tbuckley/cabot-search huggingface dataset:
Real-world aromatase inhibitor use and failure in women with metastatic ER+/HER2- breast cancer.
Authors: Pamela Landsman-Blumberg, Madhav Namjoshi, Erin Thomson, William Johnson
Journal: Journal of Clinical Oncology (2012)

593 Background: Aromatase Inhibitors (AIs) have replaced tamoxifen as first-line therapy for postmenopausal women with metastatic, ER+ breast cancer (BC). However, little information is available on the real-world use of AIs. The objectives of this retrospective claims study were to compare demographic, clinical and treatment characteristics of postmenopausal women with metastatic ER+/HER2- BC treated with AIs and experiencing 0, 1, 2 or ≥ 3 AI failures (AIF). Methods: Women ≥ 55 years old, newly diagnosed with metastatic BC (index) were identified in the 2006-2010 Thomson Reuters MarketScan databases and followed until chemotherapy or 03/31/2011. ER+/HER2- disease was defined as any endocrine therapy (ET: tamoxifen, fulvestrant) or AI (anastrozole, letrozole, or exemestane) use and no trastuzumab or lapatinib use in the 6-month pre-or variable post-index periods. Those with any post-index AI use were retained for study. AIF post-index was defined as a switch to an alternative AI, ET or chemotherapy, or AI discontinuation with no further BC treatment. Patients were stratified by number of post-index AIF: 0, 1, 2 or ≥ 3. Results: Among 4,274 patients identified, 61% had ≥ 1 AIF (1: 80%, 2: 15%, ≥3: 5%). There was no difference in pre-index AI use across AIF cohorts: 0, 1, 2, and ≥3 (54%, 52%, 48%, 56%; p=0.073). AIFs increased with Medicare-eligibility (51%, 56%, 60%, 61%) and bone metastases at index (48%, 53%, 62%, 63%). Among those with ≥1 AIF, median follow-up (FU) increased with each failure but there was no notable pattern to reason for FU end. Median FU of the 0 AIF cohort (408 days) fell between those of the 1 and 2 AIF cohorts, 335 and 517 days. Anastrozole was the most common first line treatment for all cohorts except ≥ 3 AIFs where letrozole was most common. Pre-index and first line fulvestrant use both increased with the number of post-index AIFs: 0.3%, 1.9%, 2.0%, 5.0% and 0.7%, 2.5%, 4.0%, 14.9% respectively. There was no association between number of AIFs and chemotherapy use (36%, 29%, 38%). Conclusions: Over 60% of women with ER+/HER2- metastatic BC treated with AIs failed at least 1 and 20% of those failed ≥ 2. Surprisingly, increased rates of prior fulvestrant treatment appear associated with increasing numbers of AIF.
Left ventricular ejection fraction (EF) screening in metastatic HER2 positive breast cancer.
Authors: Craig A. Mescher, Christine Ding, Todd E. DeFor, Chetan Shenoy, Suma Konety, Anne Hudson Blaes
Journal: Journal of Clinical Oncology (2016)

e12074 Background: Monoclonal antibodies directed against the HER2 receptor are effective in HER2 positive metastatic breast cancer. HER2 (ErbB2) receptors are present on cardiac myocytes and inhibition can lead to cardiomyopathy. Guidelines recommend evaluation of EF every 3 months due to potential cardiac dysfunction, despite little data to support this recommendation. Additionally, if there is a decrease in EF during treatment defined as a drop in EF > 10% or EF < 50%, consideration of holding therapy is recommended despite the known clinical benefit of this treatment. In this study, the impact of frequent EF screening on clinical practice was evaluated. Methods: We conducted a retrospective analysis of women with metastatic breast that received HER2 directed therapy between 2011 through 2015 to evaluate local trends in EF screening. The primary objectives were to determine whether aggressive screening defined as ≥ 3 echocardiograms (echos) or MUGAs impacted treatment strategies. Results: 147 HER2 positive metastatic breast cancer patients receiving HER2 blocking therapy were identified. 87% underwent ≥ 1 echo or MUGA cardiac screening exam for EF. The average number of EF screenings in the first year of therapy was 3.4 and was 3.0 in patients with longer follow up. 29 of 147 (23%) patients with EF screening in first year of therapy had an asymptomatic decrease in EF. These 29 patients had more EF screenings (p < 0.01), were more likely to receive a cardiology consult (p < 0.01) and to have an ace inhibitor added (p = 0.02). 8 of 29 patients halted therapy for a decreased EF while 15 of 29 did not. The average EF in patients with a decrease was 47.1% in those who stopped therapy and 52.9% in those who did not (p = 0.08). Conclusions: In patients with metastatic breast cancer on Her2 blocking therapy, routine EF screening was common. Though more aggressive screening was associated with identification of decreased EF it was not associated with stopping therapy and few stopped. Given the benefit of Her2 directed therapy and low incidence of stopping therapy for decreased EF, it is reasonable to screen less frequently in asymptomatic patients. Supported in part by NIH Building Interdisciplinary Research Careers in Women’s Health NIH # K12-HD055887.
Assessing the effect of obesity-related traits on multiple myeloma using a Mendelian randomisation approach
Authors: M Went, A Sud, P J Law, D C Johnson, N Weinhold, A Försti, M van Duin, J S Mitchell, B Chen, R Kuiper, O W Stephens, U Bertsch, C Campo, H Einsele, W M Gregory, M Henrion, J Hillengass, P Hoffmann, G H Jackson, O Lenive, J Nickel, M M Nöthen, M I da Silva Filho, H Thomsen, B A Walker, A Broyl, F E Davies, C Langer, M Hansson, M Kaiser, P Sonneveld, H Goldschmidt, K Hemminki, B Nilsson, G J Morgan, R S Houlston
Journal: Blood Cancer Journal (2017)

Multiple myeloma (MM) accounts for around 15% of new cases and 20% of deaths amongst patients diagnosed with haematological malignancy. To date, few risk factors have been robustly confirmed for MM, these include increasing age, male sex, black race and a family history of MM.1
Assessment of Measures to Reduce Infusion-Related Reactions in Patients with Chronic Lymphocytic Leukemia Treated with Obinutuzumab in the GREEN Study
Authors: Francesc Bosch, Robin Foà, Agostino Cortelezzi, Jens Kisro, Veronique Leblond, Gayane Tumyan, Ekaterina Gresko, Susan Robson, Stephan Stilgenbauer
Journal: Blood (2016)
Ablation of osteopontin expression suppresses UVB-induced carcinogenesis
Authors: Pi-Ling Chang, Yu-Hua Hsieh, Chao-Cheng Wang, Margaret Juliana, Patricia Hicks, Craig Elmets
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2237 

Nonmelanoma skin cancer comprising of basal cell carcinoma and squamous cell carcinoma (SCC) is the most prevalent malignancy in Caucasian. Cutaneous SCC is a life threatening malignancy as it has the potential to metastasize and its incidence is increasing each year in the United States. It is clear that prolonged exposure to ultraviolet radiation (UVB) leads to genetic changes in skin cells producing initiated cells, but prolonged UVB exposure may also lead to changes in the microenvironment that in turn contributes to carcinogenesis. Osteopontin (OPN) is a matricellular protein that has been shown to be elevated in several cancer types. We have recently shown that OPN is highly expressed in both actinic keratoses (precursor to SCC) and human cutaneous SCC. We therefore tested whether UVB-induces increase secretion of the OPN in an animal model and whether OPN contributes to photocarcinogenesis. The dorsal skins of female OPN null and wild-type mice in 129S6/SvEv genetic background were subjected to 200 mJ/cm2 of UVB for 43 weeks. Our short term studies of UVB-treated 129/SvEv mice indicate that OPN was induced as early as 24 h after UVB exposure. Further, the percent of mice with tumors and the number of tumors per mouse were higher in 129S6/SvEv mice than OPN null mice on the same genetic background. TUNEL analyses of UVB treated dorsal skin revealed that 2.5-fold more apoptotic basal cells were present in the OPN null than wild-type mice. These data confirm and extend our findings in the two-stage skin chemical carcinogenesis model by indicating that induced expression of OPN during carcinogenesis provides an altered microenvironment for the increased transformation of initiated cells.
Elevated Ferritin Predicts for Inferior Survival in Patients with Acute Leukemia and May be an Early Marker of a Underlying Systemic Pathologic Inflammation
Authors: Preetesh Jain, Kelly Casteel, Carl E. Allen, Kenneth L. McClain, Sa Wang, Sergej Konoplev, Elias J. Jabbour, Graciela Nogueras Gonzalez, Xuelin Huang, Sarah Miller, Waleed Abdelall, Gevorg Tamamyan, Tapan M. Kadia, Gautam Borthakur, Zeev Estrov, Farhad Ravandi, Guillermo Garcia-Manero, Jorge E. Cortes, Hagop M. Kantarjian, Naval Daver
Journal: Blood (2016)
Stress at work
Authors: Thomas Despréaux, Olivier Saint-Lary, Florence Danzin, Alexis Descatha
Journal: BMJ (2017)

A 55 year old senior executive presents with low back pain.He appears anxious.A reorganisation within his company has increased his workload and he has been working more hours but receiving no recognition from management.Last week he felt humiliated by a colleague.Since then he has not been able to sleep for more than a couple of hours each day.Stress accounts for more than a third of all cases of work related ill health and almost half of all working days lost due to illness. 1 Internationally, systematic reviews and meta-analysis of observational data suggest that job strain and poorly functioning work environments are associated with the development of depressive symptoms. 2-4A longitudinal cohort study from Norway found workplace bullying to be associated with subsequent suicidal ideation. 5Long working hours are also associated with increased risk of stroke, heart disease, 6 and diabetes, 7 and poor lifestyle including inactivity, 7 smoking, 7 and risky alcohol use.
A phase I study of brostallicin (B) combined with either bevacizumab (BV) or irinotecan (I) in patients (pts) with advanced solid malignancies
Authors: R. B. MacArthur, J. Singer, C. Becerra, S. Weitman, D. Von Hoff
Journal: Journal of Clinical Oncology (2009)

e13531 Background: B is a DNA minor groove binding (MGB) agent with single agent cytotoxic activity. B has shown synergy with BV and I. The combinations were studied using a “complete” phase I design. Methods: The primary objective was to determine the maximally tolerated dose (MTD) and dose limiting toxicities (DLT) of B+BV and B+I. For B+BV cohort 1 both drugs were infused on day 1 of a 21 day cycle. BV was dosed at 15mg/kg, B was dosed at 6 mg/m2. For cohort 2, the BV dose was unchanged, and B dose reduced to 4 mg/m2. For B+I cohort 1 both drugs were also infused on cycle day 1. I was dosed at 200 mg/m2 with B at 4 mg/m2. For cohort 2, I was reduced to 125 mg/m2 and B reduced to 2 mg/m2. Cycle 1 DLT was defined: grade 4 neutropenia lasting ≥ 5 days, grade 3 or higher febrile neutropenia, grade 4 thrombocytopenia or grade 3 or 4 thrombocytopenia with bleeding, grade 3 or higher diarrhea, nausea or vomiting despite optimal management, grade 3 or higher for all other non-hematologic toxicities. For pts receiving BV, grade 2 or higher proteinuria. Eligible pts had treatment refractory metastatic/unresectable solid tumors, acceptable performance status, and adequate hematologic parameters and organ function. Results: 19 pts were enrolled. 11 pts received B+BV and 8 received B+I. Median age was 58 years. For B+BV 5 patients were treated in cohort 1, 6 in cohort 2. For B+I, 2 patients were treated in cohort 1, 6 in cohort 2. The MTD has not been defined for either treatment combination. In the current preliminary dataset 18/19 pts (93.3%) experienced one or more adverse events (AEs). In the B+BV group, grade 4 neutropenia was reported in 2/11 patients, both in cohort 1, and grade 3 neutropenia in one additional patient, also in cohort 1. In the B+I group, grade 4 AEs included neutropenia (DLT), febrile neutropenia (DLT), severe abdominal pain, and thrombocytopenia. Of the evaluable pts, no complete or partial responses were seen. For B+BV 5/11 pts have received 4 or more cycles, and for B+I 2/8. Conclusions: The combination of B+BV and B+I show manageable toxicity in advanced solid tumors at the doses reached in cohort 2. Additional data will be provided at the time of presentation. [Table: see text]
The anti-angiogenic effect of halofuginone (halo): inhibition of collagen type i tube formation, matrix metalloproteinase-2 (mmp-2) acnvntes and extracellua r matrix (ecm) deposition
Authors: Arnon Nagler, E. Elkin, H. Q. Miao, Reich, M. Pines, I. Vlodavsky
Journal: Blood (2000)
A New Prognostic Scoring System for Multiple Myeloma in the Era of Novel Agents and Autologous Stem Cell Transplantation: A Multicenter Retrospective Collaborative Study of the Japanese Society of Myeloma
Authors: Shuji Ozaki, Takayuki Saitoh, Hiroshi Handa, Kenshi Suzuki, Naoki Takezako, Kazutaka Sunami, Yoshiaki Kuroda, Mitsuhiro Itagaki, Hideki Asaoku, Eiichi Nagura, Shimizu Kazuyuki, Hirokazu Murakami
Journal: Blood (2016)
Small‐molecule AT2 receptor agonists
Authors: Mathias Hallberg, Colin Sumners, U. Muscha Steckelings, Anders Hallberg
Journal: Medicinal Research Reviews (2017)

Abstract The discovery of the first selective, small‐molecule ATR receptor (AT2R) agonist compound 21 (C21) ( 8 ) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8 , encompassing a phenylthiofen scaffold is the drug‐like agonist with the highest affinity for the AT2R reported to date ( K i = 0.4 nM). Structure‐activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8 , are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8 ) or AT2R antagonists (e.g. 9 ), respectively, are briefly addressed. A summary of the pharmacological actions of C21 ( 8 ) is also presented.
Indian Medical Association’s call to relax pregnancy scan data angers campaigners
Authors: Sumi S Dutta
Journal: BMJ (2017)

The Indian Medical Association (IMA), the country’s largest body of private doctors, has urged the government to amend the country’s 23 year old law that prohibits prenatal fetal sex determination, angering many doctors and women’s rights activists.

The IMA, which staged a rally in New Delhi on 6 June, said that more than 53 700 doctors from around the country had expressed support for its campaign opposing criminal action against doctors who may have breached certain documentation requirements mandated under the law.

The Preconception and Prenatal Diagnostic Techniques (Prohibition of Sex Selection) Act of 1994 (PC-PNDT) requires doctors to maintain detailed records of each pregnant woman on whom they conduct …
A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis
Authors: Praveen Agrawal, Barbara Fontanals-Cirera, Elena Sokolova, Samson Jacob, Christopher A. Vaiana, Diana Argibay, Veronica Davalos, Meagan McDermott, Shruti Nayak, Farbod Darvishian, Mireia Castillo, Beatrix Ueberheide, Iman Osman, David Fenyö, Lara K. Mahal, Eva Hernando
Journal: Cancer Cell (2017)
Outcomes and Role of Urgent Endoscopy in High-Risk Patients With Acute Nonvariceal Gastrointestinal Bleeding
Authors: Soo-Han Cho, Yoon-Seon Lee, Youn-Jung Kim, Chang Hwan Sohn, Shin Ahn, Dong-Woo Seo, Won Young Kim, Jae Ho Lee, Kyoung Soo Lim
Journal: Clinical Gastroenterology and Hepatology (2017)
Thrombospondin-1-Derived Peptide Rfyvvmwk Improves the Adhesive Phenotype of CD34+ Cells from Atherosclerotic Patients with Type II Diabetes
Authors: Sylvie Cointe, Eric Rhéaume, Catherine Martel, Olivier P. Blanc-Brude, Evemie Dubé, Florence Sabatier, Francoise Dignat-George, Jean-Claude Tardif, Arnaud Bonnefoy
Journal: Blood (2016)
Enhancement of IFNγ Production by Distinct Commensals Ameliorates Salmonella-Induced Disease
Authors: Sophie Thiemann, Nathiana Smit, Urmi Roy, Till Robin Lesker, Eric J.C. Gálvez, Julia Helmecke, Marijana Basic, Andre Bleich, Andrew L. Goodman, Ulrich Kalinke, Richard A. Flavell, Marc Erhardt, Till Strowig
Journal: Cell Host & Microbe (2017)
Enhanced Therapeutic Efficacy and Memory of Tumor-Specific CD8 T Cells by <i>Ex Vivo</i> PI3K-δ Inhibition
Authors: Rasha Abu Eid, Shamim Ahmad, Yuan Lin, Mason Webb, Zuzana Berrong, Rajeev Shrimali, Takumi Kumai, Sudha Ananth, Paulo C. Rodriguez, Esteban Celis, John Janik, Mikayel Mkrtichyan, Samir N. Khleif
Journal: Cancer Research (2017)

Inhibition of specific Akt isoforms in CD8+ T cells promotes favored differentiation into memory versus effector cells, the former of which are superior in mediating antitumor immunity. In this study, we investigated the role of upstream PI3K isoforms in CD8+ T-cell differentiation and assessed the potential use of PI3K isoform-specific inhibitors to favorably condition CD8+ T cells for adoptive cell therapy. The phenotype and proliferative ability of tumor antigen-specific CD8+ T cells was assessed in the presence of PI3K-α, -β, or -δ inhibitors. Inhibition of PI3K-δ, but not PI3K-α or PI3K-β, delayed terminal differentiation of CD8+ T cells and maintained the memory phenotype, thus enhancing their proliferative ability and survival while maintaining their cytokine and granzyme B production ability. This effect was preserved in vivo after ex vivo PI3K-δ inhibition in CD8+ T cells destined for adoptive transfer, enhancing their survival and also the antitumor therapeutic activity of a tumor-specific peptide vaccine. Our results outline a mechanism by which inhibitions of a single PI3K isoform can enhance the proliferative potential, function, and survival of CD8+ T cells, with potential clinical implications for adoptive cell transfer and vaccine-based immunotherapies. Cancer Res; 77(15); 4135-45. ©2017 AACR.
Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis
Authors: David Baur, Beryl Primrose Gladstone, Francesco Burkert, Elena Carrara, Federico Foschi, Stefanie Döbele, Evelina Tacconelli
Journal: The Lancet Infectious Diseases (2017)
Surveillance Colonoscopy Following Colorectal Cancer Resection: Are we Doing it Right?
Authors: J Mathew, S Absar, M Borghol
Journal: Endoscopy (2004)

Background: There is dispute among surgeons with regard to interval between surveillance colonoscopies following colorectal cancer resection. Our objective was to assess the incidence of metachronous cancers and recurrence in our less intensive surveillance programme and compare with intensive programmes elsewhere.
Abstract #5596: Ultrasound-activated microbubbles as novel radiosensitizers with vascular disrupting effects
Authors: Amanda Caissie, Melissa Furukawa, Raffi Karshafian, Anoja Giles, Yu-Qing Li, Shun Wong, Gregory Czarnota
Journal: Cancer Research (2009)

Background:  Ultrasound (US)-activated microbubbles have recently been identified as novel radiosensitizers, enhancing cell kill in a xenograft model of prostate cancer.  Purpose/Objective(s):   As diagnostic agents, microbubbles are intravascular US contrast agents. The present study therefore aims to investigate the effect of these microbubbles on vasculature when US activated to be used in a therapeutic context with or without radiation (XRT).  Materials/Methods:  Human prostate cancer PC3 cells were implanted in the hind leg of SCID mice. Tumour vascualture was imaged with power Doppler ultrasound prior to animal sacrifice at 24 and 72 hours after treatment with US-activated microbubbles (0, 1.67% and 3%) with and without radiation (0, 2Gy and 8Gy). Tumour sections were stained with HE.  Results:  3D power Doppler imaging detected a significant reduction in tumour blood flow 24 hours after treatment followed by an increase 72hours after treatment. Immunohistological examination confirmed damage to the vasculature, showing that endothelial cell apoptosis increased with combined treatment. Endothelial cell apoptosis was not observed with 2Gy XRT, however, it was detected with US-activated microbubbles alone as determined by TUNEL/CD31 co-staining.  As compared to controls with no treatment, both XRT and US-activated microbubbles caused increased factor VIII staining, interpreted as increased leakiness of tumour vasculature at 24 hours which decreased by 72 hours. The effect was enhanced with combined treatment. Similar to other vascular disrupting agents, microbubbles caused central tumour cell kill with a residual rim of peripheral tumour that was HIF-1\#945; positive. Combined treatment decreases this rim of viable tumour.  Conclusions:  This study provides insight into biological mechanisms underlying the recently identified radiosensitizing effect of US-activated microbubbles. Microbubbles are routinely used as diagnostic imaging contrast agents. With US used to activate the microbubbles locally within tumours, these novel vascular disrupting agents show great promise as therapeutic agents in oncology.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5596.
Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention
Authors: Ruixin Liu, Jie Hong, Xiaoqiang Xu, Qiang Feng, Dongya Zhang, Yanyun Gu, Juan Shi, Shaoqian Zhao, Wen Liu, Xiaokai Wang, Huihua Xia, Zhipeng Liu, Bin Cui, Peiwen Liang, Liuqing Xi, Jiabin Jin, Xiayang Ying, Xiaolin Wang, Xinjie Zhao, Wanyu Li, Huijue Jia, Zhou Lan, Fengyu Li, Rui Wang, Yingkai Sun, Minglan Yang, Yuxin Shen, Zhuye Jie, Junhua Li, Xiaomin Chen, Huanzi Zhong, Hailiang Xie, Yifei Zhang, Weiqiong Gu, Xiaxing Deng, Baiyong Shen, Xun Xu, Huanming Yang, Guowang Xu, Yufang Bi, Shenghan Lai, Jian Wang, Lu Qi, Lise Madsen, Jiqiu Wang, Guang Ning, Karsten Kristiansen, Weiqing Wang
Journal: Nature Medicine (2017)
The Sorting Nexin 3 Retromer Pathway Regulates the Cell Surface Localization and Activity of a Wnt-Activated Polycystin Channel Complex
Authors: Shuang Feng, Andrew J. Streets, Vasyl Nesin, Uyen Tran, Hongguang Nie, Marta Onopiuk, Oliver Wessely, Leonidas Tsiokas, Albert C.M. Ong
Journal: Journal of the American Society of Nephrology (2017)

Autosomal dominant polycystic kidney disease (ADPKD) is caused by inactivating mutations in PKD1 (85%) or PKD2 (15%). The ADPKD proteins encoded by these genes, polycystin-1 (PC1) and polycystin-2 (PC2), form a plasma membrane receptor–ion channel complex. However, the mechanisms controlling the subcellular localization of PC1 and PC2 are poorly understood. Here, we investigated the involvement of the retromer complex, an ancient protein module initially discovered in yeast that regulates the retrieval, sorting, and retrograde transport of membrane receptors. Using yeast two-hybrid, biochemical, and cellular assays, we determined that PC2 binds two isoforms of the retromer-associated protein sorting nexin 3 (SNX3), including a novel isoform that binds PC2 in a direct manner. Knockdown of SNX3 or the core retromer protein VPS35 increased the surface expression of endogenous PC1 and PC2 in vitro and in vivo and increased Wnt-activated PC2-dependent whole-cell currents. These findings indicate that an SNX3-retromer complex regulates the surface expression and function of PC1 and PC2. Molecular targeting of proteins involved in the endosomal sorting of PC1 and PC2 could lead to new therapeutic approaches in ADPKD.