tbuckley/cabot-search huggingface dataset:
Abstract 12275: Knock-down of Insulin-like Growth Factor-1 Receptor in the Endothelium Decreases Anti-oxidant Capacity of Aorta, Leading to Increased Atherosclerosis
Authors: Yusuke Higashi, Shaw-Yung Shai, Xuwei Hou, Sergiy Sukhanov, Patrice Delafontaine
Journal: Circulation (2015)

Systemic infusion of insulin-like growth factor-1 (IGF-1) in Apoe-deficient mice exerts anti-atherogenic effects by reducing oxidative stress and pro-inflammatory responses in lesions, yet precise mechanisms remain elusive. We have shown that smooth muscle specific IGF-1 overexpression does not reduce atherosclerotic burden, suggesting that smooth muscle cells do not mediate anti-atherogenic effects of IGF-1. The endothelium is integral in atherogenesis, however a potential role of endothelial IGF-1 receptor (IGF1R) signaling in atherogenesis is unknown. To investigate, we generated Apoe-deficient/endothelial IGF1R-knockdown (En-IGF1R-KD) mice, which are Igf1r-floxed and express Cre recombinase driven by the Cdh5-promoter. IGF1R expression levels were lower by 60% in endothelial cells isolated from En-IGF1R-KD mice compared to IGF1R-flox cells. After 12 weeks of high-fat diet feeding, En-IGF1R-KD mice had more atherosclerotic plaque than IGF1R-flox control (Oil Red O staining of en face aorta, 33±8% increase, P&lt;0.05), indicating that loss of endothelial IGF1R signaling enhanced atherogenesis. Intriguingly, En-IGF1R-KD did not alter systolic blood pressure (IGF1R-flox; 119.5±2.6 vs. En-IGF1R-KD; 119.1±2.0 mmHg) or plasma nitrate/nitrite levels (index of nitric oxide bioavailability, IGF1R-flox; 8.6±0.4 vs. En-IGF1R-KD; 7.3±0.9 uM). Vasorelaxation to acetylcholine (Ach) was equivalent in aortas of En-IGF1R-KD and IGF1R-flox mice after high-fat diet feeding, suggesting that endothelial function was not affected by En-IGF1R-KD. Intriguingly, high-fat diet feeding made aortas hyporesponsive to Ach both in En-IGF1R-KD and IGF1R-flox mice, and in normal chow fed mice En-IGF1R-KD aortas were more responsive to Ach than IGF1R-flox aortas, indicating that loss of IGF-1 signaling improved endothelial function. On the other hand, anti-oxidant capacity as measured by Hydroxyl Radical Antioxidant Capacity Activity Assay was significantly lower in En-IGF1R-KD aorta by 30.0±6.7%, consistent with anti-oxidant effects of IGF-1 on endothelial cells. In summary, our results indicate that IGF1R signaling in the endothelium is atheroprotective, and that this atheroprotective effect is mediated via an anti-oxidant mechanism.
Prevention of enteric bacterial infections and modulation of gut microbiota with conjugated linoleic acids producing <i>Lactobacillus</i> in mice
Authors: Mengfei Peng, Zajeba Tabashsum, Puja Patel, Cassandra Bernhardt, Chitrine Biswas, Jianghong Meng, Debabrata Biswas
Journal: Gut Microbes (2019)

Probiotics are recognized for outcompeting pathogenic bacteria by competitive receptor-mediated colonization and secretion of functional metabolites which are antimicrobial against certain microbes as well as improving host's gut health and immunity. Recently, we have constructed a bioactive Lactobacillus casei (LC) strain, LC+mcra, by inserting mcra (myosin cross-reactive antigen) gene, which stimulates the conversion of conjugated linoleic acids. In this study, we evaluated the modulation of gut microbiome and protective roles of LC+mcra against pathogenic Salmonella enterica serovar Typhimurium (ST) and enterohemorrhagic E. coli (EHEC) infections in BALB/cJ mice. We observed that LC+mcra colonized efficiently in mice gut intestine and competitively reduced the infection with ST and EHEC in various locations of small and large intestine, specifically cecum, jejunum, and ileum (p < 0.05). Positive modulation of the cecal microbiota, for example, higher relative abundances of Firmicutes, lower relative abundances of Proteobacteria, and increased bacterial species diversity/richness, was detected in ST-challenged mice pretreated with LC+mcra based on 16S metagenomic sequencing. Cytokine gene expression analysis indicated that mice pretreated with LC+mcra associated with attenuated bacterial pathogen-induced gut inflammation. Furthermore, mice fed daily with LC+mcra for one week could protect themselves from the impairments caused by enteric infections with ST or EHEC. These impairments include weight loss, negative hematological changes, intestinal histological alterations, and potential death. This in vivo study suggests that daily consumption of novel conjugated linoleic acids over-producing probiotic effectively improves intestinal microbiota composition and prevents/combats foodborne enteric bacterial infections with pathogenic Salmonella and diarrheagenic E. coli.
MKK signaling is required for fibrosarcoma growth and vascularization.
Authors: Yan Ding, Elissa Boguslawski, Bree Berghuis, John Young, Zhongfa Zhang, Nicholas Duesbery
Journal: Cancer Research (2007)

323  Fibrosarcoma is a malignant tumor derived from fibrous connective tissue and characterized by immature proliferating fibroblasts or undifferentiated anaplastic spindle cells. We have hypothesized that signaling through multiple MKK pathways is essential for growth and vascularization of fibrosarcomas. We tested this using anthrax lethal toxin (LeTx), a protease that cleaves and inactivates MKKs. Western blots confirmed that the phosphorylation levels of ERK, JNK and p38 MAPK in fibrosarcoma cell lines in vitro were reduced after 72 hours LeTx treatment. Concomitant with inhibition of MKK signaling, LeTx also blocked soft agar colony formation and proliferation but appeared to be neither cytotoxic nor cytostatic, causing only a minor G1 phase block and lengthened cell cycle progression. Because growth proliferation can be affected by autocrine growth factors we examined the effects of LeTx upon cytokine release from these cells. We observed that LeTx could decrease the release of many pro-angiogenic factors, notably VEGF. The effects of LeTx on fibrosarcoma growth and vascularization were also evaluated in vivo using a xenograft model. Both tumor volume and mean vascular density were significantly decreased by LeTx treatment. These changes correlated with altered in vivo cytokine expression. In conclusion, our results are consistent with the hypothesis that MKK signaling is required for the growth and vascularizaion of fibrosarcomas both in vitro and invivo.
Inhibition of AP-1 transcriptional activity blocks the migration and invasion of murine osteosarcoma cells with high metastatic potential.
Authors: Virna D. Leaner, Jeffrey J. Chick, Chand Khanna, Michael J. Birrer
Journal: Cancer Research (2004)

3402  A murine osteosarcoma (OSA) model for metastasis and invasion was used in this study to determine the role of AP-1 in the progression of this disease. Two clonally related osteosarcoma cell lines, K12 and K7M2 have been characterized as low or high metastatic respectively (1). To determine the role of AP-1 in OSA, we analyzed its components and activity in K12 and K7M2. While AP-1 transcriptional activity was enhanced in K7M2 relative to that in K12, AP-1 DNA-binding was unchanged between the two cell lines. The AP-1 complex in K7M2 was composed of primarily Fra1 and cJun, while in K12 the complex was composed of cJun and JunD. In addition, an increase in phosphorylated cJun, JNK activity, and phosphorylated ERK1/2 were associated with the more metastatic osteosarcoma phenotype. The significance of AP-1 activation was confirmed by conditional expression of a cJun dominant negative mutant, Tam67. Under conditions where Tam67 inhibited AP-1 activity in K7M2, migration and invasion potential was significantly blocked. This study shows that differences in metastatic activity in K12 and K7M2 OSA are in part due to AP-1 activation. The inhibition of AP-1 activity may serve as a therapeutic tool in the management of osteosarcoma. 1. Khanna, C., Khan, J., Nguyen, P., Prehn, J., Caylor, J., Yeung, C., Trepel, J., Meltzer, P., and Helman, L. Metastasis-associated differences in gene expression in a murine model of osteosarcoma. Cancer Res, 61: 3750-3759, 2001.
Hepatic resection for colorectal cancer metastasis: A retrospective review of the Ottawa Hospital Cancer Centre over 7 years.
Authors: Nana Boame, Gillian Gresham, Guillaume Martel, Janelle Rekman, Derek J. Jonker, Abdulsalam Alnajjar, Waleed Mohammad, Fady Balaa, Timothy R. Asmis
Journal: Journal of Clinical Oncology (2012)

e14154 Background: The timing of chemotherapy (adjuvant vs neoadjuvant) for patients undergoing potentially curative hepatic resection of metastasis from colorectal cancer origin is controversial. Methods: We performed a retrospective review of all patients at TOHCC who underwent successful surgical resection of hepatic metastasis from CRC between 2002-2009. Patients receiving intra-operative radiofrequency ablation (RFA) as part of their management were included. Factors associated with overall survival were evaluated. Results: 168 patients had median age 62 years (31-84), 57/43% male/female. Median pre-op CEA was 5.5 ng/ml (0.3 - 529.2). Primary tumor location included 40% left, 35% rectum, 20% right, 5% transverse. 61.5% patients were node positive. Following hepatectomy 10.2% had positive resection margins. Intra-operative RFA was used in 26 (15.4%) patients. Chemotherapy was administered in a neo-adjuvant (47.6%), adjuvant (58.4%) or “perioperative” (both neoadjuvant and adjuvant; 36.1% ) setting. Use of intraoperative RFA vs. no RFA was not associated with overall survival (HR: 0.94 [95%CI: 0.49-1.80],p=0.85). In both univariate and multivariate analysis, the only adverse factor found associated with survival was R1 status (HR 2.38 [95% CI 1.49-5.0], p=0.0198). Other baseline variables (age, gender, node status, histologic grade, primary tumour site, timing of metastatic diagnosis [metachronous vs. synchronous]) did not reach statistical significance. Conclusions: While statistical significance was not achieved, ability to demonstrate benefit of chemotherapy may have been limited by sample size. Hazard ratios suggest trend to greatest benefit with use of post-operative adjuvant chemotherapy. 3y and 5y survival data is encouraging. Use of RFA where required as an adjunct to hepatic resection appeared as effective as resection of all disease in this series. Recurrence and morbidity data will be presented. [Table: see text]
A 90 kDa Filamin A fragment regulates androgen dependence in prostate cancer
Authors: Roble G. Bedolla, Yu Wang, Margarita Mikhailova, Naveen K. Krishnegowda, Chong Jin Loy, Eu Leong Yong, Paramita M. Ghosh, Jeffrey I. Kreisberg
Journal: Cancer Research (2005)

969  Prostate cancer is the second leading cause of cancer-related deaths among men in the United States. Initially, prostate tumors are dependent on androgens for growth, and respond to androgen-deprivation therapy; however, the majority of prostate cancers treated with androgen ablation progress to an androgen-independent phenotype for which there is no established therapy. Filamin A (FlnA) is a 280kDa membrane-associated actin-binding protein consisting of an actin-binding domain followed by 24 100-residue repeats. FlnA is cleaved intracellularly to a 90kDa fragment consisting of repeats 16-24 (FlnA16-24). FlnA16-24 translocates to the nucleus and represses androgen receptor (AR) transcriptional activity. Here, we show that in the androgen-dependent human prostate cancer cell line LNCaP, the 90 kDa fragment translocates to the nucleus, whereas in an androgen-independent clone of LNCaP cells, C4-2, FlnA remains largely in the cytoplasm. Western blotting with an antibody to the C-terminal domain of FlnA which recognizes the 90 kDa fragment shows that C4-2 cells express decreased levels of FlnA16-24 compared to LNCaP. We hypothesize that failure of FlnA cleavage to FlnA16-24 results in the androgen independence of C4-2 cells. Unlike LNCaP cells, C4-2 cells are not growth arrested by the antiandrogen Casodex, reflecting their androgen-independent nature. Transfection of FlnA16-24, but not FlnA1-15, results in Casodex-induced growth arrest in C4-2 cells. The AR is a transcription factor that binds to androgen responsive elements (ARE) in the promoter region of target genes. P21Cip1/Waf1, an inhibitor of cyclin dependent kinases and cell cycle progression, contains an ARE in its promoter region. Casodex fails to induce p21Cip1/Waf1 expression in C4-2 cells. However, transfection with FlnA(16-24), but not FlnA(1-15) stimulated Casodex-induced p21 Cip1/Waf1 expression. These results suggest that FlnA16-24 reverses C4-2 cells to an androgen-dependent phenotype and that FlnA may be a suitable target for therapy in prostate cancer progression.
Effects of occlusal forces on the peri‐implant‐bone interface stability
Authors: Rafael Arcesio Delgado‐Ruiz, Jose Luis Calvo‐Guirado, Georgios E. Romanos
Journal: Periodontology 2000 (2019)

Abstract The occlusal forces and their influence on the initiation of peri‐implant bone loss or their relationship with peri‐implantitis have created discussion during the past 30 years given the discrepancies observed in clinical, animal, and finite element analysis studies. Beyond these contradictions, in the case of an osseointegrated implant, the occlusal forces can influence the implant‐bone interface and the cells responsible for the bone remodeling in different ways that may result in the maintenance or loss of the osseointegration. This comprehensive review focuses on the information available about the forces transmitted through the implant‐crown system to the implant‐bone interface and the mechano‐transduction phenomena responsible for the bone cells’ behavior and their interactions. Knowledge of the basic molecular biology of the peri‐implant bone would help clinicians to understand the complex phenomenon of occlusal forces and their effects on the implant‐bone interface, and would allow better control of the negative effects of mechanical stresses, leading to therapy with fewer risks and complications.
Adverse Events Associated With the Use of Sipuleucel-T Reported to the US Food and Drug Administration’s Adverse Event Reporting System, 2010-2017
Authors: Graça M. Dores, Marthe Bryant-Genevier, Silvia Perez-Vilar
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Sipuleucel-T was the first therapeutic cancer vaccine approved by the US Food and Drug Administration (FDA) in 2010. Although almost a decade has passed since its approval for the treatment of asymptomatic or minimally symptomatic castration-resistant prostate cancer (CRPC), there remains a paucity of literature describing safety data in the postmarketing period. <h3>Objective</h3> To describe the postmarketing safety experience for sipuleucel-T. <h3>Design, Setting, and Participants</h3> In this case series study, US reports for sipuleucel-T submitted to the FDA's Adverse Event Reporting System were searched and reviewed between April 29, 2010, and December 31, 2017. This system is a spontaneous safety surveillance database for drug and therapeutic biologic products. The analysis of 3216 reports and select case reviews were undertaken between February and November 2018. <h3>Main Outcomes and Measures</h3> Descriptive statistics were used to assess adverse event reports for sipuleucel-T. Empirical Bayes Geometric Means (EBGM) and their 90% confidence intervals (CIs) were computed to identify disproportionate (ie, at least twice the expected) reporting of sipuleucel-T–event pairs. Selected adverse events and death reports were individually reviewed. <h3>Results</h3> In total, 3216 reports were identified for sipuleucel-T, of which 2014 (62.6%) were serious. For all included reports, the patients' median (interquartile range) age was 73 (67-79) years, and 3149 were specified to be males. Chills (n = 318), malaise (n = 196), pyrexia (n = 189), culture positive (n = 184), fatigue (n = 180), and nausea (n = 173) were among the most commonly reported adverse events. Infusion-related reactions (EBGM, 12.1; 90% CI, 9.4-15.3), infections, vascular events, and transient ischemic attacks (EBGM, 2.9; 90% CI, 2.2-3.9) were reported disproportionately. Among 249 deaths for which relevant dates were available, 128 (51.4%) were reported within 30 days of a sipuleucel-T infusion, of which 81.2% included a specified cause of death; of these 104 deaths, there were 37 neoplasms (35.6%), 25 cardiac disorders (24.0%), 18 nervous system disorders (17.3%), and 9 infections (8.7%). <h3>Conclusions and Relevance</h3> Reported adverse events were generally consistent with the safety experience observed in prelicensure studies and described in the sipuleucel-T package insert. Off-label use among overtly symptomatic men with CRPC, reporting bias, or lack of product effectiveness may have influenced the reporting of deaths within 30 days of treatment initiation. With this overview of sipuleucel-T experience, the present study serves as a resource for health care professionals and patients as they weigh the risks and benefits of treatment in the context of all available therapeutic options for CRPC.
Carcinoma of the unrivaled bilharzial urinary bladder of Egyptians: Expanding radiotherapy and decline of obligate cystectomy—Historic perspective and a demonstration study of 34 patients.
Authors: Gamal Moustafa Saied, Karim G Moustafa
Journal: Journal of Clinical Oncology (2013)

e15571 Background: The objective is to validate the new clinicopathological features involving carcinoma of the unrivaled urinary bladder of Egyptian patients, alongside studying their reflection on management. Methods: Timely contributions of leading Egyptian experts in bladder cancer in the last 4 decades were reviewed. Additionally, 34 patients were studied in 2 subsets based on planned treatment modality: group A (12 cases) treated by cystectomy and group B (22 cases) treated by transurethral resection plus stipulated radiotherapy. Treatment results were evaluated. Results: An overview of studies published in the last 4 decades is given, demonstrating a striking change in the characteristic features of bladder carcinoma in this country, more obvious in 2007 and after. Present work revealed 44.1% of patients had their tumor erupting in a bilharzial bladder where walls demonstrated classical cystoscopic features of the disease. Histologically 86.7 % of them were squamous cell carcinoma. Almost 60% of patients had had their tumors in a non-bilharzial bladder, 94.7% of them were transitional cell carcinoma. Thirteen out of 15 patients in group A were treated by cystectomy carrying 7.7 % perioperative mortality, whereas 11 out of 12 patients in group B received radiotherapy preceded by transurethral resection. Distribution of clinicopathological findings and treatment modalities is tabulated. Conclusions: Bladder cancer in Egyptian patients has lost its weird features imposed by bilharzial cystitis. It is shifting towards alien types making it suitable for organ preserving management.
Patient information desire in actual decision making for advanced cancer treatment: Do doctors know their patients?
Authors: Linda JM Oostendorp, Petronella B Ottevanger, Winette T.A. Van Der Graaf, Peep FM Stalmeier
Journal: Journal of Clinical Oncology (2012)

9036 Background: Providing information is an important element of cancer care. While several studies have investigated patients' information desire, to our knowledge, this study is the first to involve patients facing an actual decision. We examined the information desire of patients at the point of decision making, the ability of doctors to judge this desire, and the information provided by the doctor. Methods: This prospective multicenter study included patients with advanced colorectal or breast cancer faced with the decision whether or not to pursue second-line chemotherapy. Patients received the usual treatment-related information from the doctor plus a decision aid from a nurse. The aid contained information on adverse events, tumor response, and survival. For each item, the nurse asked the patient whether the information was desired and whether it had been disclosed by the doctor and the doctor made a substitute judgment of the patient’s information desire on the inclusion form. The match between patient’s desire and doctor’s judgment was expressed in percentage agreement and agreement corrected for chance (κ). Results: By 01/2012, 71 patients had received the decision aid. Median age was 62 years (range 39-80), 38% were male, and 28% had college education or higher. Information on adverse events, tumor response, and survival was desired by 94%, 90%, and 73% of patients. The doctors judged that information desire would be 100%, 97%, and 81%, respectively. There was a poor match between doctor’s judgment and actual information desire for adverse events (94%, κ not applicable), tumor response (87%, κ = -0.049), and survival (61%, κ = -0.104). When asked whether the information was previously disclosed by the doctor, 73%, 57%, and 30% of patients answered affirmatively. Conclusions: Patients expressed a high information desire, which was accurately judged by the doctors. However, doctors were unable to judge an individual patient’s information desire beyond chance. According to the patients, doctors did not disclose all desired information, especially on survival. Decision aids, similar to those used here, have been shown to help doctors provide safe, effective, and timely information to patients.
The Ribonucleotide Reductase Inhibitor, Didox, Reduces the In Vivo Vascular Inflammation and Oxidative Stress Induced By Acute Hemolysis
Authors: Nicola Conran, Juliete A.F. Silva, Erica M.F. Gotardo, Hanan Chweih, Lediana I. Miguel, Flávia Costa Leonardo, Wilson A. Ferreira, Bo E. Hedlund, Howard L. Elford, Fernando F. Costa
Journal: Blood (2018)
Statewide Implementation of Postoperative Opioid Prescribing Guidelines
Authors: Joceline V Vu, Ryan A Howard, Vidhya Gunaseelan, Chad M Brummett, Jennifer F Waljee, Michael J Englesbe
Journal: New England Journal of Medicine (2019)

Statewide Implementation of Postoperative Opioid Prescribing GuidelinesTo the Editor: Opioids are widely overprescribed after surgery. 1 Leftover medication is often diverted into the community, contributing to the opioid epidemic. 2The lack of evidence on which to base prescribing practices after surgery may hinder efforts to reduce overprescribing. 3In this study, we developed and disseminated postoperative prescribing guidelines and measured the effect on prescribing in a statewide hospital collaborative.The Michigan Surgical Quality Collaborative (MSQC) is a statewide quality-improvement collaborative that maintains a clinical registry of general, vascular, and gynecologic surgical procedures, capturing a random sample of 50,000 patients per year.From January through September 2017, the MSQC collected data on patientreported opioid consumption after surgery.In partnership with the Michigan Opioid Prescribing Engagement Network (Michigan OPEN), these data were used to develop prescribing guidelines for nine surgical procedures (see the Supplementary Appendix, available with the full text of this letter at NEJM.org).