tbuckley/cabot-search huggingface dataset:
Nonalcoholic Steatohepatitis
Authors: Carrie A. Redlich
Journal: Annals of Internal Medicine (1997)

Letters1 September 1997Nonalcoholic SteatohepatitisCarrie A. Redlich, MD, MPH and Mark R. Cullen, MDCarrie A. Redlich, MD, MPHYale University School of Medicine; New Haven, CT 06510Search for more papers by this author and Mark R. Cullen, MDYale University School of Medicine; New Haven, CT 06510Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-127-5-199709010-00014 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:In their excellent review article on nonalcoholic steatohepatitis (NASH) [1], Sheth and colleagues discussed many clinical settings and drugs associated with NASH but did not mention a frequently overlooked cause of this condition. Carbon tetrachloride, a chlorinated solvent and extensively studied hepatotoxin, is well known to cause steatosis and hepatic necrosis. Although carbon tetrachloride is no longer in wide use in the United States, several solvents still common used, such as dimethylformamide and perchloroethylene, have been associated with similar hepatotoxicity [2-4]. The clinical, laboratory, and histologic features of NASH described by the authors are also typical of ...References1. Sheth SG, Gordon FD, Chopra S. Nonalcoholic steatohepatitis. Ann Intern Med. 1997; 126:137-45. Google Scholar2. Redlich CA, Brodkin D. Occupational liver disease. In: Rosenstock L, Cullen MR, eds. Clinical Occupational and Environmental Medicine. Philadelphia: WB Saunders; 1994; 423-36. Google Scholar3. Redlich CA, West AB, Fleming L, True LD, Cullen MR, Riely CA. Clinical and pathologic characteristics associated with occupational exposure to dimethylformamide. Gastroenterology. 1990; 99:748-57. Google Scholar4. Brodkin CA, Daniell W, Checkoway H, Johnson J, Wang K, Sohaey R, et al. Hepatic ultrasonic changes in workers exposed to perchloroethylene. Occup Environ Med. 1995; 52:679-85. Google Scholar5. Wright PB, Moore L. Potentiation of the toxicity of model hepatotoxicants by acetaminophen. Toxicol Appl Pharmacol. 1991; 109:327-35. Google Scholar Author, Article, and Disclosure InformationAffiliations: Yale University School of Medicine; New Haven, CT 06510 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byNonalcoholic steatohepatitis: Summary of an AASLD Single Topic ConferenceNonalcoholic Fatty Liver (NAFL): Overview 1 September 1997Volume 127, Issue 5Page: 410KeywordsDrugsFatty liverHepatotoxinsLiverLiver diseasesNecrosisNonalcoholic steatohepatitisSerum glutamic oxaloacetic transaminaseSteatosisTetrachloride Issue Published: 1 September 1997 Copyright & PermissionsCopyright © 1997 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies
Authors: Kathleen Stergiopoulos, Fabio V Lima, Jie Yang
Journal: New England Journal of Medicine (2016)

To the Editor: Ware et al. (Jan.21 issue) 1 describe a very similar distribution of presumably causative genetic variants in TTN and other genes in women with peripartum cardiomyopathy and in persons with idiopathic dilated cardiomyopathy.The clinical outcome of peripartum cardiomyopathy is highly variable, ranging from full recovery to rapid progression to end-stage heart failure, 2 and the appropriate duration of therapy is controversial.I therefore wonder whether analysis of the data of Ware et al. can shed light on whether TTN-truncating variants are associated with late recovery or persistent left ventricular dysfunction in patients with peripartum cardiomyopathy.
Abstract 3662: Analysis of the tumor suppressor function of B55alpha, the PP2A regulatory subunit encoded by PPP2R2A, in prostate cancer cells
Authors: Ziran Zhao, Alison kurimchak, Mary Adeyemi, Patrick Woodruff, Vladimir Kolenko, Xavier Graña
Journal: Cancer Research (2016)

Abstract Genome wide DNA copy number studies in prostate cancer (PCa) have identified deletions on chromosome 8p21.2 affecting the PPP2R2A gene, which encodes B55α, a B regulatory subunit of Protein Phosphatase 2A (PP2A). The frequency of PPP2R2A hemizygous and homozygous deletions in prostate tumors is 38-58% and 2-7%, respectively. Moreover, PPP2R2A hemizygous loss correlates with reduced mRNA expression. In contrast, no significant correlation is observed for NKX3.1, a tumor suppressor also located at 8p21.2. Bioinformatics analysis indicates that PPP2R2A may belong to the class of “mutator alterations” occurring early in tumorigenesis that promote driver gene mutations. Indeed, PCa patients with these alterations exhibit reduced disease free progression. PP2A consists of a collection of trimeric holoenzymes whose substrate specificity and function is determined by the regulatory B subunit. There are 14 B subunit genes. While it is well accepted that PP2A plays a key tumor suppressor function in human cells, the particular holoenzyme(s) implicated in different tumor types is unclear. We have found, that limited ectopic expression of B55α in PCa cell lines that naturally express low levels of B55α results in dramatic toxicity. We have linked this to G2/M arrest, without concomitant loss in DNA replication, which leads to euploidy, nuclear enlargement and cell death. Thus, early hemizygous loss of PPP2R2A may facilitate effective mitotic progression. We have also seen that increased expression of B55α in these cells dramatically reduces their tumorigenic potential in SCID mice. Moreover, we observe inhibition in the phosphorylation of PP2A/B55α substrates when B55α activity is reconstituted, including AKT and pRB, suggesting alterations in multiple cancer pathways when B55α is downregulated in tumor cells. Interestingly, treatment of PC3 cells with PP2A activating drugs mimic cell cycle effects seen with B55α reconstitution. Citation Format: Ziran Zhao, Alison kurimchak, Mary Adeyemi, Patrick Woodruff, Vladimir Kolenko, Xavier Graña. Analysis of the tumor suppressor function of B55alpha, the PP2A regulatory subunit encoded by PPP2R2A, in prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3662.
Abstract 2424: Genomic landscape of aggressive tumor subtype in MYCN-non-amplified neuroblastoma
Authors: Miki Ohira-Ichikawa
Journal: Cancer Research (2016)

Abstract Neuroblastoma is known to exhibit wide ranges of clinical phenotypes, from spontaneous regression to highly resistant to chemotherapy. One of the challenges in the clinic is to develop suitable therapeutic strategies for the intermediate risk-type of patients (stage 3 or 4 without MYCN amplification) whose prognosis sometimes tends to be poor in terms of long-term follow-up (10 years survival rate was 51% in our database, n = 161). To identify key biological pathways involved in the unfavorable phenotypes in this patient group, we have analyzed 63 primary tumors (dead:32, alive:31) without MYCN amplification nor ALK alteration by integrated genomic analyses such as array CGH, whole exome sequencing (SureSelect XT Human All Exon V4, average read depth:157, x20 coverage:95%), RNA sequencing, as well as Methylome profiling (Infinium HumanMethylation450 BeadChip). By using the Karkinos and ANNOVAR software, we found so far 816 non-synonymous somatic single nucleotide variations (SNVs) in coding exons in total (approximately 20 per tumor in average) and number of alterations in each tumor strongly correlated with age at diagnosis (p&amp;lt;0.0001) and patient prognosis (p = 0.0077). Recurrent somatic SNVs (n = 2 to n = 5) were found in 66 genes, 19 of those were involved only in the tumors from the 24 patients with poor outcome. Gene Ontology and pathway analysis (GeneMANIA) using the 66 genes showed that mutations occurred in the features including cytoskeleton, ion channel and extracellular matrix were significantly correlated with patient survival of the 63 MYCN-non-amplified tumors with logrank p-values of 0.0039, 0.0482 and 0.0011, respectively. ATRX mutations were observed in four tumors (6.3%), all of them were occurred in patients with unfavorable phenotypes (3 dead, 1 alive but relapsed twice). By methylome signature, the 63 tumors were subdivided into at least three clusters, which also showed strong correlation with patient prognosis (cluster-1 vs. cluster-2 and -3, p = 0.0368). Unfavorable cluster-2 and -3 exhibited hyper-methylation phenotypes in CpG islands and the former was quite similar to that of MYCN-amplified tumors. Thus, these prognosis-related genomic features could be useful markers for risk classification and help understanding molecular mechanism for aggressive phenotypes of MYCN-non-amplified neuroblastomas. Citation Format: Miki Ohira-Ichikawa. Genomic landscape of aggressive tumor subtype in MYCN-non-amplified neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2424.
Management of non metastatic castrate resistant prostate cancer (NM-CRPC), results of a UK wide national survey.
Authors: Muhammad Farooq Latif, Syed Hammad Tirmazy, Syed A. Hussain, Richard Jackson, Carmel Barnett, Faisal Azam
Journal: Journal of Clinical Oncology (2016)

e16520 Background: There is no clear consensus on the management of NM-CRPC outside a clinical trial. Due to lack of clinical trials in NM-CRPC, clinicians are left to choose the best treatment option on the basis of the studies conducted in patients (pts) with metastatic CRPC. Methods: We conducted an online survey of 120 Oncologists responsible for the management of prostate cancer (PC) in the United Kingdom. The survey was designed as a questionnaire on SurveyMonkey website. The Oncologists were asked to select the management option for a 65 year old man developing NM-CRPC 2 years after radical radiotherapy (RT) on 1st line, 2nd line and 3rd line setting with a prostate specific antigen doubling time (PSA-DT) of < 6 months, < 3 months and < 2 months respectively. They were then asked to select the factors influencing their treatment decision in this situation including absolute PSA value, PSA-DT, (doubling time) both or other. Results: 96 of 120 oncologists (80%) responded. The preferred treatment option for the pt aged 65 with (PSA 18 ng/ml, PSADT < 6mo), (PSA 38ng/ml, PSADT < 3mo), (PSA 95ng/ml, PSA-DT < 2mo) and (PSA > 95ng/ml, PSA-DT < 2mo) was active monitoring by 36%, 29%, 41% and 57% oncologists respectively. For pts with (PSA 38ng/ml, PSA-DT < 3mo), both 2nd generation hormone therapy (23%) and Dexamethasone (23%) were considered reasonable approaches. Estrogen was the least preferred option for all patient groups (5%, 4%, 4% and 5% respectively). Most (49%, n = 45) of the Oncologists consider both PSA absolute value and PSA-DT as a decision making factor while 27 (30%) consider other factors [development of metastases (33%) n = 9, symptoms (22%) n = 6, PSADT, absolute PSA value & development of metastases 22% n = 6] for treatment of these pts. 18 (20%) Oncologists consider only PSA-DT as a main treatment decision making factor in NM-CRPC patients. Conclusions: In NM-CRPC pts, active monitoring is the most widely preferred choice by oncologists in UK. They consider both absolute PSA value and PSA-DT as important treatment decision making factors. Second generation hormones are preferred than chemotherapy. Results from ongoing clinical trials will help clinicians decide treatments for this group of pts.
Abstract 169: Drug resistance gene expression pathways in primary refractory breast cancer
Authors: Charlene Kan, Shikha Parsai, Stefanie Avril, Janice Lyons, Hannah Gilmore, Junran Zhang, Lyndsay Harris
Journal: Cancer Research (2016)

Abstract Purpose/Objective: Breast cancer is a collection of diseases with distinct molecular subtypes with differing prognoses. Clinically, there is a group of therapy resistant breast cancers characterized by resistance to conventional chemo- and radiotherapy with short overall survival and poor prognosis, which we termed primary refractory breast cancer (PRBC). We hypothesized that PRBC is characterized by specific genomic changes that may contribute to therapy resistance. The aim of this study was to identify changes in gene expression profiles of PRBC compared to triple negative (TNBC) and ER+/-PR positive (HR) breast cancer cohorts. Methods: PRBC was defined as patients with an initial diagnosis of Stage I-III breast cancer who either I) developed metastatic disease within 6 months of completing treatment or II) died of breast cancer within two years of initial diagnosis. Formalin-fixed paraffin-embedded (FFPE) tissue was obtained under an IRB approved protocol 01-13-43c. RNA was extracted from macro-dissected FFPE tumor tissue. Gene expression profiling was performed with Affymetrix Human Transcriptome Array 2.0 and gene signatures were analyzed using a single sample gene set enrichment methodology. Gene signatures of PRBC patients were compared to signatures of two TNBC and HR cohorts with gene expression data generated by identical methodology. Results: A total of nineteen samples from eight patients had sufficient tumor material to obtain RNA. The median age at diagnosis was 44.3 years, 62.5% were triple negative. At initial diagnosis the stage ranged from IA to IIIC. Sixty-three percent received neoadjuvant chemotherapy. The median time to relapse was 8.4 months and median time to death 1.7 years. Genomic analysis identified highly significant (p&amp;lt;10-6) increased expression of ABC transporters, hypoxia, interferon, DNA repair and AKT signatures compared to control cohorts. Conclusions: PRBC is characterized by significant upregulation of multiple gene expression signatures important in drug resistance including ABC transporters, hypoxia, AKT and DNA repair pathways. Confirmation of these results would allow the development of alternative treatment strategies for PRBC to help improve the devastatingly poor prognosis of this subgroup of patients. Citation Format: Charlene Kan, Shikha Parsai, Stefanie Avril, Janice Lyons, Hannah Gilmore, Junran Zhang, Lyndsay Harris. Drug resistance gene expression pathways in primary refractory breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 169.
A Randomized, Placebo-Controlled, Double Blind Trial of the MDR Modulator, Zosuquidar, during Conventional Induction and Post-Remission Therapy for Pts &amp;gt; 60 Years of Age with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (HR-MDS): ECOG 3999.
Authors: Larry D. Cripe, Xiaochun Li, Mark Litzow, Elisabeth Paietta, Jacob M. Rowe, Selina Luger, Martin Tallman
Journal: Blood (2006)
Case 48-1967
Authors: Gordon A. Donaldson, Austin L. Vickery
Journal: New England Journal of Medicine (1967)

Presentation of CaseA fifty-four-year-old man entered the hospital because of abdominal cramps and diarrhea.He had been well until four months previously, when there was the onset of abdominal cramps and diarrhea, with the passage of semiformed stools containing mucus and occasionally blood. The cramps often awakened him from sleep and were usually relieved by a bowel movement. Sigmoidoscopic examination was said to be negative. Three months before entry a barium-enema examination revealed an area of narrowing, 10 cm in length, in the sigmoid colon; the wall of the abnormal segment was irregular and lobulated, with scattered diverticula; the . . .
Abstract CT033: Phase 1b study of heat shock protein 90 inhibitor onalespib in combination with paclitaxel in patients with advanced, triple-negative breast cancer (NCT02474173)
Authors: Robert Wesolowski, Maryam B. Lustberg, Ewa Mrozek, Rachel Layman, Raquel Reinbolt, Ming Poi, Nadia Osman, Andrea Lively, Julie Stephens, Michael Grever, Bhuvaneswari Ramaswamy
Journal: Cancer Research (2016)

Abstract Background: Heat shock protein 90 (HSP90) is a molecular chaperone that is required for proper folding and stabilization of proteins. Client proteins of HSP90 include many mediators of signal transduction known to be over-activated in triple negative breast cancer such as AKT, EGFR, members of RAS/MAPK signaling pathways and androgen receptor. Expression of HSP90 has been found to be upregulated in multiple triple negative breast cancer cell lines and associated with poor outcome of breast cancer patients. In addition, over-expression of HSP90 client proteins such as AKT and c-RAF has been implicated in paclitaxel resistance. Onalespib (AT13387) is a synthetic non-ansamycin small molecule that acts as an inhibitor of HSP90 by binding to the amino terminal of the protein and has dissociation constant (Kd) of 0.71 nM. Materials and Methods: Patients with inoperable or metastatic triple negative or weakly hormone receptor positive breast cancer are treated with onalespib and paclitaxel on days 1, 8, 15 every 28 days. Paclitaxel is given at a standard dose of 80 mg/m2 while the dose of onalespib is gradually increased using standard 3+3 design (see table). In order to assess the effect of each drug on pharmacokinetics of the other drug, onalespib is given on day -7 prior to cycle 1 and skipped on day 1 of cycle 1 during which paclitaxel in administered alone. The primary objective of the study is to determine recommended phase 2 dose and assess the toxicity profile of the combination. The secondary objectives include effect of onalespib on pharmacokinetics of paclitaxel and effect of paclitaxel on pharmacokinetics of onalespib. Overall response rate, response duration and progression-free survival will also be assessed. Dose Escalation ScheduleDose LevelDoseOnalespib (mg/m2 IV on days 1, 8, 15)Paclitaxel (mg/m2 IV on days 1, 8, 15)Level -110080Level 112080Level 215080Level 320080Level 426080 Conclusion: The study opened to accrual on January 15, 2016 and is currently enrolling the first 3 patients to dose level 1. Citation Format: Robert Wesolowski, Maryam B. Lustberg, Ewa Mrozek, Rachel Layman, Raquel Reinbolt, Ming Poi, Nadia Osman, Andrea Lively, Julie Stephens, Michael Grever, Bhuvaneswari Ramaswamy. Phase 1b study of heat shock protein 90 inhibitor onalespib in combination with paclitaxel in patients with advanced, triple-negative breast cancer (NCT02474173). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT033.
Case 38-1965
Authors: John E. Howard, Benjamin Castleman
Journal: New England Journal of Medicine (1965)

Presentation of Case First admission. A fifty-three-year-old man was admitted to the hospital because of pain in the knee.For the previous six years he had had episodes of low-back pain. Three years before entry, while stepping off a curb, he suddenly experienced severe lumbar pain. At the advice of his physician he reduced his weight from 335 to 275 pounds. X-ray treatment of the lumbar region was without benefit. Eleven months before admission, in the course of other studies, an x-ray film revealed a fracture of the left hip. Two months later an attempt at nailing the hip was . . .
BMJ Learning
Authors: E. Briffa
Journal: BMJ (2003)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following BMJ Learning Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Unilateral metamorphopsia in a 73 year old woman
Authors: Ilias Georgalas, Menelaos Kanakis, Dionisis Pagoulatos, Petros Petrou
Journal: BMJ (2016)

A 73 year old woman presented to her general practitioner with a two month history of distorted and blurred vision. Her symptoms had worsened in the two weeks before presentation. Her history was unremarkable. Clinical examination showed visual acuity of 20/25 in the right eye and 20/100 in the left eye. Apart from early cataracts, the examination of the anterior segment was unremarkable. Direct fundoscopy showed a haemorrhagic elevated lesion at the macula in the left eye (fig 1⇓).



Fig 1  Fundus of left eye showing haemorrhagic elevated lesion in macular area



1.  What is the most likely underlying diagnosis?

2.  Do patients with this condition need further investigations?

3.  Is the other eye at risk?

4.  Are there any predisposing factors for this condition?

5.  How should this condition be treated?

### 1. What is the most likely underlying diagnosis?

#### Short answer

Wet age related macular degeneration (AMD).

#### Discussion

AMD is a degenerative disease of the retina that might involve a substantial area of the macula. In the developed world, AMD is regarded as the leading cause of irreversible loss of vision. In US alone, it is estimated to affect 1.75 million people, with an additional 7 million at risk of developing the disease.1 2 3 4

Symptoms include metamorphopsia (image distortion), decreased or blurred vision, difficulties in adapting to the dark, and the development of scotomas.5 Metamorphopsia might be an early symptom. Images might seem smaller (micropsia) or larger (macropsia). Patients often report straight lines, such as window frames and telephone poles, appearing to be curved or notched.

Neovascular AMD or exudative AMD are alternative terms to wet AMD. Dry AMD is characterised by pigmentary changes and the presence of drusen (yellow fatty deposits) at the retinal pigment epithelium.6 7 In fundoscopy, drusen appear as focal white-yellow excrescences—varying in number, size, shape, and distribution—located in the deep layers of the …