tbuckley/cabot-search huggingface dataset:
Abstract PR3: Preclinical and molecular profiling data suggest LumB breast cancer as a potential indication for co-targeting IGF1R and mTOR with MK-0646 and MK-8669
Authors: Theresa Zhang, Igor Feldman, Sriram Sathyanarayanan, Brian Haines, Cloud Paweletz, Michael Nebozhyn, Stuart Shumway, Brian Roberts, William Arthur, Peter Strack, Pearl Huang, Hongyue Dai, Carolyn Buser-Doepner, Andrey Loboda, James Watters
Journal: Clinical Cancer Research (2010)

Abstract There has been increasing interest in developing cancer therapies targeting PI3K pathway nodes. However, inhibition of a single node in PI3K pathway such as mTOR by rapamycin analogues results in compensatory activation of survival signaling pathway such as AKT and thereby limiting monotherapy activity. Therefore, in most tumor types, multipathway inhibition, guided by an in-depth understanding of feedback and crosstalk between pathways, may be required for tumor regression. It is well known that that mTOR inhibition upregulates pAKT via the S6K-IRS2 negative feedback loop. Inhibiting both mTOR and IGF1R may therefore ablate such feedback upregulation and lead to clinical response. However, it is unclear which tumor types will respond to the combination in the clinic. Here, we present preclinical and molecular profiling data that supports LumB breast cancer as a potential indication for MK-8669/MK-0646 (mTOR/IGF1 R inhibitor combination). When a panel of over 60 breast cancer cell lines was treated with MK-8669, ER+ cell lines and HER2+ cell lines were clearly more responsive than the triple negative ones. Meanwhile, the status of the MAPK pathway, as captured by a RAS gene expression signature, correlated with resistance to MK-8669 across the panel. Moreover, MK-8669 treatment unregulated multiple key nodes of the IGF1R pathway in the breast cell line panel, especially IRS2, whose upregulation correlated with the response to MK-8669. Furthermore, IGF1R, whose mRNA level correlates with the response to MK-0646 (IGF1 Ri) in multiple internal and external studies, is the highest in a subset of LumB tumors, suggesting a potential dependency on the IGF1R pathway in those tumors. Finally, a comparison between the gene expression profiles of breast cancer cell lines and tumors revealed that the ER+ breast cancer cell lines only represented the LumB, not LumA, subtype of human breast tumors. Taken together, these findings allow us to hypothesize that LumB breast cancer may be enriched in responders to the MK-0646/MK-8669 combination. In 2009, Merck initiated a phase I trial of MK-8669/MK-0646 in which clinical response was observed in LumB breast cancer patients. A phase II clinical trial has been initiated to test the hypothesis retrospectively. This talk is also presented as Poster A52. Citation Information: Clin Cancer Res 2010;16(14 Suppl):PR3.
Handbook of Differential Diagnosis in Internal Medicine: Medical Book of Lists
Authors: Mohan Singh Dhariwal
Journal: Annals of Internal Medicine (1999)

Medical Writings19 January 1999Handbook of Differential Diagnosis in Internal Medicine: Medical Book of ListsMohan Singh Dhariwal, DO, PhDMohan Singh Dhariwal, DO, PhDMedical College of Wisconsin, Milwaukee, Wisconsin.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-130-2-199901190-00031 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Handbook of Differential Diagnosis in Internal Medicine: Medical Book of Lists5th edition. Greenberger NJ, Bernsten MS, Jones DK, Velakaturi VN. 347 pages. St. Louis: Mosby-Year Book; 1998. $24.95. ISBN 0323001319. Order phone 800-426-4545.Field of medicine: General internal medicine.Format: Softcover book.Audience: General internal medicine practitioners, residents, medical students, physician assistants, and nurse practitioners.Purpose: To provide concise but thorough lists of differential diagnoses.Content: The book has 11 sections covering major areas of internal medicine. Each chapter has subheadings with lists of possible causes and symptoms of a given disease entity. Several tables present statistical data, such ... Author, Article, and Disclosure InformationAffiliations: Medical College of Wisconsin, Milwaukee, Wisconsin. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byThe Hidden Diet 19 January 1999Volume 130, Issue 2Page: 168KeywordsAIDSComputer softwareDermatologyNursesStatistical data ePublished: 15 August 2000 Issue Published: 19 January 1999 Copyright & PermissionsCopyright © 1999 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Elective Cardioplegia by Local Cardiac Hypothermia
Authors: Harold C. Urschel, Jack J. Greenberg, Charles A. Hufnagel
Journal: New England Journal of Medicine (1959)

ELECTIVE cardiac arrest is an important adjunct to open-heart surgery. It provides a motionless, dry operative field with minimal blood loss and less chance for gaseous embolism to the coronary arteries. Cardioplegia reduces metabolic requirements of the heart and prolongs myocardial tolerance to cessation of coronary blood flow.1 Deep cardiac hypothermia produces an effective arrest.2 Simultaneously, it reduces metabolic requirements and protects against tissue anoxia.3 , 4 By differentially cooling the heart and maintaining the body at mild hypothermic temperature levels with extracorporeal circulation, it avoids the disadvantages of deep, total-body hypothermia. Rapid arrest and reversibility are possible without protracted total-body cooling . . .
Regulated expression of a foreign gene targeted to the ischaemic myocardium
Authors: Howard Prentice, Nanette H Bishopric, Martin N Hicks, Daryl J Discher, Xiaosu Wu, Andrew A Wylie, Keith A Webster
Journal: Cardiovascular Research (1997)

Objectives: Regulated expression of transferred foreign genes may be an important feature of gene therapy. Because coronary artery disease often involves intermittent myocardial ischaemia followed by periods of normal cardiac function it will probably be necessary to regulate the expression of putative therapeutic/cardioprotective genes directly in response to ischaemia-associated signals. The objectives of the current study were to develop a combination of gene regulatory components that can be used to target a product to the myocardium and limit the expression of the gene to periods of ischaemic activity. Methods: Expression plasmids were constructed containing muscle-specific promoters and hypoxia-responsive enhancer elements linked to a reporter gene. The regulation of these constructs by hypoxia or experimental ischaemia was measured following transient expression in cultured cells or after direct injection of DNA into the rabbit myocardium. Results: A single set of hypoxia response elements placed immediately upstream of the minimal muscle-specific α-myosin heavy chain promoter conferred potent positive regulation of this promoter by hypoxia in vitro and by ischaemia in vivo. Induction by ischaemia persisted for at least 4 h and returned to the baseline level within 8 h. Conclusions: Hypoxia responsive regulatory elements, in combination with weak tissue-restricted promoters incorporated into an appropriate vector system may allow controlled expression of a therapeutic gene in ischaemic myocardium.
Bacteria differentially induce degradation of Bcl-xL, a survival protein, by human platelets
Authors: Bjoern F. Kraemer, Robert A. Campbell, Hansjörg Schwertz, Zechariah G. Franks, Adriana Vieira de Abreu, Katharina Grundler, Benjamin T. Kile, Bijaya K. Dhakal, Matthew T. Rondina, Walter H. A. Kahr, Matthew A. Mulvey, Robert C. Blaylock, Guy A. Zimmerman, Andrew S. Weyrich
Journal: Blood (2012)
Regional NHS profile. To flourish or fade: the NHS in Dumfries and Galloway.
Authors: R. Smith
Journal: BMJ (1989)

them or because they remain on their doctor's list in their "home" borough.In response to this problem the family practitioner committee has set up a special primary care service for homeless families.For our health district the presence of a substantial homeless population has clear resource implications.Overall, 9% of the beds at St Mary's Hospital were being used by homeless people for whom the health authority received no additional financial allocation.Given the current stringent budget constraints under which all health authorities operate, this is a great extra burden in a very deprived district.Antenatal and childcare services are most affected by the influx of homeless families.Further research is needed to measure the true size of the homeless population, how long they remain homeless, and the levels of morbidity they experience to understand and develop services to meet their needs.If the white paper on the reform of the health service is fully implemented the implications for health care for homeless people are profound.
Ultraviolet B-exposed major histocompatibility complex class II positive keratinocytes and antigen-presenting cells demonstrate a differential capacity to activate T cells in the presence of staphylococcal superantigens
Authors: L. SKOV, O. BAADSGAARD
Journal: British Journal of Dermatology (1996)

In this study we tested the capacity of ultraviolet B (UVB)-irradiated major histocompatibility complex (MHC) class II+ keratinocytes, monocytes and dendritic cells to activate T cells in the presence of Staphylococcus enterotoxin B. We demonstrated that UVB irradiation of MHC class II+ keratinocytes does not change their capacity to activate T cells in the presence of Staphylococcus enterotoxin B. In contrast, UVB irradiation of antigen-presenting cells decreases their capacity to activate T cells. This differential capacity to activate T cells after UVB irradiation was not due to factors released from UVB-irradiated cells. The interferon-gamma induced upregulation of HLA-DR and intercellular adhesion molecule-1 on keratinocytes does not seem to be the only explanation, since UVB irradiation decreased the accessory cell function of interferon-gamma pretreated monocytes. Differential requirements for and UVB regulation of costimulatory molecules may be involved, since blocking of the B7/CD28 pathway affects the capacity of dendritic cells but not keratinocytes to activate T cells in the presence of Staphylococcus enterotoxin B. Thus, MHC class II+ keratinocytes in the presence of superantigens released from staphylococci may activate T cells and maintain inflammation despite UVB treatment.
INJURIES PRODUCED by an EXPLOSION of GUN-COTTON
Authors: G. Sichel
Journal: BMJ (1899)

ON February gth, I897, in the afternoon, when we were lying at Zanzibar, an explosion of a dry primer for a torpedo occurred on board the ship I was then in.The primer contained 124 OZS. of dry gun-cotton, and the detonator 38 grs. of fulminate of mercury; the weight of the metal fittings was probably under -1 lb.Four men were fatally injured, and two slightly.CASE i.-A.M., aged 23, was killed at once.The body was almost severed.The anterior wall of the abdomen was blown away, the intes- tines protruding, and all his clothes were blown off.There were severe injuries to the limbs also, with much pulping and splintering of bones.CASE II.-J.J. J., aged 23.The left band was blown off, the right hand was just hanging on by a little skin and a few tendons.There was compound fracture of the left femur.Much contusion generally, and nuimerous smaller wounds.Shock was great.Amputation was performed in the upper third of the left thigh.Death occurred in two lours.CASE III.-A.W. R., aged 21.Wounids of scalp (from one of whiclh there was arterial bleeding), limbs, and trunk, especi lly of the riglht thigh, in which numerous large splinters of bone from Another man (A.M.) were stickiDg.There was much laceration and contusion and intense slhock.Death cecurred in three hours.CASE IV.-C.H., agcd 29.There was pulping of the right tlligh along tlhe line of the femoral arter-y, a punciehed-out wound of the anterior abdomiiinal wall, not penetrating, a conipound fracture of the right meta- tarsal bones, and numerous othier cuts and bruises.Shock was intense, and death occurred in five hours.CASE v.-J.J., aged 22. Two scalp wounds, a wound of the uipper lip, the alveolar margin of the uipper jaw was fractured, and the central inicisors were loose.There wvas a skin abrasion over the front of the cliest, and mnuchl bruising of the face.The patient recovered.CASE vi.-A Seedieboy, wvho lhad a sliglht cut of the left side of the chest, also recovered.
Kleihues is New IARC Director
Authors: C. Vanchieri
Journal: JNCI Journal of the National Cancer Institute (1993)

Journal Article Kleihues is New IARC Director Get access Cori Vanchieri Cori Vanchieri Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 85, Issue 10, 19 May 1993, Pages 777–778, https://doi.org/10.1093/jnci/85.10.777 Published: 19 May 1993
Relationship between copper, zinc and metallothionein in hepatocellular carcinoma and its surrounding liver parenchyma
Authors: Masaaki Ebara, Hiroyuki Fukuda, Ryouji Hatano, Hiromitsu Saisho, Yoshinori Nagato, Keiji Suzuki, Katuyuki Nakajima, Masae Yukawa, Fukuo Kondo, Akihiro Nakayama, Hiromu Sakurai
Journal: Journal of Hepatology (2000)
Double irregular ventricular parasystole: rate-dependent entrance block and "supernormal" exit conduction.
Authors: J Tenczer, L Littmann
Journal: Circulation (1978)

An analysis of electrocardiograms from a patient with spontaneous double irregular ventricular parasystole is presented. Irregularity in one of the two parasystoles was produced by intermittence based on rate-dependent (phase 3) entrance block, and in the other parasystole it was attributed to "supernormal" exist conduction. Critical analysis of electrocardiograms revealed that first degree block, rate-dependent block, and "supernormal" conduction in the exit pathway may account for the alterations in the arrangement and manifestation of the parasystolic beats. An electrocardiographic approach to these properties of the parasystolic structure and demonstration of double ventricular parasystole with irregularity in both parasystoles has not previously been found in the literature.
Increasing US Mortality From Infectious Diseases
Authors: Anthony L. Suchman
Journal: JAMA (1996)

<h3>To the Editor.</h3> —While reading the thoughtful analysis of trends in infectious diseases mortality by Dr Pinner and colleagues,<sup>1</sup>I was troubled that something is missing in the way we look at mortality data. Fewer cardiovascular deaths, for example, mean that more people will live long enough to develop malignancies or Alzheimer disease. Pneumonia can be the precipitating event in a "good death" for a nonagenarian. I would urge authors and editors to provide readers with a little more context for mortality statistics, using years of potential life lost or other similar tools. We need to be open to the possibility that a rising death rate for some diseases could actually be a good sign.
Data to support assisted dying
Authors: J. Downar, M. Boisvert, D. Smith
Journal: BMJ (2014)

The editors of The BMJ have taken an important stand in the assisted death debate in the UK.1 In Canada, we are also coming to terms with this issue. Quebec province has legalised it, and our supreme court is set to hear a case that could strike down the federal laws that prohibit it.2

In Canada, about 80% of the public supports the legalisation of assisted …
Association of hypokalaemia and hypophosphataemia
Authors: D. C. Anderson, T. J. Peters, W. K. Stewart
Journal: BMJ (1969)

A prospective study of 13 patients with hypokalaemia due to a variety of causes demonstrated that six had hypophosphataemia. In 10 patients the plasma inorganic phosphate level rose on correction of the hypokalaemia. Before treatment seven patients had an excessive rate of excretion of phosphate relative to creatinine in the urine. Following correction of the hypokalaemia 11 patients had an increase in renal tubular reabsorption of phosphate relative to creatinine. It is suggested that hypokalaemia may be causally related to the hypophosphataemia, and that in chronic potassium depletion this may affect bone mineralization.
Antibiotic Dosage in Newborn and Premature Infants
Authors: Sumner J. Yaffe
Journal: JAMA (1965)

The intelligent use of a drug in any patient demands adequate knowledge of the mechanisms of absorption, metabolism, and excretion of the given agent, as well as its therapeutic actions and possible untoward effects. When antibiotic therapy is undertaken, another variable, the microorganism, is introduced. Determination of the therapeutic dosage of an antibiotic on a rational basis, which is mandatory in any case, requires recognition of the potential interplay among these entities. After absorption, the concentration of an antibiotic agent is determined mainly by metabolism (detoxication) and excretion, which are fairly constant in the healthy adult, child, and older infant. In practice, therefore, antibiotic dosages for those beyond the neonatal period are usually achieved by adjusting adult dosage on the basis of age (Young's rule), body weight (or correction for body weight according to Clark's rule), or surface area. However, because the neonatal period is one of changing body and
The BMJ and its plans
Authors: F. Godlee
Journal: BMJ (2014)

One UK reader, and perhaps others, didn’t like the Essay we published from the United States on “flipping healthcare” (doi:10.1136/bmj.g5852). “What does a country that spends a staggering 18% of gross domestic product on healthcare—yet has the same life expectancy and worse infant mortality than Cuba—have to teach others on this subject,” writes Nikolai Manassiev in a letter this week (doi:10.1136/bmj.g6847). Other respondents were more positive about the article, but Manassiev goes on to slam The BMJ . “The fact that this paper is not just published, but is given the same space as research plus a mention on the cover, tells me about the difficulties The BMJ has in attracting credible research and reviews and how shallow it has become.”

The BMJ revels in criticism. Perhaps because of that, we have, by general assent, …
Book Reviews; Coronary Blood Flow.
Authors: J. M Downey
Journal: Cardiovascular Research (1992)

Journal Article Book Reviews; Coronary Blood Flow. Get access James M Downey James M Downey Mobile, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 26, Issue 9, September 1992, Page 912a, https://doi.org/10.1093/cvr/26.9.912a Published: 01 September 1992
Indian doctor arrested under antiterrorism law
Authors: Owen Dyer
Journal: BMJ (2007)

Officials in Nigeria have filed criminal and civil charges against Pfizer for its role in the deaths and disabilities of children who were treated with an experimental drug during a meningitis outbreak in Kano in 1996.The charges, filed by government prosecutors in Nigeria, follow three attempts by families of the children to sue in US courts.All three attempts were denied after Pfizer successfully argued that the US courts were not an appropriate forum.Four separate legal actions have been filed in Nigeria, including 31 criminal counts against 10 people, according to the Washington Post (www.washingtonpost.com, 2 Jun, "Pfizer faces new charges over Nigerian drug test").The plaintiffs also seek a total of $9bn (£4.5bn; €7bn) in civil suits.The charges stem from Pfizer's test of its unlicensed drug, trovafloxacin (Trovan) to treat 100 children with meningitis.A comparator group of 100 children were treated with a low dose of ceftriaxone.Suits on appeal in US courts charge Pfizer with causing harm to the children in both arms of the trial, alleging that a number of the children either died or were left deaf, mute, or brain damaged.The families allege that the company failed to tell them that their children were being enrolled in an experimental drug trial and that free, effective treatment was available from Médecins Sans Frontières at the same hospital.Five children in the trovafloxacin arm and six in the ceftriaxone arm died, according to Pfizer.Pfizer issued a statement in response to the charges, saying "Pfizer continues to emphasise-in the strongest terms-that the 1996 Trovan clinical study was conducted with the full knowledge of the Nigerian government and in a responsible and ethical way consistent with the company's abiding commitment to patient safety."Any allegations in these lawsuits to the contrary are simply untrue." Niger�ia files cr�iminal char�ges against Pfizer�
Perfusion Lung Scanning With Tc-99m MAA in the Assessment of Churg-Strauss Syndrome
Authors: LUCA BURRONI, PAOLO BERTELLI, ALESSANDRA VELLA, DUCCIO VOLTERRANI, GIOVANNI CONIGLIO, ANGELO VATTIMO
Journal: Clinical Nuclear Medicine (1995)

Churg-Strauss syndrome (CSS) is a rare allergic disease characterized by eosinophilia, asthma, fever, and necrotizing vasculitis. Unlike polyarteritis nodosa, CSS presents pulmonary vasculitis with extravascular granulomatous inflammation. The lung is the organ most frequently Involved. However, any organ can be affected; particularly the skin, the nervous system, the heart, or the gastrointestinal tract. The clinical picture of pulmonary allergy may precede the other components of the disease by months or years. Pulmonary perfusion scintigraphy with Tc-99m MAA is able to detect focal hypoperfusion corresponding to praecox eosinophilic infiltrations. At present, CSS usually responds to corticosteroid therapy.
Note on Cholecystotomy
Authors: L. Tait
Journal: BMJ (1885)

bably be less thani that wvhich accomlpanies a large irreducible scrotal hernia.The extra-opening into the abdominal cavity is not attended by much more danger, if the opcration be performed witlh strict antiseptic precautiois ; and the risks attendant upon it are, I think, not greater than those wliich accompany the leaving of the bowel unreduced in the sac, or the attem t to forcibly reduce it by dividing or tearing through old adhesions, when exceptionally dense and firm.
Pre-pyloric site gastric cancer after pylorus-preserving gastrectomy (PPG): A case report
Authors: Atsuo Shida, Shuichi Fujioka, Katsutoshi Kobayashi, Yoshio Ishibashi, Nobuo Omura, Norio Mitsumori, Mitsuhiro Ohmura, Katsuhiko Yanaga
Journal: International Journal of Surgery (2006)
Natural murine autoantibodies and conventional antibodies exhibit similar degrees of antigenic cross-reactivity.
Authors: D M Klinman, S Banks, A Hartman, A D Steinberg
Journal: Journal of Clinical Investigation (1988)

Splenic B cells from normal and autoimmune mice were transferred to MHC-compatible xid recipients. Monoclonal antibodies were secreted by the transferred B cells in splenic fragment cultures. These antibodies were evaluated for reactivity and cross-reactivity against a panel of six autoantigens and two conventional antigens using an ELISA assay. The autoantibodies and conventional antibodies produced in splenic fragment cultures by normal DBA/2 and autoimmune NZB B cells expressed similar degrees of antigenic cross-reactivity. Previous studies have demonstrated that ELISA assays of splenic fragment culture supernatants detect antibodies with affinities of 5 x 10(6) M-1 or greater. We therefore also analyzed the cross-reactivity of monoclonal antibodies derived from hybridomas. This permitted an assessment of antibodies with lower binding affinities. Cross-reactivity was detected more frequently among these hybridomas. Consistent with our earlier observations, hybridoma antibodies specific for conventional antigens exhibited cross-reactivity with a frequency similar to that of antibodies specific for autoantigens.