tbuckley/cabot-search huggingface dataset:
Clinical features and outcome of septic arthritis in a single UK Health District 1982-1991
Authors: V C Weston, A C Jones, N Bradbury, F Fawthrop, M Doherty
Journal: Annals of the Rheumatic Diseases (1999)

To determine the clinical features of a large number of unselected UK hospital patients with confirmed septic arthritis and to determine those features associated with a poor outcome.Retrospective, case-note survey.A single English Health District.All patients admitted to hospital in Nottingham during the period 1 January 1982 to 31 December 1991 with confirmed septic arthritis were included.Death, osteomyelitis and recorded functional impairment.The spectrum of causative organisms remains similar to that seen in previous studies with the Gram positive organisms Staphylococcus aureus and Streptococci responsible for 74% of cases, gonococcal infections though were less common. Culture of joint aspirates and or blood were positive in 82% of cases, with the Gram stain demonstrating the causative organism in 50% of cases. Pre-existing joint disease was evident in 35% of cases. The mortality remains high at 11.5% with a significant additional morbidity of 31.6%. Multivariate analysis suggests that important predictors of death are: confusion at presentation, age > or = 65 years, multiple joint sepsis or involvement of the elbow joint, and of morbidity are: age > or = 65 years, diabetes mellitus, open surgical drainage, and Gram positive infections other than S aureus.Septic arthritis continues to be associated with a considerable degree of morbidity and mortality. These results confirm the importance of obtaining synovial fluid and blood for culture before starting antimicrobial treatment. The apparent poorer outcome found with surgical intervention is in line with some previous suggestions but should be interpreted with caution in light of the retrospective nature of this study.
Overexpression of the Low Molecular Weight Cyclin E in Transgenic Mice Induces Metastatic Mammary Carcinomas through the Disruption of the ARF-p53 Pathway
Authors: Said Akli, Carolyn S. Van Pelt, Tuyen Bui, Asha S. Multani, Sandy Chang, David Johnson, Susan Tucker, Khandan Keyomarsi
Journal: Cancer Research (2007)

Abstract In tumor cells, cyclin E deregulation results in the appearance of five low molecular weight (LMW) isoforms. When overexpressed in breast cancer cells, these forms of cyclin E induce genomic instability, resistance to inhibition by p21 and p27, and resistance to antiestrogen therapy. Additionally, the LMW forms of cyclin E strongly correlate with decreased survival in patients with breast cancer. However, the oncologic role of the LMW forms of cyclin E in breast cancer tumorigenesis is yet to be determined. To this end, we generated transgenic mice expressing full-length cyclin E alone (M46A), full-length and the EL4 isoforms (EL1/EL4), or the EL2/3 isoforms of cyclin E (T1) under the control of the mouse mammary tumor virus promoter. Compared with full-length cyclin E, LMW cyclin E overexpression induces delayed mammary growth during the pubertal phase and abnormal cell morphology during lactation. Both primary mammary tumor formation and metastasis were markedly enhanced in LMW cyclin E transgenic mice. LMW cyclin E overexpression in mammary epithelial cells of mice is sufficient by itself to induce mammary adenocarcinomas in 34 of 124 (27%) animals compared with 7 of 67 (10.4%) mice expressing only the full-length cyclin E (P &amp;lt; 0.05). In addition, metastasis was seen in 25% of LMW cyclin E tumor–bearing animals compared with only 8.3% of tumors in the full-length cyclin E background (P &amp;lt; 0.05). Moreover, LMW cyclin E overexpression selects for inactivation of p53 by loss of heterozygosity and spontaneous and frequent inactivation of ARF. Therefore, LMW cyclin E overexpression strongly selects for spontaneous inactivation of the ARF-p53 pathway in vivo, canceling its protective checkpoint function and accelerating progression to malignancy. [Cancer Res 2007;67(15):7212–22]
<i>CYP3A4*22</i> Genotype and Systemic Exposure Affect Paclitaxel-Induced Neurotoxicity
Authors: Anne-Joy M. de Graan, Laure Elens, Jason A. Sprowl, Alex Sparreboom, Lena E. Friberg, Bronno van der Holt, Pleun J. de Raaf, Peter de Bruijn, Frederike K. Engels, Ferry A.L.M. Eskens, Erik A.C. Wiemer, Jaap Verweij, Ron H.J. Mathijssen, Ron H.N. van Schaik
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity. Experimental Design: In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C&amp;gt;T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239). Results: Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P &amp;lt; 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T&amp;gt;0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001). Conclusions: Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment. Clin Cancer Res; 19(12); 3316–24. ©2013 AACR.
Morning Rounds in the Neighborhood
Authors: Elizabeth J Glazier
Journal: Annals of Internal Medicine (2010)

On Being a Doctor20 April 2010Morning Rounds in the NeighborhoodElizabeth J. Glazier, MD, MPHElizabeth J. Glazier, MD, MPHFrom Brooke Army Medical Center, Fort Sam Houston, TX 78234.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-152-8-201004200-00014 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail I wasn't sure what to expect when I drove up to the dilapidated apartment building. His neighbor, who had made the referral, thought that he had broken his leg when he had tried to leave his third-story walk-up apartment for the first time in 6 months. I parked my car and took out my black bag, which had grown over the last year—now able to hold a portable EKG machine, lab supplies, handheld Doppler, and a host of other diagnostics. These were the resources that I had initially come to rely on in my practice. As a young, white, female ... Author, Article, and Disclosure InformationAffiliations: From Brooke Army Medical Center, Fort Sam Houston, TX 78234.Corresponding Author: Elizabeth J. Glazier, MD, MPH, Brooke Army Medical Center, Department of Medicine, 3851 Roger Brooke Drive, Fort Sam Houston, TX 78234. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 20 April 2010Volume 152, Issue 8Page: 535-536KeywordsAlcoholsCaregiversElderlyFallsFoodPatient advocacyPatientsSmellVital signsWalking ePublished: 20 April 2010 Issue Published: 20 April 2010 Copyright & PermissionsCopyright © 2010 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Apoptosis, autophagy, necroptosis, and cancer metastasis
Authors: Zhenyi Su, Zuozhang Yang, Yongqing Xu, Yongbin Chen, Qiang Yu
Journal: Molecular Cancer (2015)

Metastasis is a crucial hallmark of cancer progression, which involves numerous factors including the degradation of the extracellular matrix (ECM), the epithelial-to-mesenchymal transition (EMT), tumor angiogenesis, the development of an inflammatory tumor microenvironment, and defects in programmed cell death. Programmed cell death, such as apoptosis, autophagy, and necroptosis, plays crucial roles in metastatic processes. Malignant tumor cells must overcome these various forms of cell death to metastasize. This review summarizes the recent advances in the understanding of the mechanisms by which key regulators of apoptosis, autophagy, and necroptosis participate in cancer metastasis and discusses the crosstalk between apoptosis, autophagy, and necroptosis involved in the regulation of cancer metastasis.
The growth hormone-insulin-like growth factor I axis and renal glomerular function.
Authors: R Hirschberg, J D Kopple
Journal: Journal of the American Society of Nephrology (1992)

This study examined whether maneuvers that chronically raise or lower serum insulin-like growth factor I (IGF-I), within physiological and pathophysiological ranges, will affect glomerular hemodynamics. Pair-fed Munich Wistar rats received, for 6 to 7 days, continuous s.c. infusions of human recombinant IGF-I (rhIGF-I; 125 micrograms/day), vehicle, or s.c. injection of a synthetic growth hormone-releasing hormone antagonist (GHRH-ANT) (N = 7 in each group). Infusion of rhIGF-I raised serum IGF-I to about 180% of control values, and GHRH-ANT injections lowered serum IGF-I to about 33% of control. The IGF-I infusion induced an increase in left kidney weight when expressed in absolute units but not when expressed as a percentage of body weight; there was also an increase in glomerular volume in the IGF-I treated rats. GFR, single nephron GFR, and single nephron plasma flow also rose with IGF-I infusion, and these changes were associated with decreased afferent and efferent arteriolar resistance and increased glomerular ultrafiltration coefficient. GHRH-ANT injection did not affect kidney weight or glomerular volume; however, GFR, single nephron GFR, and single nephron plasma flow were reduced in association with an increase in efferent arteriolar resistance. There also was a tendency, not significant, for the glomerular ultrafiltration coefficient to decrease. The findings that a low dose of rhIGF-I, which raised the serum IGF-I only modestly, increased glomerular ultrafiltration and that reducing serum IGF-I below control values decreased glomerular dynamics suggest that physiological or pathophysiological changes in IGF-I may affect and possible help to regulate glomerular function.(ABSTRACT TRUNCATED AT 250 WORDS)
The benefit of mass eradication of<i>Helicobacter pylori</i>infection: a community-based study of gastric cancer prevention
Authors: Yi-Chia Lee, Tony Hsiu-Hsi Chen, Han-Mo Chiu, Chia-Tung Shun, Hung Chiang, Tzeng-Ying Liu, Ming-Shiang Wu, Jaw-Town Lin
Journal: Gut (2012)

Objective To evaluate the benefit of mass eradication of Helicobacter pylori infection in reducing premalignant gastric lesions. Design Mass eradication of H pylori infection was started from 2004 for a Taiwanese population with prevalent H pylori infection, who were >30 years of age. Participants positive for the 13C-urea breath test underwent endoscopic screening and 1-week clarithromycin-based triple therapy. For subjects whose initial treatment failed, 10-day levofloxacin-based triple therapy was administered. The main outcome measures were changes in the prevalence of H pylori infection and premalignant gastric lesions, and changes in the incidence of premalignant gastric lesions and gastric cancer before (1995–2003) and after (2004–2008) chemoprevention using various comparators. Results The reduction in H pylori infection was 78.7% (95% CI 76.8% to 80.7%), and the estimated incidence of re-infection/recrudescence was 1% (95% CI 0.6% to 1.4%) per person-year. The effectiveness of reducing the incidence of gastric atrophy resulting from chemoprevention was significant at 77.2% (95% CI 72.3% to 81.2%), while the reduction in intestinal metaplasia was not significant. Compared with the 5-year period before chemoprevention and in the absence of endoscopic screening, the effectiveness in reducing gastric cancer incidence during the chemoprevention period was 25% (rate ratio 0.753, 95% CI 0.372 to 1.524). The reduction in peptic ulcer disease was 67.4% (95% CI 52.2% to 77.8%), while the incidence of oesophagitis was 6% (95% CI 5.1% to 6.9%) after treatment. Conclusions Population-based eradication of H pylori infection has led to a significant reduction in gastric atrophy at the expense of increased oesophagitis. The ultimate benefit in reducing gastric cancer incidence and its mortality should be validated by a further long-term follow-up. Trial registration number NCT00155389.
Multiple pulmonary nodules in a patient with polyarteritis nodosa
Authors: Genevieve Chalifoux, Isabelle Coiteux, Claude Poirier
Journal: European Respiratory Journal (2011)

We are reporting the case of a 58-year-old woman, investigated for a 6 weeks history of abdominal pain, nausea, shortness of breath and weight loss of 25 pounds. Her medical history was otherwise insignificant.  Upon presentation, the woman was febrile at 38,5 C, had tachycardia, low blood pressure despite aggressive volume repletion, leukocytosis and acute renal failure. A CT scan of the thorax and abdomen showed multiple nodules within the thyroid gland, the lungs, liver and kidney parenchyma. The patient was put on broad-spectrum antibiotics and anti-fungal medication. BAL (bronchoscopy) and all cultures remained negative. A screen for vasculitis and virus were negative. A liver biopsy showed areas of necrosis due to ischemic insults. Later, the patient developed gastro-intestinal bleeding. An angio-embolization meant to be curative turned out to be diagnostic. We discovered many small aneurysms affecting the mesenteric, hepatic, gastroepiploic and the bleeding site from an ileal branch was succesfully embolized. A vasculitic origin (PAN) to the patient9s symptoms was undeniable: unexplained weight loss 4 kg; myalgias; elevated creatinine; characteristic angiographic abnormalities. The patient rapidly recovered with IV steroids and cyclophosphamide.  Polyarteritis nodosa is known to affect multiple organs, but the lung. Very few cases of polyarteritis nodosa involving the lung have been reported. Necropsy reports also described pulmonary fibrosis. Cases of acute interstitial pneumonia, BOOP and alveolar hemorrhage have been described. To our knowledge, it would be the first case of micronodular lung involvement in association to PAN. This case raises awareness to a possible pulmonary involvement in PAN.
Somatic Hypermutation in Muts Homologue (Msh)3-, Msh6-, and Msh3/Msh6-Deficient Mice Reveals a Role for the Msh2–Msh6 Heterodimer in Modulating the Base Substitution Pattern
Authors: Margrit Wiesendanger, Burkhard Kneitz, Winfried Edelmann, Matthew D. Scharff
Journal: The Journal of Experimental Medicine (2000)

Although the primary function of the DNA mismatch repair (MMR) system is to identify and correct base mismatches that have been erroneously introduced during DNA replication, recent studies have further implicated several MMR components in somatic hypermutation of immunoglobulin (Ig) genes. We studied the immune response in mice deficient in MutS homologue (MSH)3 and MSH6, two mutually exclusive partners of MSH2 that have not been examined previously for their role in Ig hypermutation. In Msh6−/− and Msh3−/−/Msh6−/− mice, base substitutions are preferentially targeted to G and C nucleotides and to an RGYW hot spot, as has been shown previously in Msh2−/− mice. In contrast, Msh3−/− mice show no differences from their littermate controls. These findings indicate that the MSH2–MSH6 heterodimer, but not the MSH2–MSH3 complex, is responsible for modulating Ig hypermutation.
Molecular Pathways: Targeting PARP in Cancer Treatment
Authors: Khanh Do, Alice P. Chen
Journal: Clinical Cancer Research (2012)

Poly (ADP-ribose) polymerases (PARP) are a family of nuclear protein enzymes involved in the DNA damage response. The role of PARP-1 in base excisional repair has been extensively characterized. More recent in vitro studies additionally implicate a role for PARP-1 in facilitating homologous recombination and nonhomologous end-joining. The more faithful process of homologous recombination repair of double-stranded DNA breaks involves localization of BRCA-1 and BRCA-2 to sites of DNA damage, resection of the double-stranded break, and gap-filling DNA synthesis using the homologous sister chromatid as a template. Simultaneous dysfunction of both DNA repair pathways decreases the ability of cells to compensate, and forms the basis for the concept of synthetic lethality. Treatment strategies, thus far, have focused on two main principles: (i) exploitation of the concept of synthetic lethality in homologous recombination-deficient tumors, primarily in breast and ovarian cancer patients with BRCA mutation, and (ii) as radiosensitizers and chemosensitizers. BRCA deficiency accounts for only a fraction of dysfunction in homologous recombination repair. Epigenetic alterations of BRCA function and defects within the Fanconi anemia pathway also result in defective DNA repair. Rational therapeutic combinations exploiting alternate mechanisms of defective DNA repair, abrogation of cell-cycle checkpoints, and additional functions of PARP-1 present novel opportunities for further clinical development of PARP inhibitors. On the basis of the results of clinical studies of PARP inhibitors thus far, it is imperative that future development of PARP inhibitors take a more refined approach, identifying the unique subset of patients that would most benefit from these agents, determining the optimal time for use, and identifying the optimal combination partner in any particular setting.
New Strategies in Lung Cancer: Translating Immunotherapy into Clinical Practice
Authors: Patrick M. Forde, Ronan J. Kelly, Julie R. Brahmer
Journal: Clinical Cancer Research (2014)

Recent breakthroughs in translating the early development of immunomodulatory antibodies into the clinic, notably with the anti-cytotoxic T-lymphocyte antigen-4 antibody, ipilimumab, have led to durable benefits and prolonged survival for a subgroup of patients with advanced melanoma. Subsequent studies have shown that related immune checkpoint antibodies, specifically those targeting the programmed death-1 pathway, have activity in non-small cell lung cancer. Non-small cell lung cancer is the commonest cause of cancer death worldwide and this exciting avenue of clinical investigation carries with it great promise and new challenges. In this article, we discuss recent developments in lung cancer immunotherapy, reviewing recent findings from therapeutic vaccine studies and in particular we focus on the refinement of immunomodulation as a therapeutic strategy in this challenging disease.
Response to Letter Regarding Article, “Prevention of High-Dose Chemotherapy–Induced Cardiotoxicity in High-Risk Patients by Angiotensin-Converting Enzyme Inhibition”
Authors: Daniela Cardinale, Alessandro Colombo, Maria T. Sandri, Giuseppina Lamantia, Nicola Colombo, Maurizio Civelli, Giovanni Martinelli, Carlo M. Cipolla, Fabrizio Veglia, Cesare Fiorentini
Journal: Circulation (2007)
New Molecular and Biological Mechanism of Antitumor Activities of KW-2478, a Novel Nonansamycin Heat Shock Protein 90 Inhibitor, in Multiple Myeloma Cells
Authors: Takayuki Nakashima, Toshihiko Ishii, Hisashi Tagaya, Toshihiro Seike, Hiroshi Nakagawa, Yutaka Kanda, Shiro Akinaga, Shiro Soga, Yukimasa Shiotsu
Journal: Clinical Cancer Research (2010)

The heat shock protein 90 (Hsp90) plays an important role in chaperoning oncogenic client proteins in multiple myeloma (MM) cells, and several Hsp90 inhibitors have shown antitumor activities both in vitro and in vivo. However the precise mechanism of action of Hsp90 inhibitor in MM has not been fully elucidated.We evaluated the antitumor activities of KW-2478, a nonansamycin Hsp90 inhibitor, in MM cells with various chromosomal translocations of immunoglobulin heavy chain (IgH) loci both in vitro and in vivo.Our studies revealed that exposure of KW-2478 to MM cells resulted in growth inhibition and apoptosis, which were associated with degradation of well-known client proteins as well as a decrease in IgH translocation products (FGFR3, c-Maf, and cyclin D1), and FGFR3 was shown to be a new client protein of Hsp90 chaperon complex. In addition, KW-2478 depleted the Hsp90 client Cdk9, a transcriptional kinase, and the phosphorylated 4E-BP1, a translational inhibitor. Both inhibitory effects of KW-2478 on such transcriptional and translational pathways were shown to reduce c-Maf and cyclin D1 expression. In NCI-H929 s.c. inoculated model, KW-2478 showed a significant suppression of tumor growth and induced the degradation of client proteins in tumors. Furthermore, in a novel orthotopic MM model of i.v. inoculated OPM-2/green fluorescent protein, KW-2478 showed a significant reduction of both serum M protein and MM tumor burden in the bone marrow.These results suggest that targeting such diverse pathways by KW-2478 could be a promising strategy for the treatment of MM with various cytogenetic abnormalities.
Report on chloroquine and dapsone in the treatment of rheumatoid arthritis: a 6-month comparative study.
Authors: P D Fowler, M F Shadforth, P R Crook, A Lawton
Journal: Annals of the Rheumatic Diseases (1984)

A controlled study compared 6 months9 treatment of 60 patients with rheumatoid arthritis (RA). Half were randomly allocated to treatment with chloroquine 250 mg daily, the other half dapsone 100 mg daily (50 mg/day for the first 7 days) following a one-month run-in assessment period. All patients had active or progressing disease. Both treatment groups showed significant improvement in morning stiffness, number of painful joints, pain scores, Ritchie index, and proximal interphalangeal joint size, and the chloroquine group alone in grip strength. Laboratory tests showed significant decreases in erythrocyte sedimentation rate, C-reactive protein, and total serum protein levels, with significant increase in serum albumin in the dapsone group, where there was a significant mean drop in haemoglobin (less than 1 g/dl) and a rise in serum bilirubin, associated with its haemolytic effect. X-ray erosion scores were not significantly affected. The clinical and laboratory responses became evident by the time of the 2-month assessment. Criteria for clinical and laboratory improvement were defined, according to which there were 21/26 improvers in the chloroquine group and 12/29 in the dapsone group. It is concluded that although both are effective preparations, chloroquine showed a significantly higher improvement rate and was certainly better tolerated. It is the preferred treatment for patients with active or progressive disease not controlled by nonsteroidal anti-inflammatory drugs, with dapsone as an alternative for patients who fail to respond to or cannot tolerate chloroquine.