tbuckley/cabot-search huggingface dataset:
Complement Pathway Is Frequently Altered in Endometriosis and Endometriosis-Associated Ovarian Cancer
Authors: Swati Suryawanshi, Xin Huang, Esther Elishaev, Raluca A. Budiu, Lixin Zhang, SungHwan Kim, Nicole Donnellan, Gina Mantia-Smaldone, Tianzhou Ma, George Tseng, Ted Lee, Suketu Mansuria, Robert P. Edwards, Anda M. Vlad
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Mechanisms of immune dysregulation associated with advanced tumors are relatively well understood. Much less is known about the role of immune effectors against cancer precursor lesions. Endometrioid and clear-cell ovarian tumors partly derive from endometriosis, a commonly diagnosed chronic inflammatory disease. We performed here a comprehensive immune gene expression analysis of pelvic inflammation in endometriosis and endometriosis-associated ovarian cancer (EAOC). Experimental Design: RNA was extracted from 120 paraffin tissue blocks comprising of normal endometrium (n = 32), benign endometriosis (n = 30), atypical endometriosis (n = 15), and EAOC (n = 43). Serous tumors (n = 15) were included as nonendometriosis-associated controls. The immune microenvironment was profiled using Nanostring and the nCounter GX Human Immunology Kit, comprising probes for a total of 511 immune genes. Results: One third of the patients with endometriosis revealed a tumor-like inflammation profile, suggesting that cancer-like immune signatures may develop earlier, in patients classified as clinically benign. Gene expression analyses revealed the complement pathway as most prominently involved in both endometriosis and EAOC. Complement proteins are abundantly present in epithelial cells in both benign and malignant lesions. Mechanistic studies in ovarian surface epithelial cells from mice with conditional (Cre-loxP) mutations show intrinsic production of complement in epithelia and demonstrate an early link between Kras- and Pten-driven pathways and complement upregulation. Downregulation of complement in these cells interferes with cell proliferation. Conclusions: These findings reveal new characteristics of inflammation in precursor lesions and point to previously unknown roles of complement in endometriosis and EAOC. Clin Cancer Res; 20(23); 6163–74. ©2014 AACR.
Clinical Relevance of Microsatellite Instability in Colorectal Cancer
Authors: Albert de la Chapelle, Heather Hampel
Journal: Journal of Clinical Oncology (2010)

Microsatellite instability (MSI) is a clonal change in the number of repeated DNA nucleotide units in microsatellites. It arises in tumors with deficient mismatch repair due to the inactivation of one of the four mismatch repair genes: MSH2, MLH1, MSH6, and PMS2. In order to determine the MSI status of a tumor, microdissection and polymerase chain reaction–based detection strategies are required. For practical purposes, MSI is equivalent to the loss of staining by immunohistochemistry (IHC) of one of the mismatch repair genes since both signify an abnormality in mismatch repair. Of all colorectal cancers (CRCs), 15% to 20% display MSI or abnormal IHC (often referred to as microsatellite instability [MIN] pathway). The remaining 80% to 85% of CRCs are microsatellite stable but most are characterized by chromosomal instability (CIN pathway). Almost all Lynch syndrome tumors have MSI or abnormal IHC and they account for up to one third of all MIN CRCs (3% to 5% of all CRCs). The remaining MIN tumors are sporadic as a result of somatic inactivation of the MLH1 gene caused by methylation of its promoter. Thus, the presence of a MSI/IHC abnormality prompts further investigations to diagnose Lynch syndrome, whereas its absence excludes Lynch syndrome. We recommend screening all CRC tumors for IHC or MSI. MIN tumors have a more favorable outcome than CIN tumors, and fluorouracil-based adjuvant chemotherapy does not improve the outcome of stage II or stage III MIN tumors. More data are needed to determine how best to treat patients with stage II and stage III MIN CRCs.
Hepatic triglyceride content and its relation to body adiposity: a magnetic resonance imaging and proton magnetic resonance spectroscopy study
Authors: E L Thomas
Journal: Gut (2004)

<b>Background:</b> Hepatic steatosis is associated with obesity and type II diabetes. Proton magnetic resonance spectroscopy (<sup>1</sup>H MRS) is a non-invasive method for measurement of tissue fat content, including intrahepatocellular lipids (IHCL) and intramyocellular lipids (IMCL). <b>Patients and methods:</b> We used <sup>1</sup>H MRS and whole body magnetic resonance imaging (MRI) to assess the relationship between IHCL accumulation, total body adipose tissue (AT) content/distribution, and IMCL content in 11 subjects with biopsy proven hepatic steatosis and 23 normal volunteers. <b>Results:</b> IHCL signals were detectable in all subjects but were significantly greater in hepatic steatosis (geometric mean (GM) 11.5 (interquartile range (IQR) 7.0–39.0)) than in normal volunteers (GM 2.7 (IQR 0.7–9.3); p = 0.02). In the study group as a whole, IHCL levels were significantly greater in overweight compared with lean subjects (body mass index (BMI) &gt;25 kg/m<sup>2</sup> (n = 23): GM 7.7 (IQR 4.0–28.6) <i>v</i> BMI &lt;25 kg/m<sup>2</sup> (n = 11): GM 1.3 (IQR 0.3–3.6; p = 0.004)). There was a significant association between IHCL content and indices of overall obesity (expressed as a percentage of body weight) for total body fat (p = 0.001), total subcutaneous AT (p = 0.007), and central obesity (subcutaneous abdominal AT (p = 0.001) and intra-abdominal AT (p = 0.001)), after allowing for sex and age. No correlation between IHCL content and IMCL was observed. A significant correlation was observed between serum alanine aminotransferase and liver fat content (<i>r</i> = 0.57, p = 0.006). <b>Conclusions:</b> Our results suggest that hepatic steatosis appears to be closely related to body adiposity, especially central obesity. MRS may be a useful method for monitoring IHCL in future interventional studies.
Prediction of residual retroperitoneal mass histology after chemotherapy for metastatic nonseminomatous germ cell tumor: multivariate analysis of individual patient data from six study groups.
Authors: E W Steyerberg, H J Keizer, S D Fosså, D T Sleijfer, G C Toner, H Schraffordt Koops, P F Mulders, J E Messemer, K Ney, J P Donohue
Journal: Journal of Clinical Oncology (1995)

PURPOSE To develop a statistical model that predicts the histology (necrosis, mature teratoma, or cancer) after chemotherapy for metastatic nonseminomatous germ cell tumor (NSGCT). PATIENTS AND METHODS An international data set was collected comprising individual patient data from six study groups. Logistic regression analysis was used to estimate the probability of necrosis and the ratio of cancer and mature teratoma. RESULTS Of 556 patients, 250 (45%) had necrosis at resection, 236 (42%) had mature teratoma, and 70 (13%) had cancer. Predictors of necrosis were the absence of teratoma elements in the primary tumor, prechemotherapy normal alfa-fetoprotein (AFP), normal human chorionic gonadotropin (HCG), and elevated lactate dehydrogenase (LDH) levels, a small prechemotherapy or postchemotherapy mass, and a large shrinkage of the mass during chemotherapy. Multivariate combination of predictors yielded reliable models (goodness-of-fit tests, P &gt; .20), which discriminated necrosis well from other histologies (area under the receiver operating characteristic (ROC) curve, .84), but which discriminated cancer only reasonably from mature teratoma (area, .66). Internal and external validation confirmed these findings. CONCLUSION The validated models estimate with high accuracy the histology at resection, especially necrosis, based on well-known and readily available predictors. The predicted probabilities may help to choose between immediate resection of a residual mass or follow-up, taking into account the expected benefits and risks of resection, feasibility of frequent follow-up, the financial costs, and the patient's individual preferences.
Patches of Mutant p53-Immunoreactive Epidermal Cells Induced by Chronic UVB Irradiation Harbor the Same p53 Mutations as Squamous Cell Carcinomas in the Skin of Hairless SKH-1 Mice
Authors: Pavel Kramata, Yao-Ping Lu, You-Rong Lou, Rayvita N. Singh, Sherry M. Kwon, Allan H. Conney
Journal: Cancer Research (2005)

Abstract Treatment of SKH-1 hairless mice with UVB (30 mJ/cm2) twice a week for 20 weeks results in the formation of cellular patches, long before the appearance of tumors, that are visualized in epidermal sheets with an antibody (PAb240) recognizing mutated p53 protein. Direct sequencing analysis of the whole coding region of the p53 gene (exons 2-11) detected one or two mutations in 64.4% of 104 analyzed patches and no mutations in nonstained adjacent normal controls. Homozygous mutation was detected in 22.4% of the mutant patches. Except for two nonsense mutations, all others were missense (exons 4-9) and mostly (95.5%) at the DNA-binding domain. Primer extension analysis of cloned PCR fragments found three of four double-mutated patches harboring different mutations in separate alleles. All mutation hotspots reported earlier in UVB-induced mouse squamous cell carcinomas (SCC) at codons 270 (Arg → Cys), 149 (Pro → Ser), 275 (Pro → Leu and Pro → Ser), and 176 (His → Tyr) with a frequency of 32.1%, 7.1%, 14.7%, and 3.2% were detected in epidermal patches at a frequency 47.7%, 9.1%, 4.5%, and 2.3%, respectively. Mutations at codons 210 and 191 found in patches at respective frequencies of 8.0% and 4.5% were not previously detected in UVB-induced mouse SCC. In summary, (a) the p53 mutation profile of UVB-induced skin patches and SCC was very similar suggesting that patches are precursor lesions for SCC, (b) a small number of patches harbored mutations that were not before observed in SCC from UVB-treated mice, and (c) about 36% of the patches did not harbor a p53 mutation.
Looking Forward: An Update to the <i>CCR</i> Instructions for Authors
Authors: Jesse Potash, Kenneth C. Anderson
Journal: Clinical Cancer Research (2014)

Dear Readers,We want to let you know about some recent changes to manuscript formats and guidelines that have been made at Clinical Cancer Research (CCR). First, we have made some changes to how research articles are categorized. We now accept submission of research articles in the following four categories: Cancer Therapy: Clinical; Personalized Medicine and Imaging; Cancer Therapy: Preclinical; and Biology of Human Tumors. Updated guidelines and descriptions for these categories can be found in the Instructions for Authors section of the journal website (http://clincancerres.aacrjournals.org/site/misc/journal_ifora.xhtml). These new guidelines emphasize that studies submitted to CCR should be highly novel and have a clear translational impact. They also describe the level of rigor with which research submitted to CCR is evaluated (for example, biomarker studies should be definitive in size and statistical power, and preclinical studies should use multiple in vitro/in vivo models). We strongly encourage authors to review these guidelines in full to determine if their study will be a good fit for the journal.In addition, we are planning to introduce a new format for manuscripts reporting clinical trials, called the Clinical Trial Brief Report. This will be the suggested format for trials of novel agents, combination treatments, or indications that contain limited correlative science but report initial findings with an extraordinary degree of clinical activity. In contrast, we typically look for accompanying pharmacokinetic, pharmacodynamic, and/or pharmacogenetic data in clinical trial manuscripts submitted as full-length research articles. As the name implies, the Clinical Trial Brief Report will be shorter in format than a standard-length research article (we expect it will be limited to 2,500 words and four figures or tables). Also, manuscripts submitted as a Clinical Trial Brief Report may be selected for an expedited review at the discretion of the editors. At this time the Clinical Trial Brief Report format is planned only for manuscripts describing clinical trials; other types of original research studies should continue to be submitted as standard research articles.We feel that these updated guidelines and table of contents sections better reflect the priorities of CCR, and we hope they will provide authors with guidance about how submitted studies are evaluated. As we approach the twentieth anniversary of CCR in 2015, which will be commemorated with special content published throughout the year, we are excited about the future of the journal and will continue to ensure it remains a vital forum for publishing cutting-edge translational and clinical research.
Quantitative Carcinogenesis in Man: Solar Ultraviolet B Dose Dependence of Skin Cancer in Maryland Watermen
Authors: P. T. Strickland, B. C. Vitasa, S. K. West, F. S. Rosenthal, E. A. Emmett, H. R. Taylor
Journal: JNCI Journal of the National Cancer Institute (1989)

Skin cancer is the most common form of cancer in humans and occurs primarily on sun-exposed areas of the body. In a study of 808 Caucasian Maryland watermen, we examined the prevalence of nonmelanoma skin cancer in relation to age and exposure to solar ultraviolet B (UVB) radiation. For each study subject, the exposure to solar UVB radiation for each year of life after the age of 16 years was calculated. We obtained the data for this analysis by combining a detailed occupational history with laboratory and field measurements. Prevalence of the three major types of nonmelanoma skin neoplasms was analyzed: squa-mous cell carcinoma (SCC), basal cell carcinoma (BCC), and actinic kerato-sis (AK). Average annual exposure to UVB radiation was strongly correlated with the prevalence of SCC, but not with the prevalence of BCC or AK. This finding is consistent with dose saturation (plateau in dose-response relationship) for the induction of BCC and AK in humans with high annual exposure to UVB radiation. In addition, two small groups of apparently hypersus-ceptible individuals were present in the population. One group had SCC despite low annual exposure to UVB radiation, and the other group had multiple skin cancers despite average exposure to UVB radiation. [J Natl Cancer Inst 81: 1910–1913, 1989].
Helper T cell differentiation enters a new era: Le Roi est mort; vive le Roi!
Authors: Cristina M. Tato, Arian Laurence, John J. O'Shea
Journal: The Journal of Experimental Medicine (2006)

In the dark ages of T cell biology, we considered two fates for differentiated CD4+ T cells: T helper (Th)1 and Th2 cells. Now we know that the reality is much more complex and interesting. The newest Th cell subset produces the cytokine IL-17. New evidence shows that the IL-17–related cytokine IL-25 is essential for Th2 responses in two infectious disease models.
Antinuclear antibodies in routine analysis: the relevance of putative clinical associations.
Authors: A J Swaak, V Huysen, R J Smeenk
Journal: Annals of the Rheumatic Diseases (1993)

Defined antinuclear antibodies (ANA), such as antibodies to Ro/SS-A, La/SS-B, Sm, and nRNP, are often present in serum samples from patients with systemic lupus erythematosus (SLE) or other connective tissue diseases (CTD). Most data on associations between the presence of these antibodies and defined disease features have been obtained with the use of predefined groups of patients. In this work the issue of disease associations was approached from a different angle: patients suspected of having CTD were selected on the presence of these ANA in their serum samples and clinical data were subsequently scored according to a defined protocol. It was then tried to relate measured ANA and clinical symptoms. No correlation was observed between the presence of antibodies to Ro/SS-A and specific clinical symptoms. The presence of antibodies to La/SS-B was associated with the diagnosis of Sjögren9s syndrome combined with leukocytopenia. In patients positive for antibodies to Sm a significantly increased incidence of skin lesions, such as butterfly rashes and discoid lesions, was seen, together with signs of myocarditis. Myocarditis was also found to be associated with the presence of antibodies to nRNP. The data presented in this study show that previously reported associations of these ANA with clinical symptoms are not confirmed when unselected patients are used.
MRI with a lymph-node-specific contrast agent as an alternative to CT scan and lymph-node dissection in patients with prostate cancer: a prospective multicohort study
Authors: Roel AM Heesakkers, Anke M Hövels, Gerrit J Jager, Harrie CM van den Bosch, J Alfred Witjes, Hein PJ Raat, Johan L Severens, Eddy MM Adang, Christina Hulsbergen van der Kaa, Jurgen J Fütterer, Jelle Barentsz
Journal: The Lancet Oncology (2008)
Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension
Authors: Vallerie McLaughlin, Richard N. Channick, Hossein-Ardeschir Ghofrani, Jean-Christophe Lemarié, Robert Naeije, Milton Packer, Rogério Souza, Victor F. Tapson, Jonathan Tolson, Hikmet Al Hiti, Gisela Meyer, Marius M. Hoeper
Journal: European Respiratory Journal (2015)

The safety and efficacy of adding bosentan to sildenafil in pulmonary arterial hypertension (PAH) patients was investigated. In this prospective, double-blind, event-driven trial, symptomatic PAH patients receiving stable sildenafil (≥20 mg three times daily) for ≥3 months were randomised (1:1) to placebo or bosentan (125 mg twice daily). The composite primary end-point was the time to the first morbidity/mortality event, defined as all-cause death, hospitalisation for PAH worsening or intravenous prostanoid initiation, atrial septostomy, lung transplant, or PAH worsening. Secondary/exploratory end-points included change in 6-min walk distance and World Health Organization functional class at 16 weeks, change in N-terminal pro-brain natriuretic peptide (NT-proBNP) over time, and all-cause death. Overall, 334 PAH patients were randomised to placebo (n=175) or bosentan (n=159). A primary end-point event occurred in 51.4% of patients randomised to placebo and 42.8% to bosentan (hazard ratio 0.83, 97.31% CI 0.58–1.19; p=0.2508). The mean between-treatment difference in 6-min walk distance at 16 weeks was +21.8 m (95% CI +5.9–37.8 m; p=0.0106). Except for NT-proBNP, no difference was observed for any other end-point. The safety profile of bosentan added to sildenafil was consistent with the known bosentan safety profile. In COMPASS-2, adding bosentan to stable sildenafil therapy was not superior to sildenafil monotherapy in delaying the time to the first morbidity/mortality event.
Home dampness, current allergic diseases, and respiratory infections among young adults
Authors: M Kilpelainen
Journal: Thorax (2001)

Background-The relation between home dampness and respiratory symptoms among adults is well confirmed, but data on specific allergic diseases and respiratory infections is more limited.Individual factors that may enhance susceptibility to the eVects of home dampness are mainly unknown.Methods-The association between home dampness and current physician diagnosed asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, common colds, and bacterial respiratory infections was studied in a questionnaire survey of 10 667 Finnish first year university students aged 18-25 years.The dampness categories analysed were visible mould and visible mould or damp stains or water damage during the last year.In multivariate analyses adjustment was made for parental education, active and passive smoking, type and place of residence, pets, and wall to wall carpets.The interaction eVect of atopic heredity and dampness was investigated.Results-Visible mould or damp stains or water damage was reported by 15.0% of the respondents.In multivariate models there was a positive association between home dampness and current asthma, allergic rhinitis, and atopic dermatitis, as well as common colds >4 times per year and other respiratory infections, but not between home dampness and allergic conjunctivitis.The strongest association was found between exposure to visible mould and asthma (OR 2.21, 95% CI 1.48 to 3.28) and common colds (OR 1.49, 95% CI 1.18 to 1.87).The risk of current asthma in damp homes was highest among subjects with atopic heredity.Conclusions-The risk of current asthma, allergic rhinitis, and atopic dermatitis was higher in damp homes.Of the respiratory infections, the risk of common colds was most clearly increased.
Placental Abruption and Adverse Perinatal Outcomes
Authors: C V Ananth, G S Berkowitz, D A Savitz, R H Lapinski
Journal: JAMA (1999)

Pregnancies complicated by abruption result in increased frequency of perinatal death and decreased fetal size and gestational duration, yet the extent of placental separation and its effect on these adverse outcomes is unknown.To assess the contribution of placental abruption and extent of placental separation to stillbirth, preterm delivery, and fetal growth restriction.Hospital-based, retrospective cohort study.Mount Sinai Hospital, New York City, NY.A total of 53,371 pregnancies occurring in 40,789 women who were delivered of singleton births between 1986 and 1996.Risks and relative risks for stillbirth (>20 weeks), preterm delivery (<37 weeks), and fetal growth restriction (birth weight below 10th percentile for gestational age) in relation to abruption.The incidence of abruption was 1 % (n = 530). Abruption was associated with an 8.9-fold (95% confidence interval [CI], 6.0-13.0) adjusted relative risk (aRR) of stillbirth. Preterm birth proportions among women with and without abruption were 39.6% and 9.1 %, respectively, yielding an aRR of 3.9 (95% CI, 3.5-4.4). In the abruption group, 14.3% of neonates were growth restricted, compared with 8.1 % among all other births (aRR, 2.0; 95% CI, 1.5-2.4). Extent of placental separation had a profound effect on stillbirth (aRR for 75% separation, 31.5; 95% CI, 17.0-58.4), although evident only among those with at least 50% separation. However, the risk of preterm delivery was substantially increased even for mild abruptions (aRR for 25% separation, 5.5; 95% CI, 4.2-7.3).In this cohort, placental abruption had a profound impact on stillbirth, preterm delivery, and fetal growth restriction. The risk of stillbirth was dramatically increased for severe placental separation, but preterm delivery was common even among women with lesser degrees of placental separation.
Immune evasion versus recovery after acute hepatitis C virus infection from a shared source
Authors: Ian Tester, Susan Smyk-Pearson, Ping Wang, Anne Wertheimer, Ermei Yao, David M. Lewinsohn, John E. Tavis, Hugo R. Rosen
Journal: The Journal of Experimental Medicine (2005)

Acute infection with hepatitis C virus (HCV) rarely is identified, and hence, the determinants of spontaneous resolution versus chronicity remain incompletely understood. In particular, because of the retrospective nature and unknown source of infection in most human studies, direct evidence for emergence of escape mutations in immunodominant major histocompatibility complex class I–restricted epitopes leading to immune evasion is extremely limited. In two patients infected accidentally with an identical HCV strain but who developed divergent outcomes, the total lack of HCV-specific CD4+ T cells in conjunction with vigorous CD8+ T cells that targeted a single epitope in one patient was associated with mutational escape and viral persistence. Statistical evidence for positive Darwinian selective pressure against an immunodominant epitope is presented. Wild-type cytotoxic T lymphocytes persisted even after the cognate antigen was no longer present.