tbuckley/cabot-search huggingface dataset:
Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation
Authors: Jia He, Yinjing Song, Gaopeng Li, Peng Xiao, Yang Liu, Yue Xue, Qian Cao, Xintao Tu, Ting Pan, Zhinong Jiang, Xuetao Cao, Lihua Lai, Qingqing Wang
Journal: Journal of Clinical Investigation (2019)

Resident and inflammatory mononuclear phagocytes (MPhs) with functional plasticity in the intestine are critically involved in the pathology of inflammatory bowel diseases (IBDs), the mechanism of which remains incompletely understood. In the present study, we found that increased expression of the E3 ligase F-box and WD repeat domain–containing 7 (FBXW) in the inflamed intestine was significantly correlated with IBD severity in both human diseases and in mouse models. Myeloid Fbxw7 deficiency protected mice from colitis induced by dextran sodium sulfate (DSS) or 2,6,4-trinitrobenzene sulfonic acid (TNBS). Fbxw7 deficiency resulted in decreased production of the chemokines CCL2 and CCL7 by colonic CX3CR1hi resident macrophages and reduced the accumulation of CX3CR1int proinflammatory MPhs in colitis-affected colon tissue. Mice that received adeno-associated virus–shFbxw7 (AAV-shFbxw7) showed significantly improved survival rates and alleviation of colitis. Mechanism screening demonstrated that FBXW7 suppressed H3K27me3 modification and promoted Ccl2 and Ccl7 expression via degradation of the histone-lysine N-methyltransferase enhancer of zeste homolog 2 (EZH2) in macrophages. Taken together, our results indicate that FBXW7 degrades EZH2 and increases Ccl2 and Ccl7 in CX3CR1hi macrophages, thereby promoting the recruitment of CX3CR1int proinflammatory MPhs into local colon tissues with colitis. Targeting FBXW7 might represent a potential therapeutic approach for the treatment of intestinal inflammation.
Is it currently reasonable to offer short, 14-day antibiotic therapies after a surgical synovectomy in native joint septic arthritis?
Authors: Guillaume Coiffier, Marion Couderc, Raphaele Seror, Geraldine Bart, Christelle Darrieutort-Laffite, Benoit Le Goff
Journal: Annals of the Rheumatic Diseases (2019)

Gjika et al 1 recently reported the non-inferiority of 2-week versus 4-week antibiotic therapy after systematic surgical washing (with or without synovectomy) in the management of septic arthritis. Although this randomised, controlled trial adds important new insights to the management of patients with infectious arthritis, it has several drawbacks that limit generalisation of the results.

First, the patients included in this study were not representative of a usual population of native joint septic arthritis patients. These patients had mainly septic arthritis affecting the small joints (metatarsophalangeal, metacarpophalangeal and proximal interphalangeal joints in 85% of cases). Moreover, in most cases, contamination occurred after direct inoculation following skin invasion (bite/scratch or post-traumatic), with only 4% of patients with systemic signs of infection. Finally, patients were included on the basis of having been treated with surgical drainage, the indications for which are largely centre dependent. These characteristics are probably explained by the monocentric design of the study. Native joint septic arthritis affects mainly …
Performance Measures of Magnetic Resonance Imaging Plus Mammography in the High Risk Ontario Breast Screening Program
Authors: Anna M Chiarelli, Kristina M Blackmore, Derek Muradali, Susan J Done, Vicky Majpruz, Ashini Weerasinghe, Lucia Mirea, Andrea Eisen, Linda Rabeneck, Ellen Warner
Journal: JNCI Journal of the National Cancer Institute (2019)

The Ontario Breast Screening Program expanded in July 2011 to screen high-risk women age 30–69 years with annual magnetic resonance imaging (MRI) and digital mammography. This study examined the benefits of screening with mammography and MRI by age and risk criteria. This prospective cohort study included 8782 women age 30–69 years referred to the High Risk Ontario Breast Screening Program from July 2011 to June 2015, with final results to December 2016. Cancer detection rates, sensitivity, and specificity of MRI and mammography combined were compared with each modality individually within risk groups stratified by age using generalized estimating equation models. Prognostic features of screen-detected breast cancers were compared by modality using Fisher exact test. All P values are two-sided. Among 20 053 screening episodes, there were 280 screen-detected breast cancers (cancer detection rate = 14.0 per 1000, 95% confidence interval [CI] = 12.4 to 15.7). The sensitivity of mammography was statistically significantly lower than that of MRI plus mammography (40.8%, 95% CI = 29.3% to 53.5% vs 96.0%, 95% CI = 92.2% to 98.0%, P < .001). In mutation carriers age 30–39 years, sensitivity of the combination was comparable with MRI alone (100.0% vs 96.8%, 95% CI = 79.2% to 100.0%, P = .99) but with statistically significantly decreased specificity (78.0%, 95% CI = 74.7% to 80.9% vs 86.2%, 95% CI = 83.5% to 88.5%, P < .001). In women age 50–69 years, combining MRI and mammography statistically significantly increased sensitivity compared with MRI alone (96.3%, 95% CI = 90.6% to 98.6% vs 90.9%, 95% CI = 83.6% to 95.1%, P = .02), with a small but statistically significant decrease in specificity (84.2%, 95% CI = 83.1% to 85.2% vs 90.0%, 95% CI = 89.2% to 90.9%, P < .001). Screening high risk women age 30–39 years with annual MRI only may be sufficient for cancer detection and should be evaluated further, particularly for mutation carriers. Among women age 50–69 years, detection is most effective when mammography is included with annual MRI.
Abstract 2120: Human epidermal growth factor receptor 3 might be a targetable molecule for treatment of chemotherapy resistant breast cancer
Authors: Takeshi Kotake, Eiji Suzuki, Fengling Pu, Tatsuki Kataoka, Masahiro Hirata, Eri Hohokabe, Masakazu Toi
Journal: Cancer Research (2019)

Abstract Introduction: Disease control of chemotherapy refractory breast cancer patients (CRBC), who do not respond to conventional treatment strategies, is important. In the setting of neoadjuvant chemotherapy (NAC), susceptibility of the chemotherapeutic agents could be confirmed with clinical relevance. Doxorubicin, docetaxel and paclitaxel have been used as conventional NAC. Eribulin and platinum may also be added in the future. When the drug sensitivity is evaluated by NAC and it is not sensitive to the drugs, there is currently no effective therapy expected to be improved. This is one of the recent unmet medical needs in breast cancer treatment strategy. Materials and Methods: In this study, in order to establish a novel therapeutic strategy for CRBC, we established chemotherapy resistant breast cancer cell lines against doxorubicin, paclitaxel, docetaxel and eribulin using BT549, Hs578t, MDA-MB231, MDA-MB468, and HCC70. We evaluated human epidermal growth factor receptor 3 (HER3) expression in these parental and resistant cell lines. We used U3-1402 (a novel anti-HER3 antibody-drug conjugate) to test if HER3 targeting treatment inhibits the cell proliferation of the chemotherapy resistant cell line with positive conversion of HER3 expression. Results: We found that the change to positive expression of HER3 in paclitaxel resistant BT549 cell line (BT549/PTX) and eribulin resistant Hs578t cell line (Hs578t/ERI) while these two cell lines initially showed negative expression of HER3. In the cell proliferation assay, as we expected, there was no inhibition of proliferation by treatment with HER3 targeting antibody agent U3-1402 in these two cell lines. However, BT549/PTX and Hs578t/ERI with positive conversion of HER3 expression were clearly inhibited their cell proliferation by treatment with U3-1402. Conclusions: It suggests that even in cases whose tumor does not express HER3 initially and show no response for chemotherapy in the NAC, U3-1402 could be effective for the patients with positive conversion of HER3 expression after NAC. We are studying for the role of positive conversion of HER3 expression in the process of acquired chemo-resistance and the elucidation of the molecular mechanism of positive conversion of HER3 expression in these unique treatment condition. Citation Format: Takeshi Kotake, Eiji Suzuki, Fengling Pu, Tatsuki Kataoka, Masahiro Hirata, Eri Hohokabe, Masakazu Toi. Human epidermal growth factor receptor 3 might be a targetable molecule for treatment of chemotherapy resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2120.
Application of cholangioscope-compatible retrieval basket
Authors: Lawrence Ku, Marco A. Paez, Jonathan Kung, Linda A. Hou, Viktor E. Eysselein, Sofiya Reicher
Journal: Endoscopy (2019)

The availability of single-operator cholangioscope-compatible accessories for object retrieval has been limited [1]. We present four cases where a recently introduced cholangioscope-specific basket (SpyGlass Retrieval Basket; Boston Scientific, USA), approved by the US Food and Drug Administration (FDA), was used for object retrieval under direct visualization.
Abstract 1003: Modulating estrogen related receptors (ERRs) activity in breast cancer using endogenous ligands
Authors: Faegheh Ghanbari, Sylvie Mader, Anie Philip
Journal: Cancer Research (2019)

Abstract Estrogen-receptor related receptors which consists of ERRα, ERRβ and ERRγ belong to the orphan nuclear receptor subfamily of NR3B (nuclear receptor subfamily 3, group B). The ERRs have been shown to actively modulate estrogenic responses, and to play an essential role in pregnancy, and are implicated in breast cancer progression. Despite intensive efforts, no endogenous ligand has been identified for ERRs so far. The discovery of ligands that bind these orphan receptors will allow the manipulation of this pathway and may lead to novel strategies for the treatment of cancer and other diseases. In this study we show two endogenous ligands of ERRs: 1) estradienolone (ED), a novel endogenous steroid during pregnancy which acts as an inverse agonist of ERRs, 2) cholesterol as an agonist of ERRs. Our recent results show that ED acts as an inverse agonist of ERRα and ERRγ by directly interacting with these receptors, and inhibiting their transcriptional activity. We also demonstrate that ED has strong anti-mitogenic properties. ED inhibits the growth of both estrogen receptor-positive (MCF-7) and estrogen receptor-negative (MDA-MB-231) breast cancer cells in a dose dependent manner, while of displaying a little effect on normal epithelial breast cells. In addition, we show that the effect of cholesterol or lovastatin (a drug known to inhibit cholesterol synthesis) in triple negative breast cancer (MDA-MB 231) requires ERRα. These data suggest that both ED-ERR and cholesterol-ERR interactions may represent novel physiologically relevant ERR pathways in the human. Citation Format: Faegheh Ghanbari, Sylvie Mader, Anie Philip. Modulating estrogen related receptors (ERRs) activity in breast cancer using endogenous ligands [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1003.
Intensive minimal residual disease monitoring to drive early intervention after allogeneic hematopoietic stem cell transplant for pediatric acute leukemia.
Authors: Thomas Pincez, Raoul Santiago, Henrique Bittencourt, Isabelle Louis, Pierre Teira, Johanne Richer, Sonia Cellot, Michel Duval
Journal: Journal of Clinical Oncology (2019)

e18531 Background: Relapse of acute leukemia (AL) remains the main cause of death after allogeneic stem cell transplantation (HSCT) in children. Minimal residual disease (MRD) allows to detect leukemia cells in the bone marrow at low level. The impact of post-HSCT MRD monitoring to detect early leukemia recurrence, to guide therapeutic intervention, and to prevent overt relapse is unknown. We report our experience of systematic MRD monitoring after pediatric HSCT. Methods: All patients who underwent HSCT from January 2012 to December 2017 for an AL had bone marrow MRD performed for 2 years (months 1, 2, 3, 5, 7, 9, 12, 15, 18, 21 and 24). MRD was assessed by flow-cytometry (FC) and, when a molecular alteration was present, by nested RT-PCR. Results: Seventy-one HSCT were performed for AL of myeloid (n=38), lymphoid (n=31) or mixed (n=2) lineage in 59 patients at a median (range) age of 6.5 (0.7-18.4) years. Nine cases did not engraft or had a refractory disease at month+1 evaluation. In all other cases (n=62) MRD was monitored using FC (n=58) and/or RT-PCR (n=34). Thirty-three cases had a MRD detection and/or an overt relapse (≥5% blasts). In 23/33 cases (70%), MRD was detected without simultaneous overt relapse. In the 10 others, an overt relapse occurred without prior MRD detection. Among the cases monitored with RT-PCR, only one relapse occurred without a prior MRD detection. The follow-up protocol was not respected in this particular case. On early MRD detection, 20/23 cases underwent therapeutic intervention, the most frequent being the discontinuation of immunosuppressive drugs (n=13), with subsequent undetectable MRD in 6. Other interventions included chemotherapy (n=8), donor lymphocyte infusion (n=6) and/or interferon ± interleukine 2 (n=3), leading to an undetectable MRD in 3 cases. Overall after first MRD detection, 9/23 (39%) cases never experienced a subsequent overt relapse. Conclusions: Intensified MRD monitoring detected 70% of leukemia recurrences before overt relapse. Therapeutic intervention were taken in most of the cases and 39% never experienced overt leukemia relapse. More efficient immunotherapies may improve the impact of preemptive interventions.
Cost-Effectiveness of brentuximab vedotin with chemotherapy in frontline treatment of CD30-expressing peripheral T-cell lymphoma.
Authors: Tatyana Feldman, Denise Zou, Mayvis Rebeira, Joseph Lee, Mack Harris, Wenkang Ma, Michelle A. Fanale, Thomas John Manley, Joseph Feliciano, Shangbang Rao, Anuraag Kansal
Journal: Journal of Clinical Oncology (2019)

e19060 Background: The most common frontline treatment for peripheral T-cell lymphoma (PTCL) is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or a CHOP-like regimen. In the recently reported phase 3 ECHELON-2 trial, brentuximab vedotin (BV) in combination with CHP (A+CHP) demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) compared to CHOP, with a manageable safety profile. The objective of this analysis was to evaluate the cost-effectiveness of A+CHP in the frontline setting for CD30-expressing PTCL. Methods: A partitioned survival model consisting of 3 health states (PFS, post progression survival, and death), was constructed using clinical and quality of life data from ECHELON-2 from a US payer perspective over a lifetime time horizon. PFS and OS observed from ECHELON-2 were extrapolated using standard parametric distributions. The best-fitting distributions (log-normal for both arms) were selected based on statistical goodness of fit and clinical plausibility of the long-term projections. Health utilities were derived from the European Quality of Life 5-Dimensions (EQ-5D) data collected in ECHELON-2. The average utility scores for the pre- and post-progression periods were estimated via a repeated-measures mixed-effects model. Medical resource use and costs were from literature. Results: The model predicted A+CHP extended undiscounted PFS by 2.92 and OS by 3.38 years over CHOP. These survival gains drive the value in the model. After adjusting for quality of life and discounting, A+CHP was associated with 1.79 quality-adjusted life years (QALYs) gained at an incremental cost of $176,842, yielding an incremental cost-effectiveness ratio (ICER) of $98,987. Sensitivity analyses of alternative model assumptions provided ICERs from $64,000 to $154,000. The estimated probability that A+CHP is cost-effective compared with CHOP was 75% at a willingness-to-pay threshold of $150,000. Conclusions: Based on the ECHELON-2 trial data, this analysis showed for patients with previously untreated CD30-expressing PTCL, treatment with BV in combination with CHP is likely to be cost-effective in comparison to CHOP.
Abstract P241: Health Literacy and Patient Activation Are not Predictors of Positive Health Behaviors Among Young Adult Women
Authors: Yasmina Mohan, Margo Sidell, Lee Tillman, Deborah Young
Journal: Circulation (2017)

Young adulthood is an important phase during which health behaviors are established. Inadequate health behaviors during this phase may increase susceptibility to future poor health. Health behaviors of young adult women, in particular, will most likely not only affect their health, but that of their families. Research exploring health literacy (enabling informed decision making) and patient activation (confidence to maintain/improve health) as predictors of health behaviors is growing. We examined these variables as predictors of positive health behaviors among a cohort of 22-23 year old females (n=476). Health literacy was assessed using the Newest Vital Sign; scores were categorized as low, marginal, and adequate. The Patient Activation Measure (PAM) was used to assess participant health activation. Scores were categorized as low (&lt;27) or high (&gt;27). Eleven health behavior variables related to nutrition, physical activity, sedentary behavior, sleep, alcohol, and smoking were used to create a health behavior score. These data were collected through health surveys and accelerometry. The health score had a possible range of 0 to 22. We included race/ethnicity, education, body mass index (BMI), and depressive symptoms (CES-D) as potential covariates in multivariable models. About 46% of the cohort was White, 25% Black, and 10% Hispanic; about 77% of middle or low socioeconomic status (SES). About 71% had adequate health literacy (18% marginal, 11% low), while 89% had a high PAM score. Participants who were White (p&lt;0.01), had higher education (p&lt;0.01), reported higher SES (p&lt;0.01), and had a lower CES-D score (p&lt;0.02) had higher health literacy. Participants who had lower CES-D scores (p&lt;0.01) also had higher PAM scores. The mean health behavior score was 12.68 (SD=3.39). Univariate analyses indicated adequate health literacy was associated with individual positive health behaviors: breakfast consumption (p&lt;0.01), low sugar sweetened beverage consumption (p&lt;.01), high physical activity (p&lt;0.01), and no smoking (p&lt;0.04). High PAM score was associated with low sugar sweetened beverage consumption (p&lt;0.04). In univariate linear regression models, higher health literacy was associated with a higher composite health score (p&lt;0.01). PAM score was not associated with health score. Multivariable linear regression models controlling for race/ethnicity, education, BMI, and CES-D score, indicated that neither health literacy nor PAM score were associated with composite health score. Among young adult women, positive health behaviors appear to not be influenced by either their individual health literacy or PAM score. Potential associations may emerge later in adulthood as they become fully independent individuals. Young adults may still be closely tied to their parents; thus parent health literacy and PAM score may predict health behaviors among young adults.
Perioperative FLOT experience: pathological regression and toxicity
Authors: A. Sánchez Vegas, A. Gil Torralvo, E. Fernández-Parra, C. Robles Barraza, M. Rodríguez de la Borbolla, A. López Ladrón, J. Rodríguez Hernández, J. Fuentes PRadera, P. López Álvarez, M. Chaves
Journal: Annals of Oncology (2019)
Abstract LB-285: SAGA functions in development and disease
Authors: Sharon Y. Dent, Aimee Farria, Evangelia Koutelou
Journal: Cancer Research (2019)

Abstract Our research is focused on defining the functions of histone modifying enzymes in normal cells, so that we can understand how alterations in these activities contribute to tumor development or progression. Our recent studies on the SAGA complex, which houses both histone acetyltransferase (HAT) and deubiquitylase (DUB) activities, revealed that the Gcn5 HAT, is an important co-activator for Myc in regulating self-renewal of mouse ES cells. Gcn5 is also important for Myc functions as a Yamanaka factor in stimulating conversion of differentiated cells towards an induced pluripotent state. These developmental functions predict that Gcn5 will also be important during Myc functions as an oncogene. In support of this idea, recent studies reveal that deletion of Gcn5 delays lymphoma onset and more than doubles survival of Eμ-Myc mice. The SAGA DUB module is also implicated in cancer, as the USP22 catalytic subunit is overexpressed in several highly aggressive human tumors. We have created USP22 knock out mice to probe the functions of this DUB. Our data indicate that USP22 drives TGF-beta and receptor tyrosine kinase signaling pathways that are critical both to normal developmental processes and to oncogenesis. Altogether, our studies indicate that both Gcn5 and USP22 may provide unique targets for development of new cancer therapies. Note: This abstract was not presented at the meeting. Citation Format: Sharon Y. Dent, Aimee Farria, Evangelia Koutelou. SAGA functions in development and disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-285.