tbuckley/cabot-search huggingface dataset:
Abstract 5378: SB225002 induces apoptosis in acute lymphoid leukemia cells
Authors: Jaira F. Vasconcellos, Angelo B. A. Laranjeira, Paulo C. Leal, Ricardo J. Nunes, Rosendo A. Yunes, Silvia R. Brandalise, Towia A. Libermann, Luiz F. Zerbini, José A. Yunes
Journal: Cancer Research (2011)

Abstract Acute Lymphoblastic Leukemia (ALL) is the most frequent childhood malignancy. We have recently shown that the leukemic bone marrow (BM) contains high levels of interleukin-8 (IL-8), whose cognate receptor CXCR2 is expressed by most primary ALL cells. ALL cell lines are sensitive to SB225002 (N-(2-hydroxy-4-nitrophenyl)-N’-(2-bromophenyl)urea), a CXCR2 antagonist. Surprisingly, the inhibitory effect of this drug was found to be independent of CXCR2 expression by leukemic cells. The current study was conducted to determine the mechanism of action of SB225002 against ALL cells, using as prototype the T-ALL cell line Jurkat. Cell cycle analysis showed that SB225002 induces G2-M cell cycle arrest. Transcriptional profiling by microarray analysis revealed that SB225002 induces 174 genes and represses 41 genes. SB225002 induced-apoptosis triggered a transcriptional program of genes involved in activation of the JUN and p53 pathways and inhibition of the TNFα pathway. Results were further confirmed by Q-PCR and/or Western blot analysis. Treatment of Jurkat cells with SB225002 also induced the activation of phospho-p44/42 MAPK (ERK1/2), which was suspected to be an anti-apoptotic pathway triggered by injured cells. In fact, the inhibition of ERK1/2 with pharmacologic inhibitors, in combination with SB225002, resulted in the enhancement of apoptosis, suggesting the blockage of ERK1/2 pathway as a strategy to increase the sensitivity of ALL cells toward SB225002. Connectivity Map analysis of the SB225002 gene signature demonstrates a positive correlation with the signatures for PI3K and HSP90 inhibitors (connectivity score 1 and 0.944, respectively), which mediate apoptosis through effects on AKT, TNFα and NF-κB, while SB225002's mediated-apoptosis demonstrated only to inhibit TNFα pathway. Furthermore, SB225002 gene signature demonstrates a positive correlation with Nocodazole and Podophyllotoxin (connectivity score 0.895 and 0.859, respectively), which are inducers of cancer cell apoptosis by interfering with microtubule polymerization and inhibiting topoisomerase II, respectively. Our data demonstrate for the first time that JUN, p53, and TNFα pathways are modulated by SB225002, and that ALL cells are sensitized to SB225002-induced apoptosis after phospho-p44/42 MAPK inhibition. Overall these data support SB225002's therapeutic potential in ALL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5378. doi:10.1158/1538-7445.AM2011-5378
Chemotherapy of Disseminated Solid Tumors
Authors: Thomas C. Hall
Journal: JAMA (1967)

While this book attempts to "serve as a ready reference to the practicing physician," it misses its goal by a great deal. In order to do the job well, a book should be reliable, complete, and readable. This volume falls short in all these respects. The data quoted primarily concern the experience of one clinical group, using one drug, in a limited number of diseases. Hence there are no sections on lymphoma, and the treatment of genitourinary and gynecological malignancies is woefully brief. The data on fluorouracil do not emphasize that it can be given with effect by a number of routes and schedules, other than that used by the Wisconsin group. Problems of drug metabolism, as they relate to such important questions as whether toxicity is necessary for response, are not considered. We find a lack of completeness or uniformity, from the table of contents through the lamentably small
B-cell tolerance. IV. Differential role of surface IgM and IgD in determining tolerance susceptibility of murine B cells
Authors: ES Vitetta, JC Cambier, FS Ligler, Kettman JR, JW Uhr
Journal: The Journal of Experimental Medicine (1977)

During ontogeny IgD appears later than IgM on splenocytes of neonatal mice (1) and at a time when mice develop a markedly increased immune responsiveness (2). Based on these observations, it was suggested that IgD serves as a "triggering" isotype for induction of immune responses, whereas surface IgM functions as a tolerizing receptor (3). To test this hypothesis, the susceptibility of adult splenocytes (which are predominantly μ(+)δ(+)[4-6]) and neonatal splenocytes (which bear predominantly IgM [μp(+); 1, 4-6]) to tolerance induction were compared. The results indicate that neonatal splenic B cells responsive to thymus dependent (TD) antigens are exquisitely susceptible to tolerance induction compared with those from adult mice (7-9). However, cells from both adult and neonatal mice were highly susceptible to tolerance induction when thymus independent (TI) antigen was used as immunogen (8). These results suggest that the major precursor for the TD response is a μ(+)δ(+)-cell which appears late in ontogeny and is resistant to tolerance induction and that the μp(+)-cell is the major precursor for the TI response and is highly susceptible to tolerance induction. Other differences between responders for TI and TD antigens have been described previously (10-12). To test this concept, adult splenocytes were treated with papain under conditions in which IgD, but not five other surface molecules, was removed (13). Such treated splenocytes were shown to be markedly susceptible to tolerance induction, resembling TD responders from neonatal animals. This experiment was interpreted as indicating that IgD confers resistance to tolerance induction on μ(+)δ(+)-cells. To prove this interpretation, it is necessary to show that specific removal of IgD with anti-δ also results in increased susceptibility to tolerance induction and that treatment with anti-μ does not have a similar effect. In the present studies, we have removed surface IgM or IgD by antibody-induced capping and assessed the tolerance susceptibility of the treated cells. Our results demonstrate that removal of IgD, but no IgM, from TD responders increases their susceptibility to tolerance induction.
cAMP-induced PKCζ activation increases functional CXCR4 expression on human CD34+ hematopoietic progenitors
Authors: Polina Goichberg, Alexander Kalinkovich, Nataliya Borodovsky, Melania Tesio, Isabelle Petit, Arnon Nagler, Izhar Hardan, Tsvee Lapidot
Journal: Blood (2005)
Patient Mix and Utilization of Resources
Authors: Betty C. Jung
Journal: JAMA (1993)

<h3>To the Editor.</h3> —Three issues are raised in the article by Kravitz et al<sup>1</sup>on patient mix and the article by Greenfield et al<sup>2</sup>on resource utilization. The first concerns the system of care and selection of specialists as being functions of patient choice, when they may, in fact, be functions of diagnosis, disease severity, the age of the system of care and the mix of physicians within it, patient-physician relationships, employee health benefits, and specialty referral. Because systems of care vary in age, this is a confounding variable in determining patient mix and physician mix. A longitudinal study of physician choices made by health maintenance organization (HMO) enrollees may clarify this. Further, any consideration of a system of care must account for the type of HMO: group, staff, independent practice association, or network.<sup>3</sup>All may affect a physician's choice of employment, the basis that Greenberg et
A CASE OF BANTI'S DISEASE WITH ENLARGED HAEMOLYMPH GLANDS
Authors: J. R. Collins, G. W. Riddel
Journal: BMJ (1915)

captivity on wlhite bread or Indian corn.Tley can remain for a consi(lerable time witlhout food, anid this without iateriallv dim-inislingc tlhe rate of their developm-lent.Stegomytiia breed well in slips, anid are occasionially found in oue part only of tlle sllip, suchl as the enigine-room or cooli's galley, where tlhe conditions scem to be most favoturable to their development.Tlhus it comes about tlhat at times* certain quarters of a sliip provide the gLeatest percentage of yellow fever cases.
Mitochondrial DNA deletion: A cause of chronic tubulointerstitial nephropathy
Authors: Matthias J. Szabolcs, Robert Seigle, Sarah Shanske, Eduardo Bonilla, Salvatore DiMauro, Vivette D'Agati
Journal: Kidney International (1994)

We report the first case of a mitochondrial DNA (mtDNA) deletion diagnosed by renal biopsy. An eight-year-old girl with megaloblastic anemia and severe growth retardation developed progressive renal insufficiency accompanied by partial Fanconi syndrome. Histologic examination of the renal biopsy disclosed nonspecific chronic tubulointerstitial disease characterized by tubular atrophy and interstitial fibrosis. On ultrastructural examination, tubular cell mitochondria were extremely dysmorphic with prominent size variation, abnormal arborization, disorientation of the cristae and osmiophilic electron-dense inclusions. Functional histochemical stains for mitochondrial enzymes performed on cryostat renal sections revealed focal tubular absence of cytochrome C oxidase (COX), a respiratory chain enzyme partially encoded by mtDNA, with preservation of succinate dehydrogenase (SDH), a respiratory chain enzyme entirely encoded by nuclear DNA (nDNA). Immunoreactivity for COX subunit 2 (encoded by mtDNA) was weak to undetectable in most tubular cells, whereas reactivity for subunit 4 (encoded by nDNA) was intense in all cells. Molecular analysis of the mtDNA of kidney and peripheral blood leukocytes was performed using Southern blot and PCR. Both techniques disclosed a 2.7 kb mtDNA deletion located between nucleotide (nt) 9700 and nt 13700, a common site for mtDNA deletions associated with encephalomyopathies. Mitochondrial DNA deletions may be an under-recognized cause of idiopathic tubulointerstitial nephropathy in children lacking neurologic or myopathic manifestations.
Abstract 1424: Enhanced pyruvate carboxylation is crucial to non-small cell lung cancer proliferation and anabolism
Authors: Katherine E. Sellers, Matthew P. Fox, Michael Bousamra, Jun Yan, Mariia Yuneva, Richard M. Higashi, Andrew N. Lane, Teresa W. Fan
Journal: Cancer Research (2014)

Abstract Proliferating cancer cells require an active Krebs cycle for generating anabolic precursors, in addition to energy production. Diversion of the Krebs cycle intermediates to meet anabolic demands cannot be sustained without anaplerosis. The two major anaplerotic pathways are the deamidation of glutamine to form glutamate catalyzed by glutaminase (GLS) or glutaminolysis, and the carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). We determined the expression of PC and GLS proteins in fresh tumor tissue and paired adjacent benign tissue from 86 human NSCLC patients. PC was elevated (median 8-10 fold) in 94% of the tumor tissues, whereas GLS expression did not differ significantly between tumor and paired non tumorous lung tissue. Using 13C6 glucose as tracer and stable isotope-resolved metabolomics (SIRM), we also observed elevated PC activity in vivo in human patients with early stage NSCLC. To examine the importance of PC in the growth and survival of NSCLC, 5 NSCLC cell lines were transduced with a lentiviral vector containing an shRNA against PC. PC knockdown slowed proliferation, induced multinucleation, and reduced colony formation in soft agar. To validate attenuated PC activity and to profile the metabolic effect of PC knockdown, A549 cells were grown in 13C6 glucose or 13C5 glutamine and the incorporation of 13C into various metabolic pathways was measured by NMR and MS by SIRM. We found reduced entry of both glucose and glutamine carbon into the Krebs cycle metabolites, fatty acyl chains of lipids, and nucleotides, suggesting that both energy production and anabolic pathways were hindered and blocking the PC pathway was not compensated by GLS activity. In addition, glutathione biosynthesis and homeostasis were perturbed by PC suppression, leading to compromised anti-oxidation capacity. We further found that PC knockdown in A549 cells reduced their growth rate in mouse xenografts, and recapitulate the metabolic perturbations seen both in cell culture and in human patients. Together, these results suggest that PC is indispensible for the growth and anabolism of NSCLC. This work was funded by 5P20RR018733, 1R01CA118434-01A2, 1P01CA163223-01A1, 1R01ES022191-01, and 3R01CA118434-02S1; and the KLCRP, CTSPGP, and the KY Challenge for Excellence. Citation Format: Katherine E. Sellers, Matthew P. Fox, Michael Bousamra, Jun Yan, Mariia Yuneva, Richard M. Higashi, Andrew N. Lane, Teresa WM Fan. Enhanced pyruvate carboxylation is crucial to non-small cell lung cancer proliferation and anabolism. [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 1424. doi:10.1158/1538-7445.AM2014-1424
What are the indications for mitral valve replacement?
Authors: J. R. Belcher
Journal: BMJ (1966)

Now that it is possible to treat mitral 'valve disease by valve replacement as well as by commissurotomy, and now that it is relatively simple to have either method readily available, it is most important to know which valves should be replaced and which can be safely treated by valvotomy.When the surgeon palpates the valve at operation he may feel stenosis, regurgita- tion, calcification, or any combination of these three, and he has to decide there and then which of the two methods is called for.This paper makes an attempt to answer this question.
Credit for Discovery of Organism of Parinaud's Conjunctivitis
Authors: George F. Keiper
Journal: JAMA (1913)

<h3>To the Editor</h3> :—In reply to Dr. Verhoeff in the August 2 number of The Journal, I submit a copy of a letter sent me by Dr. Alburger after sending him the slide that Dr. Verhoeff submitted to me: June 5, 1913. <i>My Dear Doctor Keiper</i>:—The slide from Dr. Verhoeff presents much the same picture that those prepared by us showed, but it is stained differentially to show the structure of the micro-organisms rather than the general histologic picture. In this section there seem to be a great many more of the fungi than in the areas we studied in your specimen. It is without doubt the same condition and seems to be the same organism. Henry R. Alburger. Dr. Alburger may be mistaken, but he is a mighty good pathologist.
ABC of colorectal cancer: Primary treatment---does the surgeon matter?
Authors: C. McArdle
Journal: BMJ (2000)

The dominant factor contributing to the relatively poor prognosis for colorectal cancer is the advanced stage of the disease at the time of initial presentation: up to a third of patients have locally advanced or metastatic disease, which precludes surgical cure. Even in the patients who undergo apparently curative resection, almost half die within five years.



Colorectal adenoma and tumour—(1);does a patient's survival depend on which surgeon operates?



In the west of Scotland, for example, about a third of 1842 patients presenting with colorectal cancer to seven hospitals between 1991 and 1994 presented as emergencies. Potentially curative resection was achieved in about 70% of patients presenting electively; the curative resection rate was lower in those presenting as emergencies. Five per cent of patients admitted for elective surgery and 13% of those admitted as emergencies died. Almost 60% of elective patients survived two years, compared with 44% of patients admitted as emergencies. These results are typical of population based studies in the United Kingdom.

Most surgeons acknowledge that the incidence of postoperative complications varies widely among individual surgeons. It is now almost 20 years since Fielding and his colleagues in the large bowel cancer project drew attention to differences in anastomotic leak and local recurrence rates after resection for large bowel cancer.

View this table:

Variation in outcome, by surgeon, after curative resection (n=338)



In the original Glasgow Royal Infirmary study, which was conducted in the 1980s, similar differences in postoperative morbidity and mortality were noted. Furthermore, after apparently curative resection, survival at 10 years varied threefold among surgeons.

View this table:

Presentation, type of surgery, and postoperative mortality, by hospital and surgeon (n=1842), west of Scotland study. Values are percentages



One …
Long-term safety of ofloxacin and ciprofloxacin in the treatment of mycobacterial infections.
Authors: S E Berning, L Madsen, M D Iseman, C A Peloquin
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Ofloxacin and ciprofloxacin are potentially useful agents for treating mycobacterial infections. We retrospectively reviewed 7 years' experience with these agents in 103 patients. Ofloxacin was used primarily to treat tuberculosis (TB), dosed to achieve 2-hour postdose serum concentrations of 8-12 micrograms/ml. Ciprofloxacin was used primarily to treat Mycobacterium avium complex (MAC) infection, dosed to achieve 2-hour post-dose serum concentrations of 4-6 micrograms/ml. Despite differences in patient characteristics, underlying disease, and concurrent medications, ofloxacin and ciprofloxacin were associated with a similar spectrum and incidence of adverse reactions. Both drugs were generally well tolerated. Adverse effects led to an ofloxacin dosage change in 1 patient (3%) and discontinuation of ofloxacin in 2 patients (6%). Adverse effects led to a ciprofloxacin dosage change in 2 patients (3%) and discontinuation of ciprofloxacin in 5 patients (7%). Ofloxacin and ciprofloxacin appear to be tolerated as well as or better than other "second-line" antimycobacterial drugs.
High Helicobacter pylori numbers are associated with low eradication rate after triple therapy.
Authors: M Moshkowitz, F M Konikoff, Y Peled, M Santo, A Hallak, Y Bujanover, E Tiomny, T Gilat
Journal: Gut (1995)

This study tested the influence of pretreatment bacterial density on the eradication rate of Helicobacter pylori with triple therapy. One hundred and thirty two patients with endoscopically confirmed H pylori positive, duodenal ulcer or antral gastritis were treated with triple therapy (colloidal bismuth/metronidazole/amoxicillin) for two weeks. Pretreatment urease activity was assessed by the 14C-urea breath test (UBT) in all patients. The mean (SD) pretreatment UBT concentration was similar in patients with duodenal ulcers (318.4 (175.0)) and patients with antral gastritis (288.9 (165.5)). Overall eradication of H pylori was achieved in 85 of 132 patients (64.4%), but was significantly different between patients with high, intermediate, or low pretreatment urease activity (37.5%, 69.5%, and 87.8% respectively). The mean post-treatment UBT value of patients in whom eradication failed was in direct correlation with the pretreatment UBT values. In conclusion, bacterial density, as assessed by urease activity, is an important factor in predicting H pylori eradication. It is suggested that the pretreatment UBT has the potential to identify patients who require modification of the standard therapeutic regimen.
Carrots, Sticks, and Health Care Reform — Problems with Wellness Incentives
Authors: Harald Schmidt, Kristin Voigt, Daniel Wikler
Journal: New England Journal of Medicine (2009)

Chronic conditions, especially those associated with overweight, are on the rise in the United States (as elsewhere). Employers have used both carrots and sticks to encourage healthier behavior. The current health care reform bills seek to expand the role of incentives, which promise a win–win bargain: employees enjoy better health, while employers reduce health care costs and profit from a healthier workforce.However, these provisions cannot be given an ethical free pass. In some cases, the incentives are really sticks dressed up as carrots. There is a risk of inequity that would further disadvantage the people most in need of . . .
The Wisdom of the Ego
Authors: Julia Frank
Journal: JAMA (1993)

Many of us enter medicine with the hope that facing and caring for suffering people will make us not only good (and rich) but wise. In reality, few physicians enjoy the systematic experience or the support for reflection that might allow them to develop more than curbside wisdom about human nature and what gives life meaning. George Vaillant, a widely acclaimed researcher on adult development and on alcoholism, is one of a handful of master clinician-researchers whose work enhances our understanding not only of disease, but of human character in all its vulnerability and resilience. Vaillant's latest book,<i>The Wisdom of the Ego</i>, focuses on the nature and evolution of psychological defenses over the course of adult life. In the tradition of Sigmund Freud, Anna Freud, and Erik Erikson, Vaillant defines defenses as mental operations that mediate between neurological impulse, learned cultural precepts, social interaction, and the material world. These
Work Disability and Workers' Compensation
Authors: George L. Bohmfalk
Journal: JAMA (1994)

To the Editor.  —In the article 1 describing a decrease in the prevalence of work disability in the United States, the author of the Centers for Disease Control and Prevention editorial note offered several potential explanations for the desirable declining trend in work disability. Not among them was the possibility that meaningful numbers of patients are opting out of the workers' compensation program.  Demoralized by the seeming impossibility of achieving reasonably similar return-to-work outcomes between my workers' compensation patients and those with no apparent secondary gain, I closed my neurosurgical practice to elective workers' compensation patients a few years ago. Although my workload and income diminished slightly, my attitude and that of my remaining patient population improved dramatically, as I expected. The surprise was the emergence of a group of patients who indicated that they had originally filed workers' compensation claims for their problems. However, after discovering that I no
Massive Abdominal Panniculectomy
Authors: Basil R. Meyerowitz
Journal: JAMA (1973)

A 40-year-old woman with a lifelong history of obesity, developed a massive abdominal pannus that almost immobilized her after partial weight reduction. The removal of the pannus required its suspension from the ceiling via orthopedic nails inserted into its dependent part. When removed, it weighed 38.5 kg, apparently the heaviest on record. The postoperative course was uneventful and the patient was overjoyed by the removal of the hindrance. Her total weight reduction was 46 kg.