tbuckley/cabot-search huggingface dataset:
Computational complexity analysis can help, but first we need a theory
Authors: Todd Wareham, Iris van Rooij, Moritz Müller
Journal: Behavioral and Brain Sciences (2008)

Abstract Leech et al. present a connectionist algorithm as a model of (the development) of analogizing, but they do not specify the algorithm's associated computational-level theory, nor its computational complexity. We argue that doing so may be essential for connectionist cognitive models to have full explanatory power and transparency, as well as for assessing their scalability to real-world input domains.
Addressing Genetic Tumor Heterogeneity through Computationally Predictive Combination Therapy
Authors: Boyang Zhao, Justin R. Pritchard, Douglas A. Lauffenburger, Michael T. Hemann
Journal: Cancer Discovery (2013)

Abstract Recent tumor sequencing data suggest an urgent need to develop a methodology to directly address intratumoral heterogeneity in the design of anticancer treatment regimens. We use RNA interference to model heterogeneous tumors, and demonstrate successful validation of computational predictions for how optimized drug combinations can yield superior effects on these tumors both in vitro and in vivo. Importantly, we discover here that for many such tumors knowledge of the predominant subpopulation is insufficient for determining the best drug combination. Surprisingly, in some cases, the optimal drug combination does not include drugs that would treat any particular subpopulation most effectively, challenging straightforward intuition. We confirm examples of such a case with survival studies in a murine preclinical lymphoma model. Altogether, our approach provides new insights about design principles for combination therapy in the context of intratumoral diversity, data that should inform the development of drug regimens superior for complex tumors. Significance: This study provides the first example of how combination drug regimens, using existing chemotherapies, can be rationally designed to maximize tumor cell death, while minimizing the outgrowth of clonal subpopulations. Cancer Discov; 4(2); 166–74. ©2013 AACR. See related commentary by Fedele et al., p. 146 This article is highlighted in the In This Issue feature, p. 131
Statin use and mortality in rheumatoid arthritis: a general population-based cohort study
Authors: Sara R Schoenfeld, Leo Lu, Sharan K Rai, John D Seeger, Yuqing Zhang, Hyon K Choi
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Dual lipid-lowering and anti-inflammatory properties of statins may lead to survival benefits in patients with rheumatoid arthritis (RA). However, data on this topic are limited, and the role of statins in RA remains unclear. <h3>Objectives</h3> To examine the association of statin use with overall mortality among patients with RA in a general population context. <h3>Methods</h3> We conducted an incident user cohort study with time-stratified propensity score matching using a UK general population database. The study population included individuals aged ≥20 years who had a diagnosis of RA and had used at least one disease-modifying antirheumatic drug (DMARD) between January 2000 and December 2012. To closely account for potential confounders, we compared propensity score matched cohorts of statin initiators and comparators (non-initiators) within 1-year cohort accrual blocks. <h3>Results</h3> 432 deaths occurred during follow-up (mean 4.51 years) of the 2943 statin initiators for an incidence rate of 32.6/1000 person-years (PY), while the 513 deaths among 2943 matched comparators resulted in an incidence rate of 40.6/1000 PY. Baseline characteristics were well-balanced across the two groups. Statin initiation was associated with a 21% lower risk of all-cause mortality (HR=0.79, 95% CI 0.68 to 0.91). When we defined RA by its diagnosis code alone (not requiring DMARD use), the corresponding HR was 0.81 (95% CI 0.74 to 0.90). <h3>Conclusions</h3> Statin initiation is associated with a lower risk of mortality among patients with RA. The magnitude of association is similar to that seen in previous randomised trials among the general population.
Multiple myeloma: 2011 update on diagnosis, risk‐stratification, and management
Authors: S. Vincent Rajkumar
Journal: American Journal of Hematology (2010)

Abstract Disease overview: Multiple myeloma is malignant plasma‐cell disorder that accounts for ∼∼10% of all hematologic malignancies. Diagnosis: The diagnosis requires (1) 10% or more clonal plasma cells on bone marrow examination or a biopsy‐proven plasmacytoma plus (2) evidence of end‐organ damage felt to be related to the underlying plasma cell disorder. Risk stratification: Patients with 17p deletion, t(4;14), t(14;16), t(14;20), and karyotypic deletion 13 or hypodiploidy are considered to have high‐risk myeloma. All others are considered to have standard‐risk disease. Risk‐adapted therapy: Standard‐risk patients are treated with nonalkylator‐based therapy such as lenalidomide plus low‐dose dexamethasone (Rd) followed by autologous stem‐cell transplantation (ASCT). If patients are tolerating the induction regimen treatment well, an alternative strategy is to continue initial therapy after stem‐cell collection, reserving ASCT for first relapse. High‐risk patients are treated with a bortezomib‐based induction followed by ASCT and then bortezomib‐based maintenance. Patients not eligible for ASCT can be treated with Rd for standard risk disease or a bortezomib‐based regimen if high‐risk features are present. To reduce toxicity, when using bortezomib, the once‐weekly dose is preferred; similarly, when using dexamethasone, the low‐dose approach (40 mg once a week) is preferred, unless there is a need for rapid disease control. Management of refractory disease: Patients with indolent relapse can be treated first with lenalidomide, bortezomib, or alkylators plus low‐dose corticosteroids. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. The most promising new agents in development are pomalidomide and carfilizomib. Am. J. Hematol. 86:57–65, 2011. © 2010 Wiley‐Liss, Inc.
The Role of Radical Prostatectomy and Lymph Node Dissection in Lymph Node–Positive Prostate Cancer: A Systematic Review of the Literature
Authors: Georgios Gakis, Stephen A. Boorjian, Alberto Briganti, Steven Joniau, Guram Karazanashvili, R. Jeffrey Karnes, Agostino Mattei, Shahrokh F. Shariat, Arnulf Stenzl, Manfred Wirth, Christian G. Stief
Journal: European Urology (2013)
Interobserver agreement in determining non-small cell lung cancer subtype in specimens acquired by EBUS-TBNA
Authors: Daniel P. Steinfort, Prudence A. Russell, Alpha Tsui, Gordon White, Gavin Wright, Louis B. Irving
Journal: European Respiratory Journal (2012)

Endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) may diagnose suspected lung cancer. Determination of non-small cell lung cancer (NSCLC) subtype may guide therapy in select patients. Small-volume biopsies may be subject to significant interobserver variability in subtype determination. Three pathologists independently reviewed specimens from 60 patients who underwent EBUS-TBNA for diagnosis/staging of suspected/known NSCLC. Smear, haematoxylin and eosin (H&E) and immunohistochemistry (IHC) specimens were reviewed without reference to other specimen types obtained from the same patient. Final diagnoses, and degree of confidence in the diagnosis, were recorded for each specimen. Almost perfect agreement was seen for distinguishing between small cell lung cancer and NSCLC for all specimen types. Agreement in determination of NSCLC subtype for smear, H&E and IHC specimens was slight (κ=0.095, 95% CI -0.164-0.355), fair (κ=0.278, 95% CI 0.075-0.481) and moderate (κ=0.564, 95% CI 0.338-0.740), respectively. Perfect agreement was seen when all three observers were confident of diagnoses made on IHC specimens. Interobserver agreement in interpretation of EBUS-TBNA specimens is moderate for determination of NSCLC subtype. Agreement is highest following examination of IHC specimens. Clinicians should be aware of the degree of pathologist confidence in the tissue diagnosis prior to commencement of subtype-specific therapy for NSCLC.
A critical investigation into the antibiotic sterilization of heart valve homografts
Authors: P. M. Waterworth, E. Lockey, E. M. Berry, H. M. Pearce
Journal: Thorax (1974)

<b>Waterworth, Pamela M., Lockey, Eunice, Berry, E. M., and Pearce, Helen M. (1974).</b><i>Thorax</i>, <b>29</b>, 432-436. <b>A critical investigation into the antibiotic sterilization of heart valve homografts.</b> Sterility tests of homograft heart valves sterilized by antibiotics were found to be invalidated by carry-over of the antibiotics. A method was devised to test the efficacy of different antibiotic mixtures using membrane filters. Fifty-five organisms, including 13 species, were tested, and sterility was achieved with only 35.
Highly variable anticoagulant response after subcutaneous administration of high-dose (12,500 IU) heparin in patients with myocardial infarction and healthy volunteers.
Authors: C Kroon, W R ten Hove, A de Boer, J M Kroon, J M van der Pol, E J Harthoorn-Lasthuizen, H C Schoemaker, F J van der Meer, A F Cohen
Journal: Circulation (1992)

BACKGROUND In this study, the anticoagulant response of 12,500 IU heparin s.c. was investigated in patients with myocardial infarction and healthy volunteers to determine variabilities in response and modifying factors. METHODS AND RESULTS On the fourth day after thrombolytic therapy, blood samples were taken before and at frequent intervals until 10 hours after the injection of 12,500 IU heparin s.c. Plasma anti-Xa activity, anti-IIa activity, and the activated partial thromboplastin time (APTT) were measured in addition to body weight and thickness of the abdominal subcutaneous fat layer. Contrary to expectations, the increase of anti-Xa activity, anti-IIa activity, and APTT compared with baseline (predrug) levels was very small, with an average maximal APTT of 42.6 seconds (SD, 12.4 seconds; range, 30.4-70.7 seconds). Subsequently, the influence of the length of the injection needle on the anticoagulant effect of 12,500 IU heparin s.c. was studied in 10 healthy volunteers to find a factor that could be responsible for the poor response in the patients. The length of the injection needle did not influence the anticoagulant effect of heparin. Large interindividual and intraindividual variabilities were seen in the volunteers. The majority of volunteers had minimal prolongation of the APTT, but very strong prolongation was also seen (maximal APTT, 163 seconds). There was no correlation between the abdominal skinfold thickness and anti-Xa activity, anti-IIa activity, or APTT (p &gt; 0.05), but in the patient study, there was a correlation between weight and anti-Xa activity and anti-IIa activity (p &lt; 0.05), and in the volunteer study, there was a correlation between weight and anti-Xa activity and APTT (p &lt; 0.05). CONCLUSIONS Subcutaneous administration of heparin in a fixed dose for prophylactic and therapeutic purposes may be inadequate because of the large interindividual and intraindividual variations in anticoagulant effect.
Differences Between Beta-Blockers in Patients With Chronic Heart Failure and Chronic Obstructive Pulmonary Disease
Authors: Andrew Jabbour, Peter S. Macdonald, Anne M. Keogh, Eugene Kotlyar, Soren Mellemkjaer, Cathie F. Coleman, Maros Elsik, Henry Krum, Christopher S. Hayward
Journal: Journal of the American College of Cardiology (2010)
POLYMERASE CHAIN REACTION AND IN-VITRO ANTIBODY PRODUCTION FOR EARLY DIAGNOSIS OF PAEDIATRIC HIV INFECTION
Authors: A.De Rossi, A. Amadori, L. Chieco-Bianchi, C. Giacquinto, F. Zacchello, A. Buchbinder, F. Wong-Staal, R.C. Gallo, C.S. Peckham
Journal: The Lancet (1988)
Atypical manifestations of visceral leishmaniasis in patients with HIV in north Ethiopia: a gap in guidelines for the management of opportunistic infections in resource poor settings
Authors: Ermias Diro, Johan van Griensven, Rezika Mohammed, Robert Colebunders, Mesfin Asefa, Asrat Hailu, Lutgarde Lynen
Journal: The Lancet Infectious Diseases (2014)
H-2 restriction of virus-specific cytotoxicity across the H-2 barrier. Separate effector T-cell specificities are associated with self-H-2 and with the tolerated allogeneic H-2 in chimeras.
Authors: R M Zinkernagel
Journal: The Journal of Experimental Medicine (1976)

During infection with lymphocytic choriomeningitis or vaccinia virus, F1 irradiation chimeras reconstituted with bone marrow cells from or both parents generate cytotoxic T cells which can lyse targets across the H-2 barrier. However, activity of chimera T cells is H-2 restricted as shown by cold target competition experiments and selective restimulation of a secondary response in vitro; T cells of H-2k specificity which lyse tolerated infected H-2d target cells do not lyse infected H-2k or unrelated target cells and vice versa. Therefore, H-2 restriction of virus-specific cytotoxic T cells probably does not reflect need for like-like self-interactions for lysis to occur. The specificity of virus immune T cells is thus determined by the H-2K and H-2D specificities present in the infected animal and which are probably recognized unidirectionally by T cells. The results are compatible with the idea the T cells are specific for "altered alloantigen", i.e., a complex of cell surface marker and viral antigen. Alternatively, explained with a dual recognition model, T cells may possess two independently, clonally expressed receptors, a self-recognizer which is expressed for one of the syngeneic or tolerated allogeneic K or D "self" markers, and an immunologically specific receptor for viral antigen.
Value of Dynamic Respiratory Changes in Left and Right Ventricular Pressures for the Diagnosis of Constrictive Pericarditis
Authors: David G. Hurrell, Rick A. Nishimura, Stuart T. Higano, Christopher P. Appleton, Gordon K. Danielson, David R. Holmes, A. Jamil Tajik
Journal: Circulation (1996)

Background Conventional cardiac catheterization criteria for the diagnosis of constrictive pericarditis (CP) rely on equalization of intracardiac pressures and have many recognized limitations. Recently, Doppler echocardiographic methods have been used to examine dynamic respiratory changes of increased ventricular interdependence and dissociation of intrathoracic and intracardiac pressures for the diagnosis of CP. These pathophysiological features may be best delineated by cardiac catheterization. Therefore, we studied the accuracy of these dynamic respiratory changes in left ventricular and right ventricular pressure for the diagnosis of CP at cardiac catheterization. Methods and Results High-fidelity manometric catheters and respirometry were used to study 36 patients: 15 patients with surgically proven CP (group 1) and 21 patients with other causes of heart failure (group 2). Conventional cardiac catheterization variables used to establish the diagnosis of CP lacked sensitivity and specificity and failed to distinguish between these groups. However, the finding of discordance between right ventricular and left ventricular pressures during inspiration, a sign of increased ventricular interdependence, accurately distinguished patients in group 1 from those in group 2 ( P &lt;.05). Conclusions Examination of dynamic respiratory changes indicating increased ventricular interdependence may be helpful in the diagnosis of CP in the cardiac catheterization laboratory.
Non-alcoholic steatohepatitis (NASH): where are we now and where are we going?
Authors: C P Day
Journal: Gut (2002)

Although non-alcoholic steatohepatitis (NASH) was considered relatively uncommon prior to the middle of the last decade, over the past three years there has been an explosion of studies on various aspects of NASH with one study reporting that after hepatitis C, NASH was the most common diagnosis in patients presenting largely with persistent abnormalities of liver function tests. The field of NASH has come a long way in a relatively short space of time. This article considers advances in knowledge that have arisen as a result of these studies and highlights areas for further work.
Lateral plantar nerve injury following steroid injection for plantar fasciitis
Authors: D M Snow, J Reading, R Dalal
Journal: British Journal of Sports Medicine (2005)

A 41 year old man presented with pain and numbness affecting the lateral aspect of his foot after a steroid injection for plantar fasciitis. Examination confirmed numbness and motor impairment of the lateral plantar nerve. The findings were confirmed by electromyographic studies. The anatomy of the lateral plantar nerve and correct technique for injection to treat plantar fasciitis are discussed.
The Bradshaw Lecture on the Treatment of Cancer: Delivered before the Royal College of Surgeons of England on December 1st, 1904
Authors: A. W. M. Robson
Journal: BMJ (1904)

MAYO ROBSON began by considering the etiology of cancer, and expreased the opinion that while cancer is not infectious in the ordinary sense of the term, there is a large accumulation of facts to prove that it is locally infectious and capable of distribution by contact and inoculation.It was also undoubtedly auto-infective, so that an imperfect operation was dangerous, since by aistributing the cancer ceells it might implant numerous foci of disease.If possible cancerous tumours should be removed without preliminary incision, leaving a wide area of healthy tissue around the growth, and wherever practicable the nearest lymphatic glands, and the vesses going to them, should be re- moved, whether enlarged or not.If the glands were already infected it was of the utmost importance to take them away cleanly without rupture, and, wherever possible, in the same piece with the tumour.If the tumour was incised for diagnostic purposes the exploratory incision should be closed by sutures, the skin purified.the lknife and needles boiled, and the surgeon's hands sterilized before proceeding with the operation.If, unfortunately, the wound has become soiled, it should be irrigated with a large quantity of saline solution, or of some antiseptic lotion, so as to wash away any loose masses of cancer cells or infected material which, if left, would probably become engrafted, and grow.Facts were quoted in support of the view that cancer ds both contagious and i-noculable among human beings, as it undoubtedly is among the lower animals.Though it might tiot be necessary to advise segregation of cancer patients, it would seem most desirable that all dressings taken from cancer patients should be burnt, that linen soiled by can- cerous sores should be destroyed or disinfected by boiling, that contact with cancerous ulcers, whether of the lip, tongue, breast, uterus, or other parts should be avoided, and that common use of beds and utensils with eancerous patients should not occur.The lecturer then said:] PREVErNTIVE TREATMENT.'Until the true and ultimate causative factor in the life-
ATP directed agent, 8-chloro-adenosine, induces AMP activated protein kinase activity, leading to autophagic cell death in breast cancer cells
Authors: Christine M Stellrecht, Hima V Vangapandu, Xiao-Feng Le, Weiqun Mao, Shujun Shentu
Journal: Journal of Hematology & Oncology (2014)

8-chloro-adenosine (8-Cl-Ado) is a unique ribonucleoside analog which is currently in a phase I clinical trial for hematological malignancies. Previously, we demonstrated in breast cancer cells that a 3-day treatment with 10 μM 8-Cl-Ado causes a 90% loss of clonogenic survival. In contrast, there was only a modest induction of apoptosis under these conditions, suggesting an alternative mechanism for the tumoricidal activity of 8-Cl-Ado. Cellular metabolism, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathway signaling, as well as autophagy induction was evaluated in breast cancer cell lines treated with 8-Cl-Ado. The effects of knocking down essential autophagy factors with small interfering RNA on 8-Cl-Ado-inhibited cell survival was assessed in breast cancer cells by examining apoptosis induction and clonogenic survival. In vivo efficacy of 8-Cl-Ado was measured in two breast cancer orthotopic model systems. We demonstrate that in breast cancer cell lines, the metabolism of 8-Cl-Ado results in depletion of endogenous ATP that subsequently induces the phosphorylation and activation of the energy sensor, AMPK. This was associated with an attenuation of mTOR signaling and an induction of the phosphorylation of the autophagy factor, Unc51-like kinase 1 on Ser555. 8-Cl-Ado-mediated induction of autophagy was evident by increased aggregates of microtubule-associated protein 1 light chain 3B (LC3B) which was associated with its conversion to its lipidated form, LC3B-II, p62 degradative flux, and increased formation of acidic vesicular organelles. Additionally, transfection of MCF-7 cells with siRNA to ATG7 or beclin 1 provided partial protection of the cells to 8-Cl-Ado cytotoxicity as measured by clonogenicity. In vivo, 8-Cl-Ado inhibited growth of both MCF-7 and BT-474 xenograft tumors. Moreover, in 9 of 22 BT-474 tumors treated with 100 mg/kg/day 3 times a week, there was an absence of macroscopically detectable tumor after 3 weeks of treatment. Our data demonstrates that 8-Cl-Ado treatment activates the AMPK pathway leading to autophagy induction of in breast cancer cells, eliciting, in part, its tumoricidal effects. Additionally, 8-Cl-Ado effectively inhibited in vivo tumor growth in mice. Based on this biological activity, we are planning to test 8-Cl-Ado in the clinic for patients with breast cancer.
Exercise-induced hemolysis in xerocytosis. Erythrocyte dehydration and shear sensitivity.
Authors: O S Platt, S E Lux, D G Nathan
Journal: Journal of Clinical Investigation (1981)

A patient with xerocytosis was found to have swimming-induced intravascular hemolysis and shortening of erythrocyte life-span. In a microviscometer, xerocytes were more susceptible than normal erythrocytes to hemolysis by shear stress. Fractionation of normal and abnormal cells on discontinuous Stractan density gradients revealed that increasingly dehydrated cells were increasingly more shear sensitive. This sensitivity was partially corrected by rehydrating xerocytic erythrocytes by means of the cation-ionophore nystatin in a high potassium buffer. Conversely, normal erythrocytes were rendered shear sensitive by dehydrating them with nystatin in a low potassium buffer. This effect of dehydration was entirely reversible if normal cells were dehydrated for less than 4 h but was only partially reversed after more prolonged dehydration. It is likely that dehydration of erythrocytes results in shear sensitivity primarily because of concentration of cell contents and reduced cellular deformability. With prolonged dehydration, secondary membrane changes may potentiate the primary effect. This increased shear sensitivity of dehydrated cells may explain atraumatic exercise-induced hemolysis in xerocytosis as cardiac output is shifted to vessels of exercising muscles with small diameters and high shear rates.