.
Recent Advances on Plasmin Inhibitors for the Treatment of Fibrinolysis‐Related Disorders
Authors: Rami A. Al‐Horani, Umesh R. Desai
Journal: Medicinal Research Reviews (2014)

Abstract Growing evidence suggests that plasmin is involved in a number of physiological processes in addition to its key role in fibrin cleavage. Plasmin inhibition is critical in preventing adverse consequences arising from plasmin overactivity, e.g., blood loss that may follow cardiac surgery. Aprotinin was widely used as an antifibrinolytic drug before its discontinuation in 2008. Tranexamic acid and ε‐aminocaproic acid, two small molecule plasmin inhibitors, are currently used in the clinic. Several molecules have been designed utilizing covalent, but reversible, chemistry relying on reactive cyclohexanones, nitrile warheads, and reactive aldehyde peptidomimetics. Other major classes of plasmin inhibitors include the cyclic peptidomimetics and polypeptides of the Kunitz and Kazal‐type. Allosteric inhibitors of plasmin have also been designed including small molecule lysine analogs that bind to plasmin's kringle domain(s) and sulfated glycosaminoglycan mimetics that bind to plasmin's catalytic domain. Plasmin inhibitors have also been explored for resolving other disease states including cell metastasis, cell proliferation, angiogenesis, and embryo implantation. This review highlights functional and structural aspects of plasmin inhibitors with the goal of advancing their design.
MRP3-polymorphisms influence the response to platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients
Authors: Angela Risch, Heike Dally, Phillip Müller, Lutz Edler, Birgit Jäger, Siegfried Tuengerthal, Jürgen R. Fischer, Peter Schmezer, Bertold Spiegelhalder, Peter Drings, Helmut Bartsch
Journal: Cancer Research (2005)

6170   The two multidrug resistance-associated proteins MRP2 (ABCC2) and MRP3 (ABCC3) are efflux pumps located in the plasma membrane. The cytostatic drug etoposide (frequently used in the treatment of small cell lung cancer (SCLC)) is a known substrate of both MRP2 and MRP3, however, whether MRP3 also transports platinum-based drugs is still controversial. MRPs confer  in vitro  multidrug resistance and recently, expression of MRP2 and MRP3 has been shown to correlate with chemotherapy reponse and lower rate of survival in AML patients. MRP genotype information may therefore be useful for individualized treatment. We examined three genetic polymorphisms in these transporters:  MRP2  3563T>A resulting in Val1188Glu,  MRP3  3890G>A leading to Arg1297His and the synonymous mutation  MRP3  3942C>T. The phenotypic impact of these changes on cytostatic-drug distribution is as yet, unknown. For 303 Caucasian patients with primary lung cancer (166 NSCLC and 137 SCLC), response to first line chemotherapy was assessed after the 2nd cycle based on the recommended response evaluation criteria in solid tumors (RECIST). The drugs administered were mostly etoposide for SCLC or gemcitabine for NSCLC combined with carbo- or cisplatin respectively. DNA isolated from peripheral blood was genotyped for  MRP2 3563 ,  MRP3 3890  and  MRP3 3942  by fluorescence-based melting curve analysis (LightCycler). Genotype frequencies were compared in responders (complete or partial remission) and non-responders (stable or progressive disease). The prognostic value of the three polymorphisms was analyzed using multiple logistic regression adjusted for pack-year group and stage. None of the investigated polymorphisms significantly modified response in the whole group, nor in the subgroup of patients treated with etoposide. However, in the subgroup of NSCLC patients who received platinum-based treatment (n=118) the risk of being a non-responder was significantly decreased for carriers of the  MRP3  3942T  allele (OR 0.29; CI 0.13-0.71) while carriers of the  MRP3 3890A  allele responded less well than those who were homozygous wild type (OR 2.94; CI 1.05-8.19). In conclusion, two MRP3 polymorphisms were identified which may have an impact on response to platinum-based therapy. Evidence of their possible linkage as well as their phenotypic characterisation will require further investigation.  Funded in part by the “Deutsche Krebshilfe”, the “Verein zur F o rderung der Krebsforschung in Deutschland” e. V. and the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israeli’s Ministry of Science (MOS) .
Ethics in the practice of psychiatry: update on the results of enforcement of the code
Authors: R A Moore
Journal: American Journal of Psychiatry (1985)

From 1950 to 1973, 82 charges of unethical conduct were made against APA members; of the 12 (15%) members who were found unethical, six were expelled. From 1972 to 1983, 382 members were charged; 86 (23%) were found unethical and 27 of them were expelled. The charges most often involved patient exploitation and illegal conduct. The proportion of the membership charged in each APA area varied by as much as 3:1; some district branches had many charges (69 was the most), and many had none. With all the limitations, the system of enforcement is valuable, but there is much room for improvement.
Transcriptomic and Proteomic Patterns of Systemic Inflammation in On-Pump and Off-Pump Coronary Artery Bypass Grafting
Authors: V. Tomic, S. Russwurm, E. Möller, R.A. Claus, M. Blaess, F. Brunkhorst, M. Bruegel, K. Bode, F. Bloos, J. Wippermann, T. Wahlers, H.-P. Deigner, J. Thiery, K. Reinhart, M. Bauer
Journal: Circulation (2005)

Background— Coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) provides controlled operative conditions but induces a whole-body inflammatory response capable of initiating devastating morbidity and mortality. Although technically more demanding, deliberate avoidance of CPB in off-pump surgery attenuates the physiological insult associated with CABG. Methods and Results— To systematically assess the molecular mechanisms underlying the better-preserved remote organ function, we studied gene expression patterns in leukocytes and plasma proteomic response to on-pump and off-pump CABG. Proteomic analysis confirmed (tumor necrosis factor-α, interleukin [IL]-6, IL-10) and expanded (eg, interferon [IFN]-γ, granulocyte colony–stimulating factor [G-CSF], monocyte chemotactic protein-1, macrophage inflammatory protein-1β) the mediators released on CPB, whereas blood leukocyte transcriptomics suggested that circulating leukocytes are not primarily responsible for this response. Interestingly, release of some cytokines (eg, IL-6, IFN-γ, G-CSF) was observed on off-pump surgery to a similar extent but with delayed kinetics. A total of 45 of 4868 transcripts were identified to be significantly altered as a result of initiation of CPB. Systematic analysis of transcriptional activation by CPB revealed primarily genes involved in inflammation-related cell–cell communication (such as L-selectin or intercellular adhesion molecule-2) and signaling (such as IL-1, IL-8, or IL-18 receptors and toll-like receptors 4, 5, and 6), thus confirming a “primed” phenotype of circulating peripheral blood mononuclear cells. Conclusions— Gene array and multiplex protein analysis, only in concert, can illuminate the molecular mechanisms responsible for systemic sequelae of CPB and indicate that circulating leukocytes overexpress adhesion and signaling factors after contact with CPB, which potentially facilitates their trapping, eg, in the lungs and may promote a subsequent tissue-associated inflammatory response.
Abstract 979: Novel Nanoparticle Cardiac Troponin I Assay Detects Myocardial Injury in Most Patients with Unstable Angina: Observations from the PROTECT-TIMI 30 Trial
Authors: Sean R Wilson, Marc S Sabatine, Sarah Sloan, Sabina A Murphy, Eugene Braunwald, David A Morrow
Journal: Circulation (2008)

At least one third of patients with non-ST elevation acute coronary syndrome present with no evidence of myonecrosis using current generation assays for cardiac troponin I (cTnI). Interest in devel...
Abstract 13315: Nanoparticle-Mediated Monocyte-Selective Delivery of Pitavastatin Prevents Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in ApoE-Deficient Mice
Authors: Shunsuke Katsuki, Tetsuya Matoba, Jun-ichiro Koga, Kaku Nakano, Kei Sato, Kenji Sunagawa, Kensuke Egashira
Journal: Circulation (2010)

Background: Abdominal aortic aneurysm (AAA) is a common disease and lethal when it progresses to rupture, but current medical treatments are insufficient to suppress AAA progression. Recent studies...
<i>Untitled (Bouquet of Flowers)</i>
Authors: Jeanette M. Smith
Journal: JAMA (2015)

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HIV and risk behaviour among men who have sex with men in Denmark – the 2006 Sex Life Survey
Authors: S  A Cowan, J Haff
Journal: Eurosurveillance (2008)

Behavioural surveys among men who have sex with men (MSM) are important for HIV surveillance. The Danish 2006 Sex Life Survey was carried out as a self administered questionnaire, which was distributed at gay venues and bars and posted on the internet. The questionnaire was completed by 3,141 MSM. We describe the methods, the respondent group and the results of the 2006 Sex Life Survey, and discuss it implications. The main finding of this survey is that 33% of the respondents have practised unsafe sex, defined as unprotected anal intercourse with one or more partners of different or unknown HIV status. In the three previous Sex Life Surveys of 2000, 2001 and 2002, this figure was between 26% and 28%.