tbuckley/cabot-search huggingface dataset:
A Pathophysiologic Role for T Lymphocytes in Murine Acute Cisplatin Nephrotoxicity
Authors: Manchang Liu, Chu-Chun Chien, Melissa Burne-Taney, Roshni R. Molls, Lorraine C. Racusen, Robert B. Colvin, Hamid Rabb
Journal: Journal of the American Society of Nephrology (2006)

Recent evidence supports a role for an inflammatory pathogenesis of cisplatin nephrotoxicity, but immune cell-mediated mechanisms in this disease are still largely unknown. The role for T lymphocytes on cisplatin-induced acute kidney injury was examined with C57BL/6 T cell-deficient (nu/nu) mice and CD4- or CD8-deficient mice and their wild-type (WT) littermates. All mice received a single dose of cisplatin at 40 mg/kg (intraperitoneally) and were followed up for 72 h. At 72 h after cisplatin administration, T cell-deficient mice had a marked attenuation in renal dysfunction (serum creatinine 3.2+/-0.5 versus 0.8+/-0.1 mg/dl; P=0.007), kidney tubular injury (scores 1.44+/-0.15 versus 0.22+/-0.08; P<0.0001), and survival. Adoptive transfer of T cells into nu/nu mice followed by cisplatin enhanced renal dysfunction and tubular injury. The increase in renal myeloperoxidase activity after cisplatin administration was blunted in nu/nu mice. Renal TNF-alpha, IL-1beta, and keratinocyte-derived chemokine protein expression was increased in WT mice but not in nu/nu mice after cisplatin administration. T cell levels significantly increased in kidneys of WT mice after cisplatin administration as early as at 1 h, peaked at 12 h, and declined by 24 h. CD4- and, to a lesser degree, CD8-deficient mice were relatively protected from cisplatin-induced mortality and renal dysfunction compared with WT mice. These data demonstrate that T lymphocytes are direct mediators of experimental cisplatin nephrotoxicity. Targeting T lymphocytes could lead to improved ways to administer cisplatin safely to cancer patients.
Rates of Hyperkalemia after Publication of the Randomized Aldactone Evaluation Study
Authors: David N. Juurlink, Muhammad M. Mamdani, Douglas S. Lee, Alexander Kopp, Peter C. Austin, Andreas Laupacis, Donald A. Redelmeier
Journal: New England Journal of Medicine (2004)

The Randomized Aldactone Evaluation Study (RALES) demonstrated that spironolactone significantly improves outcomes in patients with severe heart failure. Use of angiotensin-converting-enzyme (ACE) inhibitors is also indicated in these patients. However, life-threatening hyperkalemia can occur when these drugs are used together.We conducted a population-based time-series analysis to examine trends in the rate of spironolactone prescriptions and the rate of hospitalization for hyperkalemia in ambulatory patients before and after the publication of RALES. We linked prescription-claims data and hospital-admission records for more than 1.3 million adults 66 years of age or older in Ontario, Canada, for the period from 1994 through 2001.Among patients treated with ACE inhibitors who had recently been hospitalized for heart failure, the spironolactone-prescription rate was 34 per 1000 patients in 1994, and it increased immediately after the publication of RALES, to 149 per 1000 patients by late 2001 (P<0.001). The rate of hospitalization for hyperkalemia rose from 2.4 per 1000 patients in 1994 to 11.0 per 1000 patients in 2001 (P<0.001), and the associated mortality rose from 0.3 per 1000 to 2.0 per 1000 patients (P<0.001). As compared with expected numbers of events, there were 560 (95 percent confidence interval, 285 to 754) additional hyperkalemia-related hospitalizations and 73 (95 percent confidence interval, 27 to 120) additional hospital deaths during 2001 among older patients with heart failure who were treated with ACE inhibitors in Ontario. Publication of RALES was not associated with significant decreases in the rates of readmission for heart failure or death from all causes.The publication of RALES was associated with abrupt increases in the rate of prescriptions for spironolactone and in hyperkalemia-associated morbidity and mortality. Closer laboratory monitoring and more judicious use of spironolactone may reduce the occurrence of this complication.
Tracer Studies in the Rat Demonstrate Misdirected Filtration and Peritubular Filtrate Spreading in Nephrons with Segmental Glomerulosclerosis
Authors: WILHELM KRIZ, INGRID HARTMANN, HILTRAUD HOSSER, BRUNHILDE HA[Combining Diaeresis]HNEL, BETTINA KRA[Combining Diaeresis]NZLIN, ABARAHAM P. PROVOOST, NORBERT GRETZ
Journal: Journal of the American Society of Nephrology (2001)

Abstract. In two genetic models of “classic” focal segmental glomerulosclerosis (FSGS), the Milan normotensive and the Fawn-hooded hypertensive rats, tracer studies were performed to test the hypothesis that misdirected glomerular filtration and peritubular filtrate spreading are relevant mechanisms that contribute to nephron degeneration in this disease. Two exogenous tracers, lissamine green and horse spleen ferritin, were administered by intravenous injection and subsequently traced histologically in serial kidney sections. In contrast to control rats, both tracers in kidneys of Milan normotensive and Fawn-hooded hypertensive rats with established FSGS were found to accumulate extracellularly at the following sites: ( 1 ) within tuft adhesions to Bowman's capsule and associated paraglomerular spaces, ( 2 ) at the glomerulotubular junction contained within extensions of the paraglomerular spaces onto the tubule, and ( 3 ) within subepithelial peritubular spaces eventually encircling the entire proximal convolution of an affected nephron. This distribution strongly suggests the existence of misdirected filtration into tuft adhesions to Bowman's capsule and subsequent spreading of the filtrate around the entire circumference of a glomerulus and, alongside the glomerulotubular junction, onto the outer aspect of the corresponding tubule. This leads to an interstitial response that consists of the formation of a barrier of sheet-like fibroblast processes around the affected nephron, which confines the filtrate spreading and, subsequently, the destructive process to the affected nephron. No evidence was found that either misdirected filtration and peritubular filtrate spreading themselves or the associated tubulo-interstitial process led to the transfer of the injury from an affected nephron to an unaffected nephron. It is concluded that in the context of FSGS development, misdirected filtration and peritubular filtrate spreading are important damaging mechanisms that underlie the extension of glomerular injury to the corresponding tubulointerstitium, thus leading finally to degeneration of both the glomerulus and the tubule of a severely injured nephron.
Apolipoprotein C-I Is Crucially Involved in Lipopolysaccharide-Induced Atherosclerosis Development in Apolipoprotein E–Knockout Mice
Authors: Marit Westerterp, Jimmy F.P. Berbée, Nuno M.M. Pires, Geertje J.D. van Mierlo, Robert Kleemann, Johannes A. Romijn, Louis M. Havekes, Patrick C.N. Rensen
Journal: Circulation (2007)

Lipopolysaccharide (LPS), which is released from gram-negative bacteria on multiplication or lysis, aggravates atherosclerosis in humans and rodents by inducing inflammation via toll-like receptors. Because apolipoprotein C-I (apoCI) enhances the LPS-induced inflammatory response in macrophages in vitro and in mice, we investigated the effect of endogenous apoCI expression on LPS-induced atherosclerosis in mice.Twelve-week-old apoe-/- apoc1-/- and apoe-/- apoc1+/+ mice received weekly intraperitoneal injections of LPS (50 microg) or vehicle for a period of 10 weeks, and atherosclerosis development was assessed in the aortic root. LPS administration did not affect atherosclerotic lesion area in apoe-/- apoc1-/- mice but increased it in apoe-/- apoc1+/+ mice. In fact, apoCI expression increased the LPS-induced atherosclerotic lesion area by 60% (P<0.05), concomitant with an increase in LPS-induced plasma levels of fibrinogen and E-selectin. This indicated that apoCI increased the LPS-induced inflammatory state, both systemically (ie, fibrinogen) and at the level of the vessel wall (ie, E-selectin). In addition, both macrophage-derived apoCI and HDL-associated apoCI increased the LPS-induced tumor necrosis factor-alpha response by macrophages in vitro.We conclude that apoCI is crucially involved in LPS-induced atherosclerosis in apoe-/- mice, which mainly relates to an increased inflammatory response toward LPS. We anticipate that apoCI plasma levels contribute to accelerated atherosclerosis development in individuals who have chronic infection.
Prediction of T-cell reconstitution by assessment of T-cell receptor excision circle before allogeneic hematopoietic stem cell transplantation in pediatric patients
Authors: Xiaohua Chen, Raymond Barfield, Ely Benaim, Wing Leung, James Knowles, Dawn Lawrence, Mario Otto, Sheila A. Shurtleff, Geoffrey A. M. Neale, Frederick G. Behm, Victoria Turner, Rupert Handgretinger
Journal: Blood (2004)
AT-30 * EFFECTS OF EVEROLIMUS ON MENINGIOMA GROWTH IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2
Authors: M. Karajannis, D. Osorio, A. Filatov, M. Hagiwara, C. Mitchell, J. Wisoff, J. Golfinos, T. Roland, J. Allen
Journal: Neuro-Oncology (2014)

BACKGROUND: Vestibular schwannomas (VS) and meningiomas are associated with biallelic loss of NF2, and may arise sporadically or in the context of the tumor predisposition syndrome neurofibromatosis type 2. Loss of NF2 activates the mammalian target of rapamycin (mTOR) pathway, and published in vitro and in vivo data indicate that mTOR inhibition may be effective in the treatment of NF2-deficient VS and meningiomas. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with anti-tumor activity in a variety of tumors. METHODS: We conducted a retrospective review of patients with NF2 and progressive vestibular schwannomas treated with everolimus on our prospective phase II clinical trial (ClinicalTrials.gov NCT01419639). Everolimus was administered at a daily dose of 10 mg in continuous 28-day courses for up to 12 courses. In this retrospective study, we included patients with at least one volumetrically measurable meningioma (>0.5 cc) who received at least six 28-day courses of therapy. Tumor response was assessed with brain MRI every three months using three-dimensional volumetric analysis. RESULTS: Three patients met criteria and had 10 evaluable meningiomas, with a total combined volume of 11.84 cc at baseline (median 1.20 cc, range 0.53–3.00 cc). Median time on therapy was 9 months (range 6–12 months). Total combined meningioma volume remained stable during treatment (-1.8%). Correspondingly, none of the individual tumors analyzed met criteria for volumetric response or progression during the treatment period (range -10% to +9.4%). CONCLUSIONS: Neither objective response nor progression was appreciated in meningiomas patients during a median treatment duration of 6 months. Further clinical studies will be required to determine whether everolimus affects meningioma growth velocity in patients with NF2. To better understand pharmacologic mTOR signaling pathway modulation in human VS and meningiomas in vivo, we are currently conducting a multi-center pharmacodynamic/pharmacokinetic (“phase 0”) study with everolimus (NCT01880749).
Endoscopic Injection Treatment in Patients with Shock and Gastrointestinal Bleeding or Stigmata of Recent Hemorrhage
Authors: G. Di Felice
Journal: Endoscopy (1987)

Forty cases of upper gastrointestinal bleeding were studied. Twenty-three patients had shock and active bleeding (3 spurting, 12 oozing and 2 a clot with oozing) or stigmata of recent hemorrhage (4 with a clot and 2 with a visible vessel). Nineteen of these were submitted to endoscopic injection. In 4 cases with multiple acute hemorrhagic lesions and shock, and in 17 patients with stigmata of recent bleeding without shock, the technique was not carried out. None of the patients had a rebleed. One patient was submitted to surgery 24 hours after injection for a large acute gastric ulcer in the process of perforating, and died of pulmonary embolism 4 days later. No technique-related complications were observed. We believe endoscopic injection treatment might be the technique of choice in patients with shock and active bleeding or stigmata of recent hemorrhage of the upper gastrointestinal tract.
Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study
Authors: N. S. Abraham, S. Singh, G. C. Alexander, H. Heien, L. R. Haas, W. Crown, N. D. Shah
Journal: BMJ (2015)

<b>Objective</b> To determine the real world risk of gastrointestinal bleeding associated with the use of the novel oral anticoagulants dabigatran and rivaroxaban compared with warfarin. <b>Design</b> Retrospective, propensity matched cohort study. <b>Setting:</b> Optum Labs Data Warehouse, a large database including administrative claims data on privately insured and Medicare Advantage enrollees. <b>Participants</b> New users of dabigatran, rivaroxaban, and warfarin from 1 November 2010 to 30 September 2013. <b>Main outcome measures</b> Incidence rates (events/100 patient years) and propensity score matched Cox proportional hazards models were used to estimate rates of total gastrointestinal bleeds, upper gastrointestinal bleeds, and lower gastrointestinal bleeds for the novel oral anticoagulants compared with warfarin in patients with and without atrial fibrillation. Heterogeneity of treatment effect related to age was examined using a marginal effects model. <b>Results</b> The incidence of gastrointestinal bleeding associated with dabigatran was 2.29 (95% confidence interval 1.88 to 2.79) per 100 patient years and that associated with warfarin was 2.87 (2.41 to 3.41) per 100 patient years in patients with atrial fibrillation. In non-atrial fibrillation patients, the incidence of gastrointestinal bleeding was 4.10 (2.47 to 6.80) per 100 patient years with dabigatran and 3.71 (2.16 to 6.40) per 100 patient years with warfarin. With rivaroxaban, 2.84 (2.30 to 3.52) gastrointestinal bleeding events per 100 patient years occurred in atrial fibrillation patients (warfarin 3.06 (2.49 to 3.77)/100 patient years) and 1.66 (1.23 to 2.24) per 100 patient years in non-atrial fibrillation patients (warfarin 1.57 (1.25 to 1.99)/100 patient years). In propensity score matched models, the risk of gastrointestinal bleeding with novel oral anticoagulants was similar to that with warfarin in atrial fibrillation patients (dabigatran <i>v</i> warfarin, hazard ratio 0.79 (0.61 to 1.03); rivaroxaban <i>v</i> warfarin, 0.93 (0.69 to 1.25)) and in non-AF patients (dabigatran <i>v</i> warfarin, hazard ratio 1.14 (0.54 to 2.39); rivaroxaban <i>v</i> warfarin, 0.89 (0.60 to 1.32)). The risk of gastrointestinal bleeding increased after age 65, such that by age 76 the risk exceeded that with warfarin among atrial fibrillation patients taking dabigatran (hazard ratio 2.49 (1.61 to 3.83)) and patients with and without atrial fibrillation taking rivaroxaban (2.91 (1.65 to 4.81) and 4.58 (2.40 to 8.72), respectively). <b>Conclusions:</b> The risk of gastrointestinal bleeding related to novel oral anticoagulants was similar to that for warfarin. Caution should be used when prescribing novel oral anticoagulants to older people, particularly those over 75 years of age.
Molecular Differences between Sporadic Serrated and Conventional Colorectal Adenomas
Authors: Kazuo Konishi, Toshiko Yamochi, Reiko Makino, Kazuhiro Kaneko, Taikan Yamamoto, Hisako Nozawa, Atsushi Katagiri, Hiroaki Ito, Kentarou Nakayama, Hidekazu Ota, Keiji Mitamura, Michio Imawari
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose is to compare the molecular characteristics of serrated adenomas (SAs) with those of conventional adenomas (CADs) and hyperplastic polyps (HPs). Experimental Design: We evaluated the proliferative activity and molecular alterations in 47 SAs (25 pure-type and 22 mixed-type), 71 CADs, and 23 HPs. Results: The proliferative activity of SAs, as evaluated by Ki-67 expression, was intermediate between CADs and HPs. There was no significant difference in the incidence of KRAS or p53 mutations between the three histological groups. In the microsatellite instability (MSI) analysis, 21% of SAs (9 of 43) showed MSI at two or more loci (MSI-H); corresponding values were 5% of CADs (3 of 64) and 8% of HPs (1 of 13; SAs versus CADs, P = 0.0125). MSI-H was more likely to be found in pure-type SAs (36%; 8 of 22) than in mixed-type SAs (5%; 1 of 21; P = 0.0212). Loss of hMLH-1 expression was found in 8 of 9 SAs with MSI-H. The incidence of BRAF or KRAS mutations was 36 and 15% of SAs, respectively; the combined incidence of BRAF and KRAS mutations occurred in 49% of SAs. However, there was no significant difference in the incidence of BRAF or KRAS mutations between SAs with and without MSI-H. Conclusions: Genetic instability is more frequently implicated in the tumorigenesis of SAs, especially pure-type SAs, than in that of CADs. In contrast, activation of the Ras/Raf/MEK/MAP kinase cascade by BRAF or KRAS mutation, independently of the genetic instability, may be associated with the progression of about half of SAs.
BRCA2, Purified, Reveals Some of Its Secrets
Authors: Charlie Schmidt
Journal: JNCI Journal of the National Cancer Institute (2010)

according to Gordon Mills, M.D., Ph.D., chair of molecular oncology at the M. D. Anderson Cancer Center in Houston. “I’d describe it as a technical tour de force,” said Mills, who was not involved in the work. “It refi nes our understanding of the mechanism by which BRCA2 coordinates DNA repair, and it could have a massive impact on developing new ways to go after abnormalities in both BRCA1 and BRCA2.” The results were published online in Nature and Nature Structural Biology in August. BRCA2 ranks among the largest human proteins, with 3,418 amino acids. Scientists struggled for 15 years to purify the giant molecule, which tends to break into fragments almost as soon as it’s transcribed in the laboratory. To get around this problem, researchers had to affi x protein tags to BRCA2’s front and back ends, which held the molecule in place during extraction from cell-based expression systems. Remarkably, each research team purifi ed BRCA2 around the same time, though each used different tags and different systems. Stephen C. Kowalczykowski, Ph.D. , a biochemist at the University of California, Davis, who led the team that published in Nature , said that hitting on the right combination of tags and expression systems took considerable trial and error. Neither bacterial nor insect cell lines possessed the protein mix that human BRCA2 relies on to fold correctly as it emerges from the genome, he said. Kowalczykowski’s postdoctoral student, Ryan Jensen, Ph.D., ultimately succeeded by using human cells and tags made of maltose binding protein, which attach preferentially to amylose resins used in chromatography columns. Like magnets on a refrigerator door, these proteins hold BRCA fast during the extraction, trapping the molecule while other proteins in the cell slip by. Wolf-Dietrich Heyer, Ph.D., also a biochemist at UC Davis, and lead author on one of the Nature Structural Biology reports, successfully purifi ed BRCA2 in yeast, using a glutathione S -transferase tag on the protein’s N terminus (front end) and a histidine affi nity tag on its C terminus (back end). “We used yeast because we’ve got a lot of experience with it,” Heyer said. “We had a lot of tricks we could use to express the protein and also to preserve it.” Finally, Stephen West, Ph.D., a geneticist at Cancer Research UK in London, and colleagues, who also published in Nature Structural Biology , purifi ed BRCA2 in cultured human HeLa cells made in a bacterial construct. While acknowledging the purifi cation’s importance to science, Kowalczykowski also describes the achievement as more of a means to an end. “The more important story is what we can do with the full-length validated protein in hand,” he said. “Now we can run detailed mechanistic and molecular studies to explore what BRCA2 does.” “The more important story is what we can do with the full-length validated protein in hand.”
Reaching Out to Patients to Identify Adverse Drug Reactions and Nonadherence
Authors: Michael A. Steinman
Journal: JAMA Internal Medicine (2013)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Hyperbilirubinemia in pazopanib- or sunitinib-treated patients in COMPARZ is associated with UGT1A1 polymorphisms
Authors: R.J. Motzer, T. Johnson, T.K. Choueiri, K.C. Deen, Z. Xue, L.N. Pandite, C. Carpenter, C.F. Xu
Journal: Annals of Oncology (2013)
The type III TGF-β receptor suppresses breast cancer progression
Authors: Mei Dong, Tam How, Kellye C. Kirkbride, Kelly J. Gordon, Jason D. Lee, Nadine Hempel, Patrick Kelly, Benjamin J. Moeller, Jeffrey R. Marks, Gerard C. Blobe
Journal: Journal of Clinical Investigation (2006)

The TGF-β signaling pathway has a complex role in regulating mammary carcinogenesis. Here we demonstrate that the type III TGF-β receptor (TβRIII, or betaglycan), a ubiquitously expressed TGF-β coreceptor, regulated breast cancer progression and metastasis. Most human breast cancers lost TβRIII expression, with loss of heterozygosity of the TGFBR3 gene locus correlating with decreased TβRIII expression. TβRIII expression decreased during breast cancer progression, and low TβRIII levels predicted decreased recurrence-free survival in breast cancer patients. Restoring TβRIII expression in breast cancer cells dramatically inhibited tumor invasiveness in vitro and tumor invasion, angiogenesis, and metastasis in vivo. TβRIII appeared to inhibit tumor invasion by undergoing ectodomain shedding and producing soluble TβRIII, which binds and sequesters TGF-β to decrease TGF-β signaling and reduce breast cancer cell invasion and tumor-induced angiogenesis. Our results indicate that loss of TβRIII through allelic imbalance is a frequent genetic event during human breast cancer development that increases metastatic potential.
Two Faces of Vitamin E in the Lung
Authors: Joan M. Cook-Mills, Hiam Abdala-Valencia, Tina Hartert
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Asthma and allergic lung disease occur as complex environmental and genetic interactions. Clinical studies of asthma indicate a number of protective dietary factors, such as vitamin E, on asthma risk. However, these studies have had seemingly conflicting outcomes. In this perspective, we discuss opposing regulatory effects of tocopherol isoforms of vitamin E, mechanisms for tocopherol isoform regulation of allergic lung inflammation, association of vitamin E isoforms with outcomes in clinical studies, and how the variation in global prevalence of asthma may be explained, at least in part, by vitamin E isoforms.
Is QT dispersion predictive of mortality in patients with severe congestive heart failure?
Authors: M.I. Anastasiou-Nana, J.N. Nanas, L.A. Karagounis, E. Tsagalou, N. Kouvelas, I. Tsolakis, S.F. Stamatolopoulos
Journal: Journal of the American College of Cardiology (1998)