tbuckley/cabot-search huggingface dataset:
Cytoplasmic Cyclin E Mediates Resistance to Aromatase Inhibitors in Breast Cancer
Authors: Iman Doostan, Cansu Karakas, Mehrnoosh Kohansal, Kwang-Hui Low, Matthew J. Ellis, John A. Olson, Vera J. Suman, Kelly K. Hunt, Stacy L. Moulder, Khandan Keyomarsi
Journal: Clinical Cancer Research (2017)

Purpose: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E [low molecular weight forms (LMW-E)] have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect.Experimental Design: LMW-E was examined in breast cancer specimens from 58 patients enrolled in the American College of Surgeons Oncology Group Z1031, a neoadjuvant AI clinical trial. The mechanisms of LMW-E-mediated resistance to AI were evaluated in vitro and in vivo using an inducible model system of cyclin E (full-length and LMW-E) in aromatase-overexpressing MCF7 cells.Results: Breast cancer recurrence-free interval was significantly worse in patients with LMW-E-positive tumors who received AI neoadjuvant therapy, compared with those with LMW-E negative tumors. Upon LMW-E induction, MCF7 xenografts were unresponsive to letrozole in vivo, resulting in increased tumor volume after treatment with AIs. LMW-E expression overcame cell-cycle inhibition by AIs in a CDK2/Rb-dependent manner, and inhibition of CDK2 by dinaciclib reversed LMW-E-mediated resistance, whereas treatment with palbociclib, a CDK4/6 inhibitor, did not.Conclusions: Collectively, these findings suggest that cell-cycle deregulation by LMW-E mediates resistance to AIs and a combination of CDK2 inhibitors and AIs may be an effective treatment in patients with HR-positive tumors that express LMW-E. Clin Cancer Res; 23(23); 7288-300. ©2017 AACR.
Screening for Occult Cancer in Patients With Unprovoked Venous Thromboembolism
Authors: Nick van Es, Grégoire Le Gal, Hans-Martin Otten, Philippe Robin, Andrea Piccioli, Ramón Lecumberri, Luis Jara-Palomares, Piotr Religa, Virginie Rieu, Matthew Rondina, Mariëlle M. Beckers, Paolo Prandoni, Pierre-Yves Salaun, Marcello Di Nisio, Patrick M. Bossuyt, Harry R. Büller, Marc Carrier
Journal: Annals of Internal Medicine (2017)

Background: Screening for cancer in patients with unprovoked venous thromboembolism (VTE) often is considered, but clinicians need precise data on cancer prevalence, risk factors, and the effect of different types of screening strategies. Purpose: To estimate the prevalence of occult cancer in patients with unprovoked VTE, including in subgroups of different ages or those that have had different types of screening. Data Sources: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials up to 19 January 2016. Study Selection: Prospective studies evaluating cancer screening strategies in adults with unprovoked VTE that began enrolling patients after 1 January 2000 and had at least 12 months of follow-up. Data Extraction: 2 investigators independently reviewed abstracts and full-text articles and independently assessed risk of bias. Data Synthesis: 10 eligible studies were identified. Individual data were obtained for all 2316 patients. Mean age was 60 years; 58% of patients received extensive screening. The 12-month period prevalence of cancer after VTE diagnosis was 5.2% (95% CI, 4.1% to 6.5%). The point prevalence of cancer was higher in patients who had extensive screening than in those who had more limited screening initially (odds ratio [OR], 2.0 [CI, 1.2 to 3.4]) but not at 12 months (OR, 1.4 [CI, 0.89 to 2.1]). Cancer prevalence increased linearly with age and was 7-fold higher in patients aged 50 years or older than in younger patients (OR, 7.1 [CI, 3.1 to 16]). Limitation: Variation in patient characteristics and extensive screening strategies; unavailability of long-term mortality data. Conclusion: Occult cancer is detected in 1 in 20 patients within a year of receiving a diagnosis of unprovoked VTE. Older age is associated with a higher cancer prevalence. Although an extensive screening strategy initially may detect more cancer cases than limited screening, whether this translates into improved patient outcomes remains unclear. Primary Funding Source: None. (PROSPERO: CRD42016033371)
Expansion and intensification of humoral autoimmune response in the transition from preclinical to full‐blown primary biliary cholangitis
Authors: Alessandra Dellavance, Maria L.G. Ferraz, Eduardo L.R. Cançado, Luís E.C. Andrade
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: We read with interest the article by Dahlqvist et al.1 about individuals with anti‐mitochondria antibodies (AMAs) and nonestablished primary biliary cholangitis (PBC). The fortuitous finding of a positive AMA test in patients with no clinical and biochemical evidence of PBC has become more frequent due to the widespread testing for antinuclear antibodies using the HEp‐2 indirect immunofluorescence (ANA‐HEp‐2) test. The suspicion of AMAs is elicited by the observation of the ANA‐HEp‐2 cytoplasmic reticular pattern, which is highly suggestive of AMAs. These cases should be then confirmed in specific AMA assays (e.g., indirect immunofluorescence on rodent tissue and solid phase immunoassay). Autoantibodies precede clinical/laboratory evidence of numerous autoimmune diseases, and AMAs may precede the clinical onset of PBC by decades (reviewed by Dellavance and Coelho Andrade2). The fact that some AMA‐positive individuals eventually develop PBC, as demonstrated by Dahlqvist et al., indicates that the preclinical occurrence of AMA may represent part of an evolving and dynamic autoimmune disorder. If this is the case, it might be that the humoral autoimmune response would become stronger with the transition to the clinical stage of the disease. The data by Dahlqvist et al (1) lend credit to this hypothesis by showing lower AMA titer and lower frequency of PBC‐specific antibodies (gp210 and sp100) in individuals with nonestablished PBC compared with patients with established PBC. These findings are in agreement with previous observations from our group in which we demonstrated a more robust autoantibody profile in established PBC than in nonestablished PBC.3 In our study, AMA‐positive individuals with nonestablished PBC (n = 151) presented lower indirect immunofluorescence AMA titer, lower levels of anti‐pyruvate dehydrogenase complex E2 subunit (PDC‐E2) antibody on enzyme‐linked immunosorbent assay, lower avidity of anti–PDC‐E2 antibodies, lower frequency of anti‐sp100, anti‐gp210, and anti–CENP‐B antibodies, and a more restricted antibody isotype use for AMA than patients with established PBC (n = 61). In a multivariate analysis, three variables were independently and strongly associated with the possibility of any given AMA‐positive sample belonging to a patient with established PBC: high titer AMA, high avidity anti–PDC‐E2 antibodies, and the occurrence of three or more PBC‐specific antibodies. These parameters may be helpful in spotting apparently healthy AMA‐positive individuals who are at risk of developing overt PBC over time.
Biomarkers of fatigue related to adjuvant chemotherapy for breast cancer: Evaluation of plasma and lymphocyte expression.
Authors: Felipe Melo Cruz, Bruna Antenussi Munhoz, Beatriz da Costa Aguiar Alves, Flavia de Sousa Gehrke, Fernando Luiz Affonso Fonseca, Renata Kelly Kuniyoshi, Daniel de Iracema Gomes Cubero, Luke Joseph Peppone, Auro Del Giglio
Journal: Journal of Clinical Oncology (2014)

e20536 Background: Fatigue is a common complain in cancer patients receiving adjuvant chemotherapy. In order to further understand its mechanism and search for potential biomarkers we conducted this prospective study. Methods: We enrolled Breast Cancer (BC) patients prior to their first adjuvant Adriamycin based chemotherapy cycle. Patients answered to the BFI and Chalder fatigue questionnaires and had their blood drawn for both plasma evaluation and of peripheral mononuclear cell fraction (PMNCF) mRNA expression of a variety of biomarkers. We evaluated FSH, LH, estradiol, DHEA, DHEAS, IL6, Il2, ILIRA, IL1β, CRP, Cortisol in the plasma and IL2, IL10, IL6, TGF-β, KLRC1, TNF, BTP, SNCA, SOD1, BLNK, PTGS2 and INF γ expression in the PMNCF. Results: We enrolled 43 patients to this trial: eleven patients did not have an increase in their BFI scores and were considered as controls, whereas 32 had an increase in their BFI scores as compared to baseline. From the biomarkers we evaluated in the PMNCF, the only one significantly associated with fatigue was TGF-β (p = 0.0343). We observed no evidence of significant associations of any plasmatic biomarkers with the development of fatigue. However when we analyzed patients with more sever fatigue, plasma IL1-RA levels correlated directly with higher fatigue scores (p = 0.0136). Conclusions: We conclude that Fatigue induced by chemotherapy in BC patients may have a different mechanism than that seen in long term BC survivors or that induced by radiation therapy. Future studies with expanded panels of biomarkers may shed light into the physiopathology of adjuvant chemotherapy induced fatigue. Clinical trial information: 02041364.
The Y Chromosome Plays a Protective Role in Experimental Hypoxic Pulmonary Hypertension
Authors: Soban Umar, Christine M. Cunningham, Yuichiro Itoh, Shayan Moazeni, Mylene Vaillancourt, Shervin Sarji, Alex Centala, Arthur P. Arnold, Mansoureh Eghbali
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Single-walled carbon nanotube: One specific inhibitor of cancer stem cells in osteosarcoma upon downregulation of the TGFβ1 signaling
Authors: Yanyan Miao, Haixia Zhang, Yubin Pan, Jian Ren, Miaoman Ye, Fangfang Xia, Rui Huang, Zhuoheng Lin, Shuai Jiang, Ya Zhang, Zhou Songyang, Yan Zhang
Journal: Biomaterials (2017)
Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017
Authors: Djillali Annane, Stephen M. Pastores, Bram Rochwerg, Wiebke Arlt, Robert A. Balk, Albertus Beishuizen, Josef Briegel, Joseph Carcillo, Mirjam Christ-Crain, Mark S. Cooper, Paul E. Marik, Gianfranco Umberto Meduri, Keith M. Olsen, Sophia Rodgers, James A. Russell, Greet Van den Berghe
Journal: Intensive Care Medicine (2017)
Differentiation of human glioblastoma U87MG cells with all-trans retinoic acid (ATRA) or 13-cis retinoic acid (13-CRA) down regulated telomerase activity and enhanced sensitivity to interferon-gamma (IFN-γ) or taxol (TXL) for apoptosis
Authors: Arabinda Das, Surajit Karmakar, Sunil J. Patel, David G. Priest, Naren L. Banik, Swapan K. Ray
Journal: Cancer Research (2005)

5098   Glioblastoma is the most common and highly malignant brain tumor, which is characterized by the poorly differentiated astroglial cells and their uncontrolled proliferation in the brain. It is not yet significantly amenable to any conventional chemotherapeutic regimen and thus remains a big challenge to both the basic scientists and clinicians. In the current investigation, we used an innovative combination therapeutic approach for controlling the growth of human malignant glioblastoma U87MG cells. We tested the hypothesis that treatment of human malignant glioblastoma cells with a retinoid would induce astrocytic differentiation and down regulate telomerase activity and thereby enhance sensitivity to apoptosis inducing agents. Treatment of U87MG cells with 1 μM all-trans retinoic acid (ATRA) or 1 μM 13-cis-retinoic acid (13-CRA) for 7 days induced astrocytic differentiation morphologically as determined by methylene blue staining, and biochemically as evidenced by overexpression of glial fibrillary acidic protein (GFAP) at the mRNA and protein levels. The telomerase repeat amplification protocol (TRAP) applied to ATRA and 13-CRA treated glioblastoma cells detected a decrease in the activity of telomerase, an enzyme responsible for lending the unlimited capability of proliferation to many cancers including glioblastomas. Cells pretreated with ATRA or 13-CRA were then exposed to 500 units/ml interferon-gamma (IFN-γ) for 48 h or 0.5 μM taxol (TXL) for 24 h for determination of the extent of apoptotic death. Wright staining and light microscopy identified the morphological features of mostly apoptosis in human glioblastoma cells. Apoptosis was associated with an increase in intracellular free Ca2+, as determined by fura-2 assay. Western blot analyses showed alterations in levels of Bax and Bcl-2 resulting in an increase in Bax:Bcl-2 ratio, and overexpression and activation of calpain and caspase-3 to cleave 270 kD α-spectrin at specific sites for generation of 145 kD and 120 kD spectrin break down products (SBDPs), repectively, during apoptosis. Phospholylation of Bcl-2 indicated inactivation of its anti-apoptotic property after treatment with TXL. Activation of caspase-3 was further confirmed by a colorimetric assay using a caspase-3-specific synthetic peptide substrate. Proteolytic activities of both calpain and caspase-3 appeared to contribute significantly to apoptotic death glioblastoma cells. The results from this investigation suggested that a treatment strategy with a combination of retinoic acid (RA) and IFN-γ, or RA and TXL could be highly effective for controlling the malignant growth of glioblastoma. This investigation was supported in part by the R01 grants from the NCI and NINDS of the NIH (Bethesda, MD), and also a grant from the State of SC.
Targeting triple-negative breast cancer by conversion into HER2-positive cancer: A novel therapeutic approach.
Authors: Christof Bernemann, Carolin Huelsewig, Ludwig Kiesel, Cornelia Liedtke
Journal: Journal of Clinical Oncology (2012)

e11534 Background: Triple negative breast cancer (TNBC) is defined by the lack of estrogen-receptor alpha (ERα) and progesterone receptor (PGR) expression as well as absence of human epidermal growth factor receptor2 (HER2/neu) overexpression. This type of breast cancer is characterized by a poor prognosis and significantly reduced survival rate compared to other BC subtypes. This is mostly due to the lack of targeted agents like endocrine or anti HER2 targets. Breast cancers which overexpress HER2 are usually treated by chemicals targeting HER2; either by blocking the extracellular domain through trastuzumab or the intracellular domain through the small molecule lapatinib. Both therapeutics lead to inhibition of downstream pathways like MAPK and PI3K, resulting in increased apoptosis as well as reduced proliferation. Methods: We hypothesize that downstream effects might be induced in TNBC cells when HER2 is artificially overexpressed and cells get treated as HER2 positive cells. Therefore, triple negative breast cancer cell lines were transfected with HER2. These cells were treated with anti-HER2 agents. Molecular analyses will demonstrate whether transfection with HER2 will yield a HER2 positive breast cancer phenotype in that all downstream signaling mechanisms act similarly to a priori HER2 positive cells. Results: Preliminary experiments suggest that proliferation of TNBC cells transfected with HER2 does not change significantly. Treatment with HER2-blocking antibody trastuzumab leads to significant decrease of proliferation in HER2 transfected, initially triple negative MDA-MB-231 breast cancer cells. Only a moderate decrease in proliferation was observed when lapatinib, a molecule directed against both EGFR and HER2, was used in both MDA-MB-231 wildtype and HER2-transfected cell lines. Conclusions: We surmise that firstly, conversion of cancer might become a clinical tool to treat cancer of poor prognosis and secondly that our results might shed light on future therapeutic approaches e.g. small molecule compound screening for endogenous HER2 reactivation / overexpression and subsequent targeted treatment of triple negative breast cancers.
Reply to Wael Agur and Jawad Freites’ Letter to the Editor re: Ferdinando Fusco, Mohamed Abdel-Fattah, Christopher R. Chapple, et al. Updated Systematic Review and Meta-analysis of the Comparative Data on Colposuspensions, Pubovaginal Slings, and Midurethral Tapes in the Surgical Treatment of Female Stress Urinary Incontinence. Eur Urol 2017;72:567–91.
Authors: Ferdinando Fusco, Giacomo Novara
Journal: European Urology (2017)
Antiplatelet Agents for the Treatment and Prevention of Coronary Atherothrombosis
Authors: Carlo Patrono, Joao Morais, Colin Baigent, Jean-Philippe Collet, Desmond Fitzgerald, Sigrun Halvorsen, Bianca Rocca, Agneta Siegbahn, Robert F. Storey, Gemma Vilahur
Journal: Journal of the American College of Cardiology (2017)
Chronic, repeated exposure to gefitinib leads to epithelial-to-mesenchymal transition and drug resistance in A549, a non-small cell lung cancer cell line
Authors: Jin Kyung Rho, Yun Jung Choi, Jin Kyung Lee, Chul Ho Lee, Cheol Hyeon Kim, Jae Cheol Lee
Journal: Cancer Research (2007)

2346  Epithelial-to-mesenchymal transition (EMT) is a process for cancer cells to acquire the ability of invasion, metastasis and therapeutic resistance. The loss of E-cadherin, an epithelial marker, has been reported to be related with the reduced sensitivity to EGFR tyrosine kinase inhibitors. To investigate whether this phenomenon would exert a role in acquired resistance to gefitinib, we performed this study. The cell line resistant to gefitinib was created by exposing A549 cells to 10 μM gefitinib for 3 months, 20 μM gefitinib for another 3 months, and finally 30 μM for 6 more months. The daughter cells (A549/GR) were 5 to 10 times more resistant to gefitinib, CL-387, erlotinib, and ZD6474. Phenotypic changes such as spindle-cell shape, increase of intercellular separation and pseudopodia formation suggesting EMT were found on immunofluorescent staining. It was accompanied by the decrease of E-cadherin and increase of vimentin, a mesenchymal marker. Western blots revealed the amount of EGFR was decreased and, in consequence, the activation of Erk was reduced in A549/GR cells. Although EGFR expression was decreased, the level of p-Akt was increased more than parent cells. Moreover, the activated Akt was not reduced by the treatment of gefitinib. In the change of factors determining sensitivity to gefitinib, no EGFR mutations were detected by sequencing and EGFR gene copy number by FISH was not changed in A549/GR cells. In conclusion, chronic, repeated exposure to gefitinib leads to EMT, which may be one of possible mechanisms to acquire the gefitinib resistance during treatment.
Synaptic Transmission Optimization Predicts Expression Loci of Long-Term Plasticity
Authors: Rui Ponte Costa, Zahid Padamsey, James A. D’Amour, Nigel J. Emptage, Robert C. Froemke, Tim P. Vogels
Journal: Neuron (2017)

Long-term modifications of neuronal connections are critical for reliable memory storage in the brain. However, their locus of expression—pre- or postsynaptic—is highly variable. Here we introduce a theoretical framework in which long-term plasticity performs an optimization of the postsynaptic response statistics toward a given mean with minimal variance. Consequently, the state of the synapse at the time of plasticity induction determines the ratio of pre- and postsynaptic modifications. Our theory explains the experimentally observed expression loci of the hippocampal and neocortical synaptic potentiation studies we examined. Moreover, the theory predicts presynaptic expression of long-term depression, consistent with experimental observations. At inhibitory synapses, the theory suggests a statistically efficient excitatory-inhibitory balance in which changes in inhibitory postsynaptic response statistics specifically target the mean excitation. Our results provide a unifying theory for understanding the expression mechanisms and functions of long-term synaptic transmission plasticity.
Phase IB/II study of nivolumab with azacytidine (AZA) in patients (pts) with relapsed AML.
Authors: Naval Guastad Daver, Sreyashi Basu, Guillermo Garcia-Manero, Jorge E. Cortes, Farhad Ravandi, Elias Jabbour, Stephany Hendrickson, Mark Brandt, Sherry Pierce, Tauna Gordon, Naveen Pemmaraju, Michael Andreeff, Jing Ning, Steven Kornblau, Tapan M. Kadia, Courtney Denton Dinardo, Marina Konopleva, James Patrick Allison, Hagop M. Kantarjian, Padmanee Sharma
Journal: Journal of Clinical Oncology (2017)

7026 Background: Blocking PD-1/PD-L1 pathways enhances anti-leukemia responses in murine AML (Zhang et al, Blood 2009). PD-1 positive CD8 T-cells are increased in bone marrow (BM) of pts with AML (Daver et al, ASH 2016). AZA up-regulates PD-1 in AML (Yang et al., Leukemia 2013). Methods: Pts were eligible if they had AML and failed prior therapy, had adequate performance status (ECOG ≤ 2), and organ function. AZA 75mg/m 2 Days 1-7 with nivolumab 3mg/kg on Day 1 and 14 was established as the recommended phase II dose. Courses were repeated every 4-5 weeks indefinitely. Responses were evaluated at the end of 3 courses. Results: 53 pts with med age 68 years (range, 44 – 90), secondary AML (43%), poor risk cytogenetics (43%), med prior regimens 2 (range, 1-7) have been enrolled. Common mutations included DNMT3A (n = 11), TP53 (n = 11), TET2 (N = 8), CEBPA (n = 8), ASXL1(n = 8). All 53 pts are evaluable for response: 11 (21%) achieved CR/CRi and 7 (14%) had hematologic improvement (HI) for an overall response rate of 35%. Additionally, 14 (26%) had ≥50% BM blast reduction, 3 (6%) had stable disease &gt; 6 months, and 12 (23%) had progression. The CR/CRi have been durable with 9 of 11 (82%) pts with CR/CRi alive at 1 year, after censoring for SCT. Med survival for the 53 evaluable pts was 5.7 months (range, 0.9 – 16.2) and in the 27 salvage 1 pts was 9.3 months (range, 1.6 – 16.2). These compare favorably to historical survival with AZA-based salvage protocols at MDACC. Grade 3/4 and Grade 2 immune toxicities were observed in 7 (14%) and 6 (12%) pts, respectively. These responded rapidly to steroids and 12 of 13 pts were successfully rechallenged with nivolumab. Multicolor flow-cytometry data were available on pretherapy, end of cycle 1, and end of cycle 2 BM aspirates in 9 CR/CRi and 22 non-responders. Pts who achieved CR/CRi had higher pre-therapy total CD3 (P = 0.02) and higher CD8 + T-cells (P = 0.07) infiltrate in the BM. Responders demonstrated progressive increase in BM CD8 + and CD4 + infiltrate. Both responders and non-responders had increase in CTLA4 + CD8 + cells on therapy. Conclusions: Full dose AZA and nivolumab are tolerable and may produce durable responses in relapsed AML. Up-regulation of CTLA4 may be a mechanism of resistance to PD1 based therapies in AML. Clinical trial information: NCT02397720.