tbuckley/cabot-search huggingface dataset:
THU0012 Observing Dysregulation of Signal Transduction Genes in the WNT Pathway Using two Methods: Table 1.
Authors: J.M. Frost, M. Tikly, M. Ramsay, X. Estivill, K. Rabionet
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> In recent years, the morphogen pathways (1), and specifically the Wnt pathway has been implicated in the development of fibrosis in Systemic Sclerosis (SSc) (2). Animal studies have shown that dysregulation frizzled related protein (<i>FRZB</i>) (3), frizzled class receptor 4 (<i>FZD4</i>) (4) and secreted frizzled related protein 1 (<i>SFRP1</i>) (5) have been implicated in the pathogenesis of SSc. <h3>Objectives</h3> Examine differential gene expression and methylation status of 84 genes in the Wnt pathway. <h3>Methods</h3> Skin biopsies were taken from 8 black South African patients with early (&lt;6 years) diffuse SSc, one from the lateral forearm (involved) and one from the back (uninvolved). Data was generated using the Wnt pathway RT<sup>2</sup> Profiler and Epitect Methyl qPCR Arrays, as well as mRNA-sequencing. Data was analysed using HTqPCR and DESeq2. <h3>Results</h3> The expression data from the qPCR array suggests that the 8 patients are segregating into two groups, and that the most significantly expressed genes are involved in signal transduction within the Wnt pathway. Results can be seen in the table below. There was no significant difference in gene expression between Involved and Uninvolved skin samples. Analysis of the methylation status of 22 Wnt pathway genes revealed no significant results. <h3>Conclusions</h3> The results of this study suggest that the dysregulation of Wnt pathway signal transduction is involved in the development of fibrosis in SSc in humans. Interestingly, although patients are phenotypically similar, they are clustering into two distinct groups based on the differential expression of the Wnt pathway genes. Involved and Uninvolved skin exhibit similar magnitudes of expression. Identification of dysregulated genes in the pathway may provide novel insights into the pathogenesis of SSc and hence potential new targets for therapy. <h3>References</h3> Distler et al. (2014) Ann Rheum Dis. 73(6): 1265-8 Lafyatis (2012) Nat Rev Rheumatol. 8(8): 441-2 De Langhe et al. (2014) Fibrogenesis Tissue Repair. 7(14) Igota et al. (2013) Int J Med Sci. 10(4): 344-54 Dees et al. (2014) Ann Rheum Dis. 73(6): 1232-9 <h3>Acknowledgements</h3> 1. Wits-Novartis-CRG Scientist Exchange Program. 2. National Research Foundation South Africa. 3. Estivill Lab (CRG, Barcelona, Spain). 4. Frank Staedtler (Novartis, Basel, Switzerland. <h3>Disclosure of Interest</h3> None declared
<i>Notes from the Field</i>: Injuries Associated with Bison Encounters — Yellowstone National Park, 2015
Authors: Cara Cherry, Kirsten Leong, Rick Wallen, Danielle Buttke
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Since 1980, bison have injured more pedestrian visitors to Yellowstone National Park (Yellowstone) than any other animal (1). After the occurrence of 33 bison-related injuries during 1983-1985 (range = 10-13/year), the park implemented successful outreach campaigns (1) to reduce the average number of injuries to 0.8/year (range = 0-2/year) during 2010-2014 (unpublished data, National Park Service, September 2015). During May-July 2015, five injuries associated with bison encounters occurred (Table). Case reports were reviewed to evaluate circumstances surrounding these injuries to inform prevention.
Induction of Hepatic Tumors in Rats by Senkirkine and Symphytine&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: I Hirono, M Haga, M Fujii, S Matsuura, N Matsubara, M Nakayama, T Furuya, M Hikichi, H Takanashi, E Uchida, S Hosaka, I Ueno
Journal: JNCI Journal of the National Cancer Institute (1979)

The carclnogenicity of the pyrrolizidine alkaloids senkirkine and symphytine was studied in male inbred ACI rats. Animals were divided into 3 groups: Group I received ip injections of freshly prepared senkirkine at a dose of 10% of the median lethal dose (LD50) twice weekly for 4 weeks and then once a week for 52 weeks. Group iI received ip injections of symphytine at a dose of 10% of the LD50 by the same injection schedule as in group I. The control group was given ip injections of a 0.9% NaCI solution following the same injection schedule as in experimental groups. All group I rats survived for more than 290 days after the start of infections, and 9 of 20 rats developed liver cell adenoma. All group II animals survived for more than 330 days after the start of injections. Of 20 rats, 4 had liver tumors, 3 had hemangioendothelial sarcomas, and 1 had liver cell adenoma. The hemangioendothelial sarcomas showed metastasis in the lungs of 2 rats. The control group had no liver tumors.
Survival of patients with breast cancer tumors 1 cm or less. Analysis of the Surveillance, Epidemiology and End Results (SEER) Registry
Authors: A. M. Gonzalez-Angulo, E. O. Hanraham, S. H. Giordano, K. Broglio, F. Morales-Vasquez, M. Cristofanilli, V. Valero, R. L. Theriault, G. N. Hortobagyi
Journal: Journal of Clinical Oncology (2005)

656 Background: The number of patients (pts) with stage I breast cancer and tumors ≤ 1 cm is increasing due to early diagnosis. In general, their prognosis is excellent, but some pts still die from their disease. There are no clear recommendations of adjuvant therapy for this group. The purpose of this analysis is to describe the characteristics of this patient population, their survival, and to evaluate the association of patient and disease characteristics with overall survival (OS) and breast specific mortality (BSM). Methods: The SEER public registry data was used to select pts who had tumors ≤ 1 cm and negative lymph nodes diagnosed between 1988 and 2001. Pts and tumor characteristics were tabulated. Kaplan-Meier product limit method was used to describe OS and log rank test to test for differences between pts groups. Cox-proportional hazard models were used to assess the multivariate relationships. Results: Analysis included 57,835 pts. Median age was 64 years (64–101). Median tumor size was 8 mm and 21% were high grade. Hormone receptor status was available in 70% of pts, 84% were ER-positive and 73% were PR-positive. Breast conservation (BCT) was done in 47% of pts, and 84% had nodal dissection. Median number of nodes examined was 11. Half of pts received adjuvant radiotherapy (XRT). Median follow up was 52 months, 90% of pts remained alive at 5 years and 76% at 10. Longer OS was seen in pts who were 50 years or older, had tumors ≤ 4 mm, PR-positive tumors, BCT and nodal dissection. Multivariate analysis showed that age, tumor size, tumor grade, XRT and number of lymph nodes examined were independent prognostic factors of OS rates. Conclusion: Overall, these pts have excellent prognosis with 90% remaining alive at 5 years. Pts with larger tumor sizes and higher nuclear grade tended to have shorter OS, however radiation, surgery, and lymph node dissection were associated with a decreased risk of mortality. A future analysis will be done to calculate the cumulative incidence of BSM and to test for univariate associations between patient characteristics and BSM. A parametric survival model will be fit for OS allowing the proportion of patients remaining alive at 20 years to be projected. No significant financial relationships to disclose.
PTH-096 Monocyte oxidative burst defect in alcoholic hepatitis is resistant to interferon gamma
Authors: K Beale, N Vergis, F Sadiq, G Petts, W Khamri, H Antoniades, M Thursz
Journal: Gut (2015)

<h3>Introduction</h3> An important cause of mortality in patients with severe alcoholic hepatitis (SAH) is infection. We and others have found that the oxidative burst response of phagocytic cells to <i>E. coli</i>is impaired in SAH which may contribute to susceptibility to infection. This is analogous to Chronic Granulomatous Disease, an inherited condition caused by a mutation in the enzyme NADPH oxidase which leads to predisposition to recurrent life-threatening infections. Treatment with interferon gamma (IFN-γ) reduces the frequency of severe infections in these patients. We sought to investigate the molecular mechanism underlying the monocyte oxidative burst (mOB) defect in SAH and determine whether IFN-γ can restore this defect <i><i>in vitro</i></i>. <h3>Method</h3> Peripheral blood mononuclear cells (PBMCs) were isolated from 6 patients with SAH and 4 healthy controls (HCs). Monocytes were isolated from PBMCs using magnetic MACS beads and negative selection. Monocytes were incubated with 50 ng/ml IFN-γ supplemented by 10% healthy serum for 24 h and the mOB to <i>E. coli</i>was quantified by oxidation of fluorogenic rhodamine and flow cytometry as previously described. Western blotting was used to quantify protein using monoclonal antibodies to components of the IFN-γ signalling pathway (pSTAT-1 and negative regulator SOCS-1) and glucose-6-phosphate dehydrogenase (G6PD, which generates NADPH substrate required for NAPDH oxidase function), in the monocytes of HCs and AH patients. G6PD enzyme activity was measured using a colorimetric kit. Quantitative PCR was used to determine expression of STAT-1 in monocytes stimulated for 24 h in 50 ng/ml IFN-γ. <h3>Results</h3> Surprisingly, SAH mOB defect was resistant to 24 h’ stimulation by 50 ng/mlIFN-γ. The level of unstimulated phosphorylated STAT-1 protein, a transcription factor activated by IFN-γ signalling was significantly reduced in monocytes of SAH patients compared to healthy controls (pSTAT-1: housekeeping gene 0.90 HC vs 0.14 SAH, <i>p &lt; 0</i>.05). q-PCR confirmed STAT-1 expression following stimulation with IFN-γ was significantly reduced in SAH compared to HCs (ΔCT 0.97 HC vs SAH 0.54, <i>p &lt; 0</i>.05). The level of SOCS-1 protein was significantly increased in monocytes of SAH patients compared to HCs (SOCS-1: housekeeping gene 0.98 HC vs 2.24 AH, <i>p &lt; 0</i>.05). There was no difference in G6PD enzyme activity or protein expression between groups. <h3>Conclusion</h3> Our study suggests that elevated levels of the inhibitory factor SOCS-1 may reduce phosphorylation and activation of STAT-1. Reduced pSTAT-1 may explain the resistance to IFN-γ observed and hence the burst defect in SAH. This work provides a novel insight into the impaired mOB in SAH and furthers our knowledge of the predisposition to infection observed in this patient group. <h3>Disclosure of interest</h3> None Declared.
Psychiatric education and training of Asian and Asian-American psychiatrists
Authors: N Wong
Journal: American Journal of Psychiatry (1978)

The Asian and Asian-American physician in a standard psychiatric residency is faced with discrimination at several levels, as well as special problems of professional role confusion and personal identity, all of which can create barriers to professional development and productivity. Further, most standard psychiatric residencies do not include teaching or supervision specific to treating Asian patients. The author proposes the establishment of a specialized program, focusing on ethnic minority groups, within a general psychiatric residency; he discusses specific features of such a program. This approach may help to alleviate the problem of inadequate resources for handling the mental health problems of Asian-Americans and underutilization of mental health resources by this group.
Long-Term Outcome of Patients (Pts) with Her2-Positive (Her2+) Metastatic Breast Cancer (Mbc) Who Achieved a Complete Response (Cr) After Antiher2 Therapy (Her2Tx)
Authors: G. Gullo, A. De Giorgi, N. O'Donovan, D. Fennelly, J. Walshe, J. Ballot, E. McDermott, D. Evoy, E.J. Jordan, J.P. Crown
Journal: Annals of Oncology (2014)
Dual Faces of IFNγ in Cancer Progression: A Role of PD-L1 Induction in the Determination of Pro- and Antitumor Immunity
Authors: Masaki Mandai, Junzo Hamanishi, Kaoru Abiko, Noriomi Matsumura, Tsukasa Baba, Ikuo Konishi
Journal: Clinical Cancer Research (2016)

Abstract IFNγ is a cytokine that plays a pivotal role in antitumor host immunity. IFNγ elicits potent antitumor immunity by inducing Th1 polarization, CTL activation, and dendritic cell tumoricidal activity. However, there are significant discrepancies in our understanding of the role of IFNγ as an antitumor cytokine. In certain circumstances, IFNγ obviously acts to induce tumor progression. IFNγ treatment has negatively affected patient outcomes in some clinical trials, while it has favorably affected outcomes in other trials. Several mechanisms, including IFNγ insensitivity and the downregulation of the MHC complex, have been regarded as the reasons for this discrepancy, but they do not fully explain it. We propose IFNγ-induced programmed cell death 1 ligand 1 (PD-L1) expression as a novel mechanism by which IFNγ impairs tumor immunity. When tumor cells encounter CTLs in the local environment, they detect them via the high concentration of IFNγ secreted from CTLs, which induces PD-L1 expression in preparation for an immune attack. Thus, tumor cells acquire the capability to counterattack immune cells. These findings indicate that although IFNγ is thought to be a representative antitumor cytokine, it actually has dual roles: one as a hallmark of antitumor immunity and the other as an inducer of the immune escape phenomenon through various mechanisms, such as PD-L1 expression. In this context, the optimization of immunotherapy according to the local immune environment is important. Anti–PD-1/PD-L1 treatment may be particularly promising when efficient tumor immunity is present, but it is disturbed by PD-L1 expression. Clin Cancer Res; 22(10); 2329–34. ©2016 AACR.
Global clinical experience with adjuvant oxaliplatin/5-fluorouracil (5-FU)-based chemotherapy for colon cancer: Outcomes of the ACCElox registry.
Authors: Young Suk Park, Jiafu Ji, John Raymond Zalcberg, Mostafa M. Elserafy, Antonio C. Buzaid
Journal: Journal of Clinical Oncology (2013)

e14624 Background: The ACCElox registry assessed the therapeutic management of early stage colon cancer with oxaliplatin/5-FU-based regimen and duration of adjuvant chemotherapy in current clinical practice. Methods: Newly diagnosed patients (N=1,548) with stage II or III colon cancer, who had undergone complete resection of the primary tumor and treated with at least one dose of "oxaliplatin" were enrolled in this prospective observational study (Feb-2006–Jul-2008) and followed up till 36 months post-treatment. Results: 72.7% and 27.3% of the patients were diagnosed with stage III and stage II colon cancer, respectively. 1,152 (74.4%) patients completed the prescribed chemotherapy. The most frequent causes of discontinuation were refusal (9.0%), adverse events (AEs) (8.1%) or relapse/recurrence of disease (3.6%). Overall, 1,512 (97.6%) patients received at least one cycle of oxaliplatin regimen. Treatment delay occurred in 1,013 patients (67%), mainly attributed to AEs (40.9%) and personal inconvenience (35.5%). During the 3-year follow-up period disease relapse/recurrence occurred in 285 (18.4%) patients with similar rates in the three groups (FOLFOX: 18.1%, FLOX: 19%, and XELOX: 18.6%). Overall number of deaths reported at the end of 3- year study period was 72 (4.7%). Majority of AEs reported during treatment were of grade 1–2 and the most common ones were neutropenia (63.9%), thrombocytopenia (23.3%), diarrhea (9.7%), sensory neuropathy (4.5%) and infection (2.6%). Sensory neuropathy was the most frequent AEs reported at 6 and 12 months of post-treatment follow-up. Conclusions: A majority of the patients completed the prescribed oxaliplatin/5-FU regimen. No unexpected AEs were reported. Our results confirm the favorable benefit/risk profile of oxaliplatin/5-FU based regimens in clinical practice. [caption]Distribution and treatment outcomes.[caption] Clinical trial information: NCT01310972. [Table: see text]
Studies of Intestinal Metaplasia in the Gastric Mucosa by Detection of Disaccharidases With “Tes-Tape”2
Authors: Takashi Kawachi, Kikuko Kogure, Noritake Tanaka, Akira Tokunaga, Takashi Sugimura, Yasuo Koyama, Kazuo Kanasugi, Teruyuki Hirota, Ryozo Sano
Journal: JNCI Journal of the National Cancer Institute (1974)

The range and intensity of intestinal metaplasia in the gastric mucosa were estimated by visualizing the activities of disaccharidases with Tes- Tape. In instances of stomach cancer and ulcer, the incidence and intensity of sucrase and maltase activities were high in the antrum and lowest along the greater curvature, especially on the oral side. The area giving a positive reaction for maltase was wider than that for sucrase and the color reaction for maltase was stronger than that for sucrase in the area where both reactions were positive. Trehalase activity was detected in some cases. The trehalase reaction was closely associated with the area where the alkaline phosphatase reaction was positive and where Paneth's cells were observed histologically. The area giving a sucrase reaction coincided well with the area where appearance of intestinalization was proved histologically by the presence of goblet cells, but was not related to the presence of Paneth's cells.
Prevalence, Prognostic Significance, and Overlap of Actionable Biomarkers in Nsclc
Authors: D. Shames, M. Kowanetz, Y. Xiao, Y. Choi, M. D'Arcangelo, C. Behrens, L.M. Solis, H. Koeppen, R. Firestein, Y. Wang, S. Mocci, T.A. Boyle, M. Lund-Iversen, C. Bowden, L.C. Amler, O.T. Brustugun, I. Wistuba, F.R. Hirsch
Journal: Annals of Oncology (2014)
Upfront bevacizumab may extend survival for glioblastoma patients who do not receive second-line therapy: an exploratory analysis of AVAglio
Authors: Olivier L. Chinot, Ryo Nishikawa, Warren Mason, Roger Henriksson, Frank Saran, Timothy Cloughesy, Josep Garcia, Cedric Revil, Lauren Abrey, Wolfgang Wick
Journal: Neuro-Oncology (2016)

In this post-hoc, exploratory analysis, we examined outcomes for patients enrolled in the AVAglio trial of front-line bevacizumab or placebo plus radiotherapy/temozolomide who received only a single line of therapy. Patients with newly diagnosed glioblastoma received protocol-defined treatment until progressive disease (PD). Co-primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). After confirmed PD, patients were treated at the investigators' discretion. PFS/OS were assessed in patients with a PFS event who did not receive post-PD therapy (Group 1) and patients with a PFS event who received post-PD therapy plus patients who did not have a PFS event at the final data cutoff (Group 2). Kaplan–Meier methodology was used. A multivariate Cox proportional hazards model for known prognostic variables was generated. Baseline characteristics were balanced. In patients with a PFS event who did not receive post-PD therapy (Group 1; n = 225 [24.4% of the intent-to-treat population]), the addition of bevacizumab to radiotherapy/temozolomide resulted in a 3.6-month extension in both median PFS (hazard ratio [HR]: 0.62, P = .0016) and median OS (HR: 0.67, P = .0102). Multivariate analyses supported this OS benefit (HR: 0.66). In the remaining patients (Group 2; n = 696), a 5.2-month PFS extension was observed in bevacizumab-treated patients (HR: 0.61, P < .0001); OS was comparable between the treatment arms (HR: 0.88, P = .1502). No significant differences in safety were observed between the 2 groups. This exploratory analysis suggests that the addition of bevacizumab to standard glioblastoma treatment prolongs PFS and OS for patients with PD who receive only one line of therapy.
Grieving and loss in parents with a schizophrenic child
Authors: S D Atkinson
Journal: American Journal of Psychiatry (1994)

The purpose of this study was to compare grief among parents who had an adult child with schizophrenia and parents who had "lost" an adult child through death or a head injury that resulted in an organic personality disorder.Twenty-five parents from each group were studied. Self-report scales that assessed grief, depression, anxiety, and substance abuse were administered.There were significant differences with regard to grieving reactions and substance abuse. The parents with schizophrenic children had more ongoing grieving, and the parents of children with head injuries had more substance abuse.Parental loss of a child through schizophrenia leads to a pattern of chronic grief.
Localization of Fluorescein-Labeled Antibodies of Epidermal Proteins in Normal and Malignant Squamous Epithelium2
Authors: C. Carruthers, A. Baumler
Journal: JNCI Journal of the National Cancer Institute (1966)

Antisera were prepared in rabbits against mouse and human epidermal proteins and mouse squamous cell carcinoma proteins. The distribution of these proteins in mouse epidermis undergoing malignant transformation and in human cancers was determined with the fluorescein-labeled antibody technique. The urea- and alkali-extractable proteins of epidermis 4 days after the hair was plucked and squamous cell carcinomas of mice, human epidermis, and its extractable proteins all shared common antigenic determinants, but specificity of staining revealed differences. The epidermises of mice had antigens not detected in the carcinomas; these carcinomas were antigen-deficient in epidermal proteins. Squamous cell carcinomas of the tongue, larynx, floor of the mouth, and bronchus (lung) of man were stained intensely with the antisera prepared against (a) normal human epidermis, (b) the alkali-extractable proteins and tonofibrin of human epidermis, and (c) urea-extractable proteins of mouse squamous cell carcinomas. Malignant melanomas did not stain with any of these antisera. The antisera prepared against the various proteins stained the human and mouse squamous cell carcinomas but not distinctively. However, some of the antisera and, particularly, tonofibrin antisera stained some samples of human epidermis uniquely in that structures resembling the intercellular bridges became evident.
Association of Blood Glucose Control and Lipids With Diabetic Retinopathy in the Veterans Affairs Diabetes Trial (VADT)
Authors: Nasrin Azad, Gideon D. Bahn, Nicholas V. Emanuele, Lily Agrawal, Ling Ge, Dominic Reda, Ronald Klein, Peter D. Reaven, Rodney Hayward
Journal: Diabetes Care (2016)

OBJECTIVE This study examined whether lipids modify the relationship between intensive glucose control (INT) and diabetic retinopathy (DR). RESEARCH DESIGN AND METHODS The incidence and progression of DR were assessed in 858 of 1,791 participants with 7-field stereoscopic fundus photographs at baseline and 5 years later. RESULTS Odds of DR progression were lower by ∼40% in those with baseline total cholesterol (TC) ≥200 mg/dL (P = 0.007), LDL-C ≥120 mg/dL (P &amp;lt; 0.02), or HDL-C ≥40 mg/dL (P &amp;lt; 0.007) in the INT arm versus standard glycemic treatment. Odds of DR progression were reduced by ∼40% in those who had TC ≤140 mg/dL (P ≤ 0.024), triglycerides (TG) ≤120 mg/dL (P = 0.004), or HDL-C ≥45 mg/dL (P = 0.01) at the fifth year. Odds of DR progression were lower by ∼40–50% with reductions of TC by ≥40 mg/dL (P &amp;lt; 0.0001), of LDL-C of ≥40 mg/dL (P &amp;lt; 0.004), and of TG by ≥60 mg/dL (P = 0.004) at the fifth year. Odds of DR progression increased by 80% with increases in TC of ≥20 mg/dL (P &amp;lt; 0.0001) and by 180% with increases in LDL-C by ≥60 mg/dL (P &amp;lt; 0.004). After adjusting for covariants, those with higher TC at baseline and lower TC during and at the fifth year and higher HDL-C throughout study had significantly decreased odds of DR progression in INT. CONCLUSIONS INT was associated with decreased odds of progression but not with onset of retinopathy in those with worse lipid levels at baseline and more improved lipid levels during the study. Higher HDL-C was consistently associated with better response to INT throughout the study.