tbuckley/cabot-search huggingface dataset:
Abstract 4181: Absence and/or functional loss of the tumor suppressor Tnk1 is associated with various human neoplasms
Authors: Kishalay Hoare, Tammy Flagg, Bernadetta M. Zamora, Mary K. Reinhard, Sarasija Hoare, W.Stratford May
Journal: Cancer Research (2012)

Abstract The protein tyrosine kinase activity of Tnk1 (Thirty-eight negative kinase) is required for cell growth suppression due to the fact that the kinase-dead Tnk1 triggers aberrant cell growth, including anchorage independent growth with hyperactivation of Ras (Hoare et. al. 2003; Azoitie et.al. 2007). Mechanistically, the cell growth suppression is associated with the inhibition of Ras activity and the down-stream Raf1-MAPK growth pathway (Hoare et.al. 2003) resulting in G2-M phase cell cycle arrest. A tumor suppressor role of Tnk1 was subsequently confirmed by developing the Tnk1 knockout mouse model by homologous recombination. The TNK1 knockout mice develop many types of tumors upon aging, with B-cell lymphomas, hepatomas, hepatocellular carcinomas, lung adenomas and adenocarcinomas being the most frequent malignancies (Hoare et.al. 2008; May et. al. 2010). Significantly, 40% of Tnk1-/-mice and 26% of Tnk1+/− mice had more than one tumor type develop, likely reflecting Tnk1's broad tumor suppressor function. To confirm the tumor suppressor function of the 72 kDa Tnk1 in human tumors and cell lines, we screened for Tnk1's expression and analyzed its intrinsic/auto kinase activity and in vitro kinase activity. Results indicate that in tumors and cell lines, Tnk1 is either expressed or absent. In B-/T-lymphoma and lung adenocarcinoma cell lines, to name a few, such as Ramos, Jurkat, REH and A549, absence of Tnk1 is associated with aberrant Ras activity, suggesting that loss of Tnk1 expression may contribute to tumor development. In patient specimens and cell lines namely, K562, T47D, MCF7, NCI H82, NCI H387, HEPG2 and HUH, the expressed Tnk1 is found to lack auto-kinase activity and is therefore, inactive in vivo. This data indicates that tumor growth depends on the maintenance of Tnk1 in its inactive form through interaction(s) with scaffolding protein(s) and/or due to SNPs found in its kinase domain. Strikingly, the Hodgkin lymphoma cell line L540 is found to express a tyrosine phosphorylated 60 kDa truncated Tnk-(C17ORF61) fusion gene product (termed tTnk1) raising doubt that it is an activated form of Tnk1 (Gu et. al. 2010). Interestingly, we found that t-Tnk1 is kinase-dead, as it fails to Y-phosphorylate Grb2, a Tnk1 substrate. This supports the concept that t-Tnk1 and/or functionally inactive Tnk1 expressed in tumor cells may function in a dominant negative manner to maintain tumor growth. In conclusion, Tnk1, in human, also functions as a tumor suppressor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4181. doi:1538-7445.AM2012-4181
Clinical carpal scaphoid injuries
Authors: M R A Young, J H Lowry, N W McLeod, R S Crone
Journal: BMJ (1988)

Etude retrospective de 161 sujets presentant des douleurs au niveau du scaphoide persistant apres 3 semaines, et pas de fractures lors des premieres radiographies. Les fractures decelees au bout de 3 semaines sont peu frequentes (2%); elles demandent une immobilisation prolongee
The role of electrosprayed apatite nanocrystals in guiding osteoblast behaviour
Authors: Eng San Thian, Zeeshan Ahmad, Jie Huang, Mohan J. Edirisinghe, Suwan N. Jayasinghe, Deborah C. Ireland, Roger A. Brooks, Neil Rushton, William Bonfield, Serena M. Best
Journal: Biomaterials (2008)
Consultation skills of young doctors: II--Most young doctors are bad at giving information.
Authors: P Maguire, S Fairbairn, C Fletcher
Journal: BMJ (1986)

Forty young doctors, half of whom had had feedback training in interviewing as students, were assessed five years later. Each interviewed three patients and after being given results of examination, investigations, and diagnosis and prognosis returned to discuss them with each patient for 10 minutes. These discussions were filmed on videotape and evaluated. There was no difference between the scores of interview trained and control doctors. Though most gave simple information on diagnosis and treatment, few mentioned investigations, aetiology, or prognosis. Very few obtained and took any account of patients' views or expectations of these matters. Some young doctors do discover for themselves how best to give patients information and advice, but most remain extremely incompetent. This is presumably because they get no training as students in this important aspect of clinical practice. This deficiency should be corrected, and competence tested before qualification to practise.
Evidence that less replacement therapy is required for dental extractions in hemophiliacs
Authors: Stephen E. Steinberg, Jack Levin, William R. Bell
Journal: American Journal of Hematology (1984)

Abstract The requirements for factor VIII (AHF) or factor IX (PTC) of hemophilic patients undergoing dental extractions were evaluated to determine the minimum effective regimen. Sixteen patients underwent 19 operative procedures. The mean total dose of factor VIII or IX was 45.8 U/kg for 11 procedures with preoperative replacement therapy and 34.5 U/kg for the 8 without. Four patients received no replacement therapy at all. Our results compared favorably to published studies employing factor replacement alone or in combination with antifibrinolytic agents such as epsilon‐amino‐caproic acid (EACA), with respect to blood products utilized and duration of hospitalization. However, our patients received less factor replacement than usually suggested. General anesthesia with intubation, a common recommendation, was not required in any patients. Dental extractions can be carried out in hemophiliacs using less replacement therapy than currently recommended. In some circumstances, no replacement therapy may be necessary. The reported efficacy of antifibrinolytic agents in reducing the requirement for replacement therapy is difficult to assess because of the relatively large amount of prophylactic factor replacement used in conjunction with these agents.
Evaluation of computer support for prescribing (CAPSULE) using simulated cases
Authors: R T Walton, C Gierl, P Yudkin, H Mistry, M P Vessey, J Fox
Journal: BMJ (1997)

<h3>Abstract</h3> <b>Objective:</b> To evaluate the potential effect of computer support on general practitioners9 prescribing, and to compare the effectiveness of three different support levels. <b>Design:</b> Crossover experiment with balanced block design. <b>Subjects:</b> Random sample of 50 general practitioners (42 agreed to participate) from 165 in a geographically defined area of Oxfordshire. <b>Interventions:</b> Doctors prescribed for 36 simulated cases constructed from real consultations. Levels of computer support were control (alphabetical list of drugs), limited support (list of preferred drugs), and full support (the same list with explanations available for suggestions). <b>Main outcome measures:</b> Percentage of cases where doctors ignored a cheaper, equally effective drug; prescribing score (a measure of how closely prescriptions matched expert recommendations); interview to elicit doctors9 views of support system. <b>Results:</b> Computer support significantly improved the quality of prescribing. Doctors ignored a cheaper, equally effective drug in a median 50% (range 25%-75%) of control cases, compared with 36% (8%-67%) with limited support and 35% (0-67%) with full support (P&lt;0.001). The median prescribing score rose from 6.0 units (4.2-7.0) with control support to 6.8 (5.8 to 7.7) and 6.7 (5.6 to 7.8) with limited and full support (P&lt;0.001). Of 41 doctors, 36 (88%) found the system easy to use and 24 (59%) said they would be likely to use it in practice. <b>Conclusions:</b> Computer support improved compliance with prescribing guidelines, reducing the occasions when doctors ignored a cheaper, equally effective drug. The system was easy to operate, and most participating doctors would be likely to use it in practice.
Dexamethasone incorporating liposomes: an in vitro study of their applicability as a slow releasing delivery system of dexamethasone from covered metallic stents
Authors: Paraskevi Kallinteri, Sophia G Antimisiaris, Dimitris Karnabatidis, Christina Kalogeropoulou, Irene Tsota, Dimitris Siablis
Journal: Biomaterials (2002)
Antiangiogenic Strategies on Defense: On the Possibility of Blocking Rebounds by the Tumor Vasculature after Chemotherapy
Authors: Yuval Shaked, Robert S. Kerbel
Journal: Cancer Research (2007)

Rapid or accelerated tumor cell repopulation after significant tumor cell killing induced by various cytotoxic agents often compromises the expected therapeutic benefit of such tumor responses. Here, we discuss the concept that tumor cell repopulation after certain cytotoxic therapies, using vascular disrupting agents as an example, may be aided by a reactive, systemic host response involving the mobilization of bone marrow-derived circulating cells, including endothelial progenitor cells, which subsequently home to the vasculature of treated tumors and promote tumor neovascularization. These vasculogenic "rebounds" can be blocked, at least in some cases, by treatment with an antiangiogenic drug. There is limited preliminary evidence that maximum tolerated dose chemotherapy causes a similar effect. This could constitute one way by which antiangiogenic therapy could increase the efficacy of conventional cytotoxic chemotherapy regimens; it also raises the specter of new molecular targets for systemic cancer therapies which are involved in therapy-induced bone marrow-derived cell mobilization, homing to tumors, and tumor retention.
SEPTICAEMIA AND ENCEPHALITIS IN RELATION TO VACCINATION
Authors: F. T. Grey, W. M. Whittaker
Journal: BMJ (1930)

I~~~~~~~~~~~~~~~~~~~~~~~f*MDCAL JcOuaMAL 15 to 16. in boy%ors the flattening starts at 10. ', a"d (t,i- tinilles to about 13', hbit the r ise to 15 toj 16 is (jilite striking.1 n11 irls t hore is ai flatteillilog 'r'o011 9. to 101, all(i .gailnat 121, Ilit tihe late iMs is iiOt so iinrkltkE io, tlog siffictienlti ojbvlotu.I'lie influielnce of puhei tv On tile Ihlowing-(do-w pel iods is, of comrse, pllrely iniferential, but it is at least si(i-estive; while tire coititiiu(ed rise-which appears to go oni after the clhil(l leaves the school, suilice tlie niliml)er of sliccesses exceeded exl)ectation-miay he dile to a -arietv of (ailses.It milay be that ini the laIter years of trainjiitr More attention is paid to man ipulative work, and that tl is 1de1)s ani iilierent power foi siici per- if1t,rm lces, wh llichi his liot llreviolisly vbeen given a Chance, anld 0o gix 10ves 0je )optplit itv for the receptioll of stimulili and ar (outsingof interest niecessary to conivert neuiro- blasts to ilell olles;.I t muillst be reilemlulered, however that the Teiina ia tests arie by no ineans p llelv iintelle(tulal ill theil S(o1)(, an(l should r(ecord (lapacity for iulpailil platlte and(l intelle(ctuial adlvance aplart firom'1 achieveuent, though uletiss mil l aoblasts have been converted cap)acity will reilbain lndiS(ov-irO)le.Oni tie other hbaind, the coliti ilariaCrk of proigress in Ill a ccorldan(ce w-ithi the filn(liil (I of a previou,s investig-atioll w-e 4m,ade ilno children of sIiglit deoreeso; of backwavrdniess.'I'lls showe '}d that while manliv (If the'se' clhi ld en in led to a(j rust to the leq ni rinent ts of Ii fe dlui ii i1(g tihe school pe riol, they una(le renmarkably good adjuiistmnenlts later on in lalte atlolese-vnce and early adult life.'I'lTe 15and.l 16 ye-ar (o(1s may he appuroachinig tliis perliwl of llo(ie sluccess,fu1ladjulst inelnt, and(I tberefore imake a better showvinug iit tlheir tests than imighit have beeir expected frollm tile _ommour spl)lIosi t ioi that mental (ldefective.sstto) sliol(t in thleir develolpmieiit.The folihewil)ng talbles shtox-tIme findings at the v-arious ages exchlsive of tlle illrociles.TABLE 1.-Ba y.s mnd 6(irl.stogethler (S? hVdrei).Age Grlm)urs: 7-8 8-9 9-10 10-11 11-12 12-13 13-14 114 15 15+ Highest I.Q.foniid 80 73 82 77 74 71 70 66 62 Averagementalage 5 51o% cr 6l% 6°, 7j3 712 7}1 8rA2 Average aetual age 7 P2 8r I 9i _ l0rf 11h1 121A 131A 141A 15jZ.Average I.Q.
REPORT ON THERAPEUTIC PROPERTIES OF PENICILLIN: VIII. Laboratory Control of Penicillin Therapy
Authors: L. P. Garrod
Journal: BMJ (1944)

JOURNAL be useful in stopping a series of recurrent boils.Probably the solution would have been more effective than the ointment, although more extravagant.Penicillin applied externally appeared to have no effect whatever on the eVolution of-an individual boil.Acne (3 Cases) Case L.-M., aged 23.Pustular acne of face, neck, chest, and back of 8 years' duration.Culture sterile. 15,000units (sodium salt in lanette base, 400 units per g.) in 12 days (applied twice daily).Very slight improvement.Case 2.-M., aged 22. Pustular acne of face, back, and chest.Duration 6 years.Organisms, Staph.aureus.37,069 units (sodium salt in lanette base, 400 units per g.) ifn 34 daily applications to left side of back only.Improvement for first 10 days; thereafter i.s.q.Case 3.-M., aged 40.Acne conglobata of 5 years' duration.Arms, chest, and back extensively affected.Organisms, Staph.
Advertisement for Zantac
Authors: F M Hickey, D L Higson
Journal: BMJ (1994)

want to lose the benefits.It seems we are each unwittingly introducing a different bias by what we say.If randomised clinical trials in cancer are to be successful in recruiting patients, clinicians need more guidance on what is meant by informed consent and how to obtain it.An article by Tobias and Souhami2 and subsequent correspondence3 aired some of the issues but did not help with the practicalities.Perhaps the BMJ could commission a "How to do it" article-or is it too difficult?
An Account of the Foxglove
Authors: W. O Goldthorp
Journal: BMJ (2009)

William Withering, discover of digitalis, began practising as a doctor in Stafford in 1767. It was a small practice, and he found time to study flowers, which were painted for him by Helena Cook, who became his wife. He soon moved to Birmingham, where his first book, A Botanical Arrangement , was published in 1776. It went through several editions and was still in print 101 years later.

In 1775 Withering, whose father was an apothecary, was given a secret family recipe for the treatment of dropsy. Withering realised that the active ingredient was the foxglove. This he tried out on his patients over the years in different preparations …
Efficacy of a general practitioner training campaign for early detection of melanoma in France
Authors: F. Grange, A.S. Woronoff, R. Bera, M. Colomb, B. Lavole, E. Fournier, F. Arnold, C. Barbe
Journal: British Journal of Dermatology (2013)

To date, no strategy for improving early diagnosis of melanoma has been evaluated on a population basis in France.To evaluate the efficacy of a general practitioner (GP) awareness and training campaign in a pilot French geographical region (Champagne-Ardenne), including 1.34 million inhabitants, 1241 GPs, 56 dermatologists and a population-based melanoma registry.All GPs received repeated awareness postal mailings in 2008 and 398 (32.1%) attended training sessions organized by 27 dermatologists. The pre- (2005-7) and post-campaign (2009-11) periods were compared for the following: primary endpoint - the world-standardized incidence of very thick melanomas (VTM) (Breslow thickness ≥ 3 mm); secondary endpoints--the mean Breslow thickness; the proportions of VTM and of thin (< 1 mm) melanomas among invasive cases; and the ratio of in situ/all melanoma cases. Similar measures were performed in the control area of Doubs/Belfort territory (655,000 ha), where no similar campaign was carried out.The incidence of VTM decreased from 1.07 to 0.71 per 100 000 habitants per year (P = 0.01), the mean Breslow thickness from 1.95 to 1.68 mm (P = 0.06) and the proportion of VTM from 19.2% to 12.8% (P = 0.01). The proportion of thin and in situ melanomas increased from 50.9% to 57.4% (P = 0.05) and from 20.1% to 28.2% (P = 0.001), respectively. No significant variation was observed in Doubs/Belfort territory.These results strongly support the efficacy of such a campaign targeting GPs and provide a rationale for a larger public health campaign in France, including training of GPs by dermatologists and encouraging patients to ask their GP for a systematic skin examination.
Nelfinavir augments proteasome inhibition by bortezomib in myeloma cells and overcomes bortezomib and carfilzomib resistance
Authors: M Kraus, J Bader, H Overkleeft, C Driessen
Journal: Blood Cancer Journal (2013)

HIV protease inhibitors (HIV-PI) are oral drugs for HIV treatment. HIV-PI have antitumor activity via induction of ER-stress, inhibition of phospho-AKT (p-AKT) and the proteasome, suggesting antimyeloma activity. We characterize the effects of all approved HIV-PI on myeloma cells. HIV-PI were compared regarding cytotoxicity, proteasome activity, ER-stress induction and AKT phosphorylation using myeloma cells in vitro. Nelfinavir is the HIV-PI with highest cytotoxic activity against primary myeloma cells and with an IC50 near therapeutic drug blood levels (8–14 μM), irrespective of bortezomib sensitivity. Only nelfinavir inhibited intracellular proteasome activity in situ at drug concentrations <40 μM. Ritonavir, saquinavir and lopinavir inhibited p-AKT comparable to nelfinavir, and showed similar synergistic cytotoxicity with bortezomib against bortezomib-sensitive cells. Nelfinavir had superior synergistic activity with bortezomib/carfilzomib in particular against bortezomib/carfilzomib-resistant myeloma cells. It inhibited not only the proteasomal β1/β5 active sites, similar to bortezomib/carfilzomib, but in addition the β2 proteasome activity not targeted by bortezomib/carfilzomib. Additional inhibition of β2 proteasome activity is known to sensitize cells for bortezomib and carfilzomib. Nelfinavir has unique proteasome inhibiting activity in particular on the bortezomib/carfilzomib-insensitive tryptic (β2) proteasome activity in intact myeloma cells, and is active against bortezomib/carfilzomib-resistant myeloma cells in vitro.
Secondary sociopathy and opportunistic reproductive strategy
Authors: Jay Belsky
Journal: Behavioral and Brain Sciences (1995)

Abstract Mealey's analysis of secondary sociopathy has much in common with Belsky, Steinberg, and Draper's (1991) evolutionary theory of socialization. Both draw attention to the potential influence of early rearing in the promotion of a cold, detached, manipulative, and opportunistic style of relating to others and, in so doing, raise the question of whether secondary sociopathy represents a facultative reproductive strategy.
Use of endogenous, stable lead isotopes to determine release of lead from the skeleton.
Authors: D R Smith, J D Osterloh, A R Flegal
Journal: Environmental Health Perspectives (1996)

The stable lead isotope methodology can be used to study the release of lead from bone into the circulation because of its potential to distinguish circulatory lead from "older" and isotopically different skeletal lead that may have been accumulated years or decades earlier. Here we report the initial results from a larger ongoing study that evaluates the skeleton as a source of lead to the circulation in environmentally exposed human subjects. Lead concentrations and stable lead isotopic compositions were measured in blood and trabecular bone samples obtained from five patients who underwent total hip or knee joint replacement. All subjects contained low blood (1-6 micrograms/dl) and bone (0.6-7 micrograms/g dry weight) lead concentrations typical of environmentally exposed individuals. There were relatively large differences in the lead isotopic compositions between the paired blood and bone samples from each subject. These isotopic differences are attributed to differences in the lead isotopic compositions of past versus current lead exposures and to the long elimination half-life of lead in the skeleton compared to lead in the circulation. Based on these data, we determined that the skeleton contributed 40-70% of the lead in the blood of these subjects. This initial study demonstrates the utility of the stable lead isotope methodology for investigating the release of lead from the skeleton. It also shows that the skeleton can be an important endogenous source of lead exposure in environmentally exposed humans.
Enrichment of functional CD8 memory T cells specific for MUC1 in bone marrow of patients with multiple myeloma
Authors: Carmen Choi, Mathias Witzens, Marianna Bucur, Markus Feuerer, Nora Sommerfeldt, Andreas Trojan, Anthony Ho, Volker Schirrmacher, Hartmut Goldschmidt, Philipp Beckhove
Journal: Blood (2004)
Orexin Receptor Antagonists Differ from Standard Sleep Drugs by Promoting Sleep at Doses That Do Not Disrupt Cognition
Authors: Jason M. Uslaner, Spencer J. Tye, Donnie M. Eddins, Xiaohai Wang, Steven V. Fox, Alan T. Savitz, Jacquelyn Binns, Christopher E. Cannon, Susan L. Garson, Lihang Yao, Robert Hodgson, Joanne Stevens, Mark R. Bowlby, Pamela L. Tannenbaum, Joseph Brunner, Terrence P. Mcdonald, Anthony L. Gotter, Scott D. Kuduk, Paul J. Coleman, Christopher J. Winrow, John J. Renger
Journal: Science Translational Medicine (2013)

Current treatments for insomnia, such as zolpidem (Ambien) and eszopiclone (Lunesta), are γ-aminobutyric acid type A (GABAA)-positive allosteric modulators that carry a number of side effects including the potential to disrupt cognition. In an effort to develop better tolerated medicines, we have identified dual orexin 1 and 2 receptor antagonists (DORAs), which promote sleep in preclinical animal models and humans. We compare the effects of orally administered eszopiclone, zolpidem, and diazepam to the dual orexin receptor antagonist DORA-22 on sleep and the novel object recognition test in rat, and on sleep and two cognition tests (delayed match to sample and serial choice reaction time) in the rhesus monkey. Each compound's minimal dose that promoted sleep versus the minimal dose that exerted deficits in these cognitive tests was determined, and a therapeutic margin was established. We found that DORA-22 has a wider therapeutic margin for sleep versus cognitive impairment in rat and rhesus monkey compared to the other compounds tested. These data were further supported with the demonstration of a wider therapeutic margin for DORA-22 compared to the other compounds on sleep versus the expression of hippocampal activity-regulated cytoskeletal-associated protein (Arc), an immediate-early gene product involved in synaptic plasticity. These findings suggest that DORAs might provide an effective treatment for insomnia with a greater therapeutic margin for sleep versus cognitive disturbances compared to the GABAA-positive allosteric modulators currently in use.