tbuckley/cabot-search huggingface dataset:
Abstract 204: Inhibition of Histone Deacetylase Activity Represses Matrix Metalloproteinase-9 Induction Through Regulation of Macrophage Polarization
Authors: Denise M Kimbrough, Santhosh K Mani, Christine B Kern, Francis G Spinale, Rupak Mukherjee, Donald R Menick
Journal: Circulation Research (2012)

Post myocardial infarction (MI) the extracellular matrix (ECM) undergoes massive remodeling in order to prevent dilation of the infarct area and maintain cardiac output. Integral players in this remodeling are matrix metalloproteinases (MMP). Post-MI macrophages are a significant source of MMP production and have been shown to have temporal expression of the two phenotypes (M1 and M2). Differential expressions of macrophage phenotypes correlate with the different phases of ECM remodeling, ECM composition and MMP expression. Increased expression of MMP-9 is associated with deleterious effects to the ECM and left ventricular (LV) dilation following MI. MMPs major mechanism of expression regulation is transcription. Histone deacetylases (HDAC) are a class of enzymes that can greatly affect transcriptional regulation of genes during pathological conditions. Therefore, we hypothesize that HDAC inhibition controls the post-MI expression of MMP-9 by mediating macrophage polarization to improve LV function. The post-MI change in LV end-diastolic volume is significantly lower with treatment of the class I and IIb HDAC inhibitor trichostatin A (TSA) and ejection fraction is improved in mice. Immunohistochemical analysis and zymography revealed that MMP-9 expression at 7 days post-MI is attributable to infiltrating macrophages. Immunoblotting shows that TSA inhibits control levels and lipopolysacharide (LPS) stimulated upregulation of MMP-9 in cultured macrophages, while the class I specific inhibitor, PD106, only inhibits control. The HDAC 6 inhibitor, Tubastatin A (Tub A), partially inhibits LPS stimulated upregulation of MMP-9, but surprisingly appears to potentiate control levels of MMP-9. Immunofluorescence revealed that direct HDAC inhibition with PD106, Tub A, and TSA leads to M1 to M2 macrophage polarization and maintenance of anti-inflammatory, M2, phenotype even with LPS stimulation in culture. From these data we conclude that macrophage secretion of MMPs is an essential component in the promotion of adverse ECM remodeling post-MI. HDAC inhibition can attenuate this remodeling possibly through macrophage polarization, but HDAC inhibition mediated M2 polarization may not be sufficient to suppress MMP-9 expression.
National trends in cholangiocarcinoma in the United States (US): 2000-2014.
Authors: Ru Min Lee
Journal: Journal of Clinical Oncology (2017)

e13056 Background: Cholangiocarcinoma (CCA) arise from the epithelial cells of the intrahepatic and extrahepatic bile ducts. Although rare in the US, they are highly lethal because most are locally advanced at presentation. The incidence of CCA has increased over time. This study aims to estimate the characteristics, outcomes, and cost burden of patients hospitalized for CCA by using a large national database. Methods: The Nationwide Inpatient Sample (NIS) database was used to obtain data from 2000-2014. The NIS contains data from over 7 million hospital stays in the US per year generalizable to the American population. The NIS was queried for ICD-9 codes for primary diagnosis of CCA with 155.1 [Malignant Neoplasm of Intrahepatic Ducts (MNID)] and 156.1 [Malignant Neoplasm of Extrahepatic ducts (MNED)]. Information for total number of hospitalizations, mortality, and hospital charges was evaluated. Results: The number of hospitalizations for MNID increased from 2,599 in to 4,840 (p &lt; 0.001) from 2000 to 2014. The number of hospitalizations for MNED decreased from 2,529 to 2,350 but was not statistically significant. Inpatient mortality of MNID decreased from 12.98% to 8.57% (p &lt; 0.05%). Inpatient mortality of MNED decreased from 7.46% to 5.11% but was not statistically significant. Mean charges for MNID increased from $27,779 to $79,096 (p &lt; 0.001). Mean charges for MNED increased from $34,212 to $89,852 (p &lt; 0.001). Conclusions: This study demonstrates that the number of hospitalizations for MNID has increased by 86% from 2000 to 2014. This number continues to rise. However, inpatient mortality of MNID is decreasing. These findings show that the incidence of cholangiocarcinoma of the intrahepatic subtype is increasing and more study is required to investigate why this is so.
Frequency of ALK rearrangement among patients (pts) with non small cell lung cancer (NSCLC), stratified by race.
Authors: Elshaddai Ephrem, Corey J. Langer, Joshua Bauml, Carmen Guerra
Journal: Journal of Clinical Oncology (2016)

e13068 Background: The presence of an ALK rearrangement in tumor cells is associated with responsiveness to treatment with ALK tyrosine kinase inhibitors in pts with NSCLC. The frequency of ALK rearrangement is 4-5% in an unselected NSCLC population, and is seen more commonly in Asian pts, females, and never smokers. The relative incidence of ALK rearrangement among Black pts is not well known. We sought to determine if there was any association between Black race and ALK rearrangement among pts with NSCLC receiving treatment at the Abramson Cancer Center (ACC) of the University of Pennsylvania. Methods: We performed a retrospective study of 611 NSCLC pts undergoing ALK rearrangement analysis at the ACC between January 2011 and July 2015. Clinical, lab and pathologic data were abstracted from the pts’ electronic medical records. Data were analyzed using Fisher’s exact tests for categorical variables and Student’s t test for continuous variables. Multivariable logistic regression analysis was used to determine the association between race and ALK rearrangement positivity after adjusting for confounders. Results: Of 568 pts with informative ALK rearrangement analyses, 85 of whom were Black, the frequency of ALK rearrangement was 4.6%. Among Black pts, ALK rearrangement was seen in one pt (1.2%). In an unadjusted analysis, the frequency of ALK rearrangement was associated with race (p= 0.01) and smoking status (p < 0.001). Mean age was significantly lower in pts with ALK rearrangement (56.2 ± SE 2.7) as compared to pts without ALK rearrangement (64.8 ± SE 0.4, p< 0.001). In a multivariable analysis, after adjusting for smoking status (p< 0.001) and gender (p= 0.62), we found that race was not significantly associated with ALK rearrangement status (Black race OR 0.32 [95% CI 0.04-2.47; p= 0.28] or Asian race OR 1.98 [95% CI 0.50-7.78; p= 0.33]). Conclusions: Current clinical guidelines for treatment of NSCLC do not include pt demographic variables (e.g. race, gender, smoking status) as criteria to physician referral for ALK rearrangement testing of lung tumor tissue. This study confirms that clinicians should not consider race when deciding to test for ALK rearrangement.
NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease
Authors: Sara Mastaglio, Pietro Genovese, Zulma Magnani, Eliana Ruggiero, Elisa Landoni, Barbara Camisa, Giulia Schiroli, Elena Provasi, Angelo Lombardo, Andreas Reik, Nicoletta Cieri, Martina Rocchi, Giacomo Oliveira, Giulia Escobar, Monica Casucci, Bernhard Gentner, Antonello Spinelli, Anna Mondino, Attilio Bondanza, Luca Vago, Maurilio Ponzoni, Fabio Ciceri, Michael C. Holmes, Luigi Naldini, Chiara Bonini
Journal: Blood (2017)
Abstract P009: Notch Signaling Regulates Pluripotent Gene Expressions in Cardiac c-Kit+ Cells
Authors: Liudmila Zakharova, Mohamed A Gaballa
Journal: Circulation Research (2011)

We and others have shown that transplantation of explant-derived cells (EDCs) obtained from cardiac biopsies improved cardiac function after myocardial infarction. The current study was designed to examine the molecular mechanisms regulating expression of pluripotent genes in these cells. Toward this end, EDCs were separated based on expression of c-Kit antigen after 21 days in culture. We found that Notch signaling was activated mainly in c-Kit+ cells, but to a lesser degree in c-Kit- cells. In addition, we found that the pluripotency markers Sca-1, Nanog and Sox2 were mainly expressed in c-Kit+ cells. Also, in c-Kit+ cells, forced activation of Notch signaling via over-expression of Notch intracellular domain (NICD) induced cellular and molecular changes typical of epithelial-mesenchymal transition (EMT), evident by a decrease in VE cadherin and increases in N-cadherin, MMP, and ICAM. . Suppression of Notch signaling was associated with c-Kit+ cells exhibition of an epithelial/endothelial morphology. This observation is further supported by the increase in Nanog, Sca1, Sox2, VEGFR2 gene expressions after Notch suppression. In contrast, overexpression of NICD resulted in down-regulation of pluripotency gene expressions. Furthermore, suppression of Notch signaling was coincided with stabilization of β-catenin and accumulation of phosphorylated glycogen synthase kinase 3 beta (pGSK3β) suggestive of a crosstalk between Notch and canonical Wnt pathway. Thus, Notch regulates expression of pluripotency genes and mesenchymal transition of c-Kit+ cardiac EDCs.
AB0022 Lactoferrin – a potent anti-inflammatory agent for treatment of adjuvant arthritis
Authors: AV Danilov, NI Korshunov, TG Danilova, VP Mikhailov, LA Tsyganova
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Lactoferrin is a multifunctional immunoregulatory protein, stored in specific granules of neutrophil granulocytes, from which it is released following cell activation. While the biochemical characterisation of lactoferrin as an iron-binding protein has been well described, its physiological role in inflammation remains undefined. Although lactoferrin was proven to exert certain antiinflammatory effects, there is a paucity of data concerning the possibility of administrating lactoferrin as an anti-inflammatory agent in rheumatoid arthritis. <h3>Objectives</h3> To evaluate the anti-inflammatory properties of lactoferrin in treatment of adjuvant arthritis ? an adequate model of rheumatoid arthritis. <h3>Methods</h3> Adjuvant arthritis was induced in Lewis rats by subplantar inoculation of a complete Freund?s adjuvant. Human milk-derived lactoferrin was administered intravenously in the acute phase (8th day after adjuvant inoculation), and in the chronic phase of adjuvant arthritis (29–31 days). <h3>Results</h3> The development of adjuvant arthritis in rats was characterised by hind paws swelling and hyperthermia, weight loss, increased white blood cell count and erythrocyte sedimentation rate, an increased level of serum elastase. In approximately 50% of rats a generalisation of inflammation with involvement of intact joints was observed. Treatment with low doses of lactoferrin (3–18 mg/kg) in the acute phase of adjuvant arthritis did not change the course of the disease, while higher doses of lactoferrin (30–60 mg/kg) caused a certain suppression of the inflammatory process, although it was not stable and lasted for only 2 weeks. The serum level of elastase remained unchanged. The administration of lactoferrin in the chronic phase of adjuvant arthritis resulted in a steady suppression of the inflammatory process (decreased hind paws swelling and local temperature, white blood cell count and erythrocyte sedimentation rate, an increase in weight gaining and a decrease in serum elastase level), which lasted until the end of experiment (day 50). This effect was achieved with lower doses of the drug (9 mg/kg), though its strength was dose-dependent. The maximal suppression of adjuvant arthritis was obtained with the repeated injections of lactoferrin (5 injections every other day with total dose of 60 mg/kg) in the chronic phase of adjuvant arthritis (days 23–31). In these rats the serum concentration of elastase was reduced down to normal level and the rate of generalisation was less than 8%. <h3>Conclusion</h3> Lactoferrin is a potent anti-inflammatory agent effective in treatment of adjuvant arthritis in rats. The maximal suppression of the inflammatory process is obtained in the chronic phase of adjuvant arthritis.
First-line gefitinib combined with simplified FOLFOX-6 in patients with epidermal growth factor receptor-positive advanced colorectal cancer
Authors: M. G. Zampino, K. Lorizzo, C. Massacesi, A. Rizzi, S. Crispino, S. Boselli, G. Pelosi, L. Zorzino, N. Fazio, F. de Braud
Journal: Journal of Clinical Oncology (2005)

3659 Background: The orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib (IRESSA) shows promising activity in several tumor types. Preclinical studies suggest gefitinib has synergistic activity in combination with oxaliplatin in colorectal cancer (CRC) cells. This Phase II multicenter study evaluated gefitinib combined with FOLFOX-6 as first-line treatment in patients (pts) with EGFR-positive advanced CRC. Methods: Pts received gefitinib 250 mg/day combined with simplified FOLFOX-6 every 2 weeks for ≥8 weeks in order to be evaluable for response. Treatment was continued until progressive disease (PD), unacceptable toxicity, or withdrawal. Pts with clinical benefit after up to a maximum of 10 courses could continue gefitinib monotherapy. Tumor assessment (CT scan) by RECIST was made at baseline and every 4 cycles. All adverse events (AEs) were assessed by NCI-CTC. Serum EGFR was evaluated at baseline and every assessment. Results: 47/49 pts met the entry criteria: 21 male, 26 female; median age 58 years (range 39–76); ECOG performance status 0/1/2: 33/10/4; stage IV at diagnosis: 37 (78.7%); 1/2/>2 disease sites: 23/16/8. At a median follow-up of 4.3 months 39 pts were evaluable for efficacy (8 too early): 29 (74.4%) PR; 9 (23.1%) SD; 1 (2.6%) PD. In 42 pts evaluable for safety (259 cycles), grade 3/4 AEs occurred in 40.5% of pts: neutropenia/leukopenia (16.7%), diarrhea (14.3%), mucositis (7.1%), nausea (4.8%), and fatigue (4.8%). As yet it is too early to assess survival or the role of gefitinib as maintenance therapy. Serum EGFR data (n=27) did not correlate with response. Conclusions: These preliminary data show that first-line gefitinib combined with simplified FOLFOX-6 has promising activity in pts with advanced CRC. Final data will be reported at the meeting. No significant financial relationships to disclose.
Lung cancer risk, diabetes, and diabetes treatments.
Authors: Alice Koechlin, Peter Boyle
Journal: Journal of Clinical Oncology (2016)

1577 Background: Lung cancer is the commonest form of cancer and diabetes is an increasingly prevalent chronic condition worldwide. Associations between these two conditions is currently the subject of discussion. Even a small, real increase in lung cancer risk associated with diabetes would represent a significant problem for Public Health. Methods: A meta-analysis on lung cancer risk in diabetic patients compared to non-diabetic subjects was undertaken according to PRISMA guidelines. Random-effects meta-analyses were computed with tests for heterogeneity and publication bias. Results: There was no increased risk of lung cancer among diabetic patients (SRR = 1.06; 95% CI 0.98, 1.14) based on 34 studies. The risk remained non-significant in studies adjusting for smoking (SRR = 0.98; 95% CI 0.90, 1.07) and among studies not adjusting for smoking (SRR = 1.09; 95% CI 0.98, 1.21). There was no significantly increased risk of lung cancer among diabetic patients in studies conducted in North America (SRR = 1.04), Europe (SRR = 1.01) or Asia (SRR = 1.10). 22 studies investigated the association between diabetes treatments and lung cancer. The risk of lung cancer was increased among patients with diabetes treated with any type of insulin (SRR = 1.20; 95% CI 1.03, 1.41) and remained unchanged when the analysis was restricted to observational studies (SRR = 1.20; 95% 1.01, 1.43). The risk of lung cancer among glargine users, the focus of the majority of studies, was not increased (SRR = 1.04; 95% CI 0.91, 1.19) and this persisted when restricted to observational studies (SRR = 1.02; 95% CI 0.88, 1.18). Risk of lung cancer among patients prescribed non-glargine insulin had an increased risk of lung cancer (SRR = 1.50; 95% CI 1.10, 2.04). Risk of lung cancer was reduced among users of Thiazolidinediones (TZDs) (SRR = 0.67; 95% CI 0.54, 0.85) but not metformin (SRR = 0.94; 95% CI 0.73, 1.22). Conclusions: The risk of lung cancer is not increased among patients with diabetes compared to non-diabetic subjects. Those diabetic patients prescribed glargine do not have an increased risk of lung cancer although users of other insulins have a significantly increased risk. Users of TZDs have a decreased risk of lung cancer while there is no significant protection conferred by using metformin.
Consider prophylaxis in systemic lupus erythematosus
Authors: K A Davies, H L C Beynon, M J Walport
Journal: BMJ (1994)

There is evidence that prophylactic penicillin is effective in children with sickle cell disease, and it seems sensible to give similar prophylaxis to hyposplenic patients with other diseases.Identifying such patients is now relatively easy with the method of counting pitted red cells under differen- tial interference contrast microscopy.The risks of fulminant sepsis in patients who may be hypo- splenic must be borne in mind, and such patients should be treated promptly with antibiotics when they become febrile.At present there is insufficient evidence to justify giving pneumococcal vaccine to all patients who may be hyposplenic.Nevertheless, it seems prudent to vaccinate certain high risk groups such as children with sickle cell disease and patients with severe extensive chronic inflammatory bowel disease.
BMA Annual Representative Meeting: Doctors criticise preparations for bioterrorist attacks
Authors: Linda Beecham
Journal: BMJ (2003)

Doctors are worried about the inadequate arrangements for caring for patients in the event of a nuclear, biological, or chemical attack or in other public health emergencies such as an epidemic of severe acute respiratory syndrome (SARS). One health trust, according to a representative, told its GPs that at the start of a SARS outbreak they should go to a builders' supplier to buy protective masks and to hold consultations with patients by shouting through the letterbox. Dr Simon Eccles, a specialist registrar in accident and emergency medicine, told the meeting that he had to treat a patient with SARS in the back of an ambulance for a time because his hospital had no secure isolation facilities. He cited as an example the nerve gas attack on the underground railway in Tokyo, when the nearest hospital was faced with 500 to 1000 patients without warning. Guidelines for dealing with victims of a bioterrorism did exist, but hospitals were still unprepared for the onslaught of thousands of people who feared that they might have been affected by an attack. Dr John Dracass, a GP in Southampton, said that too little information was available to GPs. Often stories appeared in the media before information from the Department of Health arrived. He wondered how many doctors knew where their local decontamination site was. But Dr Jackie Cassall, from Brighton, said out that all primary care trusts should have an emergency plan and there should be liaison between the Public Health Laboratory Service and the Health Protection Agency. Opposing the call for better arrangements to be put in place, Dr Richard Jarvis, from the Committee for Public Health Medicine and Community Health, said that the key to any response was the involvement of several agencies. He accepted that more funds were needed for such things as practising responses to emergencies. But he criticised the fact that earlier in the year a government select committee had criticised the work that was being done, with the result that the confidence of the agencies concerned had plummeted. The chairman of the BMA's board of science, Sir David Carter, said, Clearly, more needs to be done. He said that his board was preparing a report on the threats.  Department of Health spokesperson said, A huge amount of work has been done to improve NHS preparedness for bioterrorist incidents or the outbreak of illnesses. This includes buying new equipment, vaccines, and antibiotics.
18F-FDG Uptake in Ischemic Colitis During Follow-up of a Patient With Lung Cancer
Authors: Sofia C. Vaz, Carla Oliveira, Joana C. Castanheira, Ângelo F. Silva, Durval C. Costa
Journal: Clinical Nuclear Medicine (2017)

A 61-year-old man with previous history of lung adenocarcinoma underwent 2 F-FDG PET/CT investigations. The first for assessment of enlarged mediastinal lymph nodes revealed an area of increased FDG uptake in the sigmoid colon (located at the right pelvis). Colonoscopy showed a segmental area of ischemic sigmoid colitis, confirmed on histology postbiopsy. The asymptomatic man had no risk factors, and no specific treatment was administered, apart from supportive measures. One year later, there was no significantly abnormal uptake on PET/CT. Incidental ischemic colitis may be demonstrated with FDG and PET/CT needing no specific therapeutic measures for resolution.
Use and adherence to breast cancer risk-reduction agents: A population-based study.
Authors: Mariana Chavez-Mac Gregor, Xiudong Lei, Hui Zhao, Therese Bartholomew Bevers, Sharon Hermes Giordano, Abenaa M. Brewster
Journal: Journal of Clinical Oncology (2016)

1558 Background: Tamoxifen, raloxifene and aromatase inhibitors (AIs) reduce the risk of developing breast cancer (BC). Risk-reduction agents are recommended for women at high risk of BC defined as a 5-year risk ≥ 1.7% using the Gail model or age ≥ 60. We describe the use of risk reduction-agents, adherence rates and determinants of adherence among women age ≥ 60. Methods: Marketscan participants age ≥ 60, with claims between 2008-2013 and 18 months of continuous coverage were identified. Women with DCIS, LCIS or any invasive cancer diagnosis were excluded. Prescriptions for risk-reduction agents were identified; however raloxifene claims linked to an osteoporosis diagnosis were excluded. Descriptive statistics and multivariable regression models were used. Among participants initiating therapy with risk-reduction agents, adherence was evaluated measuring the proportion of days covered (PDC) in 12 continuous months. Adherence was defined as PDC ≥ 80%. Results: Among 3,398,001 women, 61,329 (1.8%) used risk-reduction agents. Determinants of use included older age (OR 1.34; 95%CI 1.31-1.37) and residence in the north-central (OR 1.61; 95%CI 1.57-1.65) and south (OR 1.5; 95%CI 1.46-1.54) regions of the US. High comorbidity score (OR 0.59; 95%CI 0.5-0.58), living in areas with the lowest income (OR 0.92; 95%CI 0.9-0.95) or -as a proxy for race- high proportion of African Americans (AA) (OR 0.87; 95%CI 0.84-0.89) and Hispanics (OR 0.82; 95%CI 0.79-0.84) were associated with decreased use. Adherence was evaluated in 12,026 women, of whom 37.4% had a PDC ≥ 80%. Factors associated with adherence included 90 rather than 30 day prescription (OR 2.66; 95%CI 2.43-2.91), and tamoxifen (OR 1.36; 95%CI 1.03-1.79) or AIs (OR 1.72; 95%CI 1.42-2.1) use compared to raloxifene. Residence in areas with high proportion of AAs (OR 0.87; 95%CI 0.76-0.99) and higher out of pocket cost (OR 0.89; 95%CI 0.82-0.97) were associated with poor adherence. Conclusions: A very small proportion of insured women age ≥ 60 are prescribed risk-reduction agents. Among those receiving treatment, adherence is low. Prescription-related factors and socio-demographic characteristics are associated with use and adherence indicating potential areas for intervention.