tbuckley/cabot-search huggingface dataset:
PTEN-deficient breast cancer in neoadjuvant treatment.
Authors: Juan de la Haba-Rodriguez, Cano M, Rangal Y, Morales Cristina, Fuentes E, Montero M, Porras I, Chia B, Rodriguez A, Enrique Aranda
Journal: Journal of Clinical Oncology (2013)

1125 Background: Loss of function mutations in the tumour suppressor gene PTEN or lack of PTEN expression have both been observed in a wide range of human tumours. PTEN encodes a phosphatase, whose activity antagonizes PI3 kinase signal pathway by dephosphorylation the plasma membrane lipid, phosphoinositide-3,4,5-trisphosphate (PIP3). Loss of PTEN phosphatase activity is thought to foster tumorigenesis, at least in part, by causing downstream constitutive activation of AKT. In addition to this role, PTEN has been suggested to have a nuclear function in maintaining genomic stability[2]. Our proposal is to identify those tumours without expression of PTEN, their characteristics and response to treatment. Methods: We have studied PTEN expression by immunohistochemistry in tumours samples from 86 patients treated with neoadjuvant treatment. Normal breast epithelium or vascular endothelium were used as positive control. PTEN was evaluated by inmunoreactive stain score, taking into account staining intensity and percentage of positive cells, PTEN deficiency (PTEN -) has been stablished by a IRS=0[1]. We analyzed the PTEN localization (nuclear vs citoplasmatic). Results: In our serie, 38 (44.2%) of the tumours samples were PTEN deficient. Taking into account as reference PTEN + tumours, we have found that PTEN deficient tumours are more frequently; ductal carcinoma (94.2% vs 81.8%), G3 (72% vs 48.7%), ER negative (47% vs 30.4%), Triple negative (24.2% vs 15%) and higher Ki67 expression (&gt;20%) in the 100% of PTEN deficient tumours. The pathological rate response was PTEN -:18.4% vs PTEN +:19.1% p:ns, and the recurrence rate was higher in PTEN- (26,3% vs 8,3%) p:0.025. Conclusions: The PTEN deficient breast tumours is associated to more histological aggressive profile, and we have not found relations with the pathological rate response to neoadjuvant treatment.
Conditionally active STAT1 and its functional role in tumor progression and invasion
Authors: Shanshan Liu, Jerome Jourquin, Yoonseok Kam, Vito Quaranta
Journal: Cancer Research (2006)

1825  The signal transducer and activator of transcription STAT1 is activated in breast carcinomas and a recent microarray study by our group suggested a potential involvement of STAT1 in the onset of bone marrow micrometastasis in breast cancer patients (1). We have now conducted the first functional experiments to unravel the precise role of STAT1 in breast cancer micrometastasis. It is known that increased gene expression of the latent cytoplasmic transcription factor STAT1 does not automatically lead to a transcriptional activation of target genes. STAT1 must be phosphorylated which triggers the dimerisation of STAT1 monomers and enables then the translocation of the homodimers into the nucleus to initiate DNA binding and gene expression. Therefore we used conditionally active STAT1 by fusing STAT1 with the ligand binding domain (LBD) of the oestrogen receptor (ER). The resulting STAT1-ERLBD chimeras were transfected into the oestrogen receptor- negative, low invasive mammary carcinoma cell line MDA-MB468. Western Blot analyses and immunocytochemical stainings with an ERLBD specific antibody confirmed the expression of the STAT1-ERLBD chimera. 10-5 to 10-8M oestrogen stimulation in the STAT1-ERLBD expressing MDA-MB468 cells as measured by luciferase reporter assays using the STAT1-inducible reporter GAS-luc resulted in a 5-8 fold activation of the reporter. Using this inducible system active STAT1 was associated with a reduced proliferation rate but had no influence on the invasive properties of the analysed breast cancer cells, as shown by in vitro invasion assays (Boyden Chamber assays). In conclusion, the established experimental model system allows the in-depth investigation of the role of STAT1 activation in breast cancer cells. STAT1 appears to be a negative regulator of cell proliferation and might therefore be a candidate for an inducer of tumor cell dormancy, a hallmark of micrometastatic cancer cells (2). References 1. Woelfle, U., Cloos, J., Sauter, G., Riethdorf, L., Janicke, F., van Diest, P., Brakenhoff, R., and Pantel, K. Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Res, 63: 5679-5684, 2003. 2. Pantel, K. and Brakenhoff, R. H. Dissecting the metastatic cascade. Nat Rev Cancer, 4: 448-456, 2004.
A novel mass spectrometry method to identify the serum monoclonal light chain component in systemic light chain amyloidosis
Authors: Faye A. Sharpley, Richa Manwani, Shameem Mahmood, Sajitha Sachchithanantham, Helen J. Lachmann, Julian D. Gillmore, Carol J. Whelan, Marianna Fontana, Philip N. Hawkins, Ashutosh D. Wechalekar
Journal: Blood Cancer Journal (2019)
Radiation-Sparing Treatment of HIV-Related Primary Central Nervous System Lymphoma with Antiretroviral Therapy, Rituximab and High-Dose Methotrexate
Authors: Kathryn Lurain, Thomas S. Uldrick, Priscila H. Goncalves, Ramya Ramaswami, Mark N. Polizzotto, Anaida Widell, Seth M. Steinberg, Elaine S. Jaffe, Stefania Pittaluga, Maryalice Stetler-Stevenson, Constance M. Yuan, Richard F. Little, Robert Yarchoan
Journal: Blood (2018)
Pulsed high-dose erlotinib with gemcitabine as second-line therapy for pancreatic adenocarcinoma.
Authors: Christopher Larson, Tony R. Reid
Journal: Journal of Clinical Oncology (2019)

421 Background: The options for treatment of pancreatic cancer follow progression on first line therapy are limited and associated with significant toxicity. Erlotinib has been approved for treatment of pancreatic cancer in first-line therapy. We conducted a phase I dose-escalation trial of erlotinib in combination with gemcitabine for patients that had failed first-line therapy. Erlotinib was administered by a novel pulse-dose schedule where the drug was given orally for 3 days every two weeks. Purpose: Assess the safety and determine a recommended phase II dose for pulsed high dose erlotinib in combination with gemcitabine for pancreatic cancer, and obtain preliminary data on activity. Methods: Patients with pancreatic cancer that progressed on or after first-line therapy were treated in a dose escalation study with erlotinib at 750 to 2,000 mg daily for three days every two weeks in combination with weekly gemcitabine at 1,000 mg/m2 for three weeks on and one week off. Results: No dose limiting toxicities were encountered and erlotinib-induced rash was mild and transient. Median overall survival was 6.7 months and 12-month overall survival was 27%. Progression free survival but not overall survival was longer in patients who did not previously receive gemcitabine. Rash was not associated with longer survival. Conclusions: The recommended phase II dose is erlotinib 2,000 mg daily for three consecutive days every two weeks in combination with gemcitabine. Tolerability was excellent, and outcomes were better than expected for second-line therapy in pancreatic cancer. Further studies are warranted, both as therapy after first-line and as first-line therapy for patients unable to tolerate more aggressive regimens. Clinical trial information: NCT02154737.
An introduction to chimeric antigen receptor (CAR) T‐cell immunotherapy for human cancer
Authors: Steven Feins, Weimin Kong, Erik F. Williams, Michael C. Milone, Joseph A. Fraietta
Journal: American Journal of Hematology (2019)

Chimeric antigen receptor (CAR) T-cell therapy represents a major advancement in personalized cancer treatment. In this strategy, a patient's own T cells are genetically engineered to express a synthetic receptor that binds a tumor antigen. CAR T cells are then expanded for clinical use and infused back into the patient's body to attack and destroy chemotherapy-resistant cancer. Dramatic clinical responses and high rates of complete remission have been observed in the setting of CAR T-cell therapy of B-cell malignancies. This resulted in two recent FDA approvals of CAR T cells directed against the CD19 protein for treatment of acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Thus, CAR T cells are arguably one of the first successful examples of synthetic biology and personalized cellular cancer therapy to become commercially available. In this review, we introduce the concept of using CAR T cells to break immunological tolerance to tumors, highlight several challenges in the field, discuss the utility of biomarkers in the context of predicting clinical responses, and offer prospects for developing next-generation CAR T cell-based approaches that will improve outcome.
Changes in alpha-fetoprotein (AFP) and systemic therapy outcomes in advanced hepatocellular carcinoma (HCC): A multicenter retrospective analysis.
Authors: Andrea Grace Bocobo, Paige M. Bracci, Anna Parks, Lindsay Marie Hannan, Kelly Bauer, Lipika Goyal, John Dozier Gordan, Alan P. Venook, William Proctor Harris, Robin Kate Kelley
Journal: Journal of Clinical Oncology (2019)

346 Background: AFP is elevated in 70% of HCC and is associated with poor prognosis. The role of AFP as a biomarker of response to systemic treatments has not been established, though small, retrospective studies show association between AFP decline and survival on sorafenib. The relationship between AFP changes and response to immune checkpoint inhibitors (CPI) has not been reported. This study examines AFP changes on treatment for association with outcomes on first-line (1L) SOR and any subsequent CPI in a contemporary, multicenter U.S. population. Methods: Design: Multicenter retrospective case series. Key eligibility: Received 1L SOR or SOR-based combination for advanced HCC; ≥ 1 post-treatment AFP value available; enrolled on IRB-approved registry. Objectives: associate AFP changes within 3 months of start of treatment with overall survival (OS) and time on treatment (TOT) on 1L SOR and any subsequent CPI; associate baseline AFP with OS and TOT for SOR and CPI; relate baseline AFP and changes on treatment to clinical covariates. Results: 152 patients were identified from two centers. Baseline characteristics: M/F 132/20; HBV/HCV/nonviral 40/71/41; Child Pugh A/B 128/23; BCLC A/B/C: 4/15/133. Baseline AFP &lt; 20/ ≥ 400: 43/59. 43 received CPI after SOR. See Table. Baseline AFP was not related to TOT or OS for SOR or CPI. Multivariable analyses for AFP with clinical covariates will be presented. Conclusions: This series is the largest multicenter analysis of AFP response to systemic therapy with SOR and CPI. AFP decrease and increase within the first 3 months of treatment with SOR and CPI were inversely and significantly associated with median OS. AFP warrants further study in randomized cohorts as a biomarker of response to systemic therapy in HCC, now with multiple treatment options available at progression.[Table: see text]
The Prognostic Significance of Minimal Residual Disease and Possibility of Its Correction in Multiple Myeloma
Authors: Andrey Garifullin, Sergei Voloshin, Alexey Kuvshinov, Anastasiya Kuzyaeva, Alexander Sсhmidt, Zhanna Chubukina, Vasily Shuvaev, Evgeniy Krasnikov, Sergey Linnikov
Journal: Blood (2018)
Addition of Melphalan to Fludarabine/Busulfan (FLU/BU4/MEL) Provides Survival Benefit for Patients with Myeloid Malignancy Following Allogeneic Bone Marrow Transplantation/Peripheral Blood Stem Cell Transplantation
Authors: Tomoaki Ueda, Tetsuo Maeda, Kentaro Fukushima, Jiro Fujita, Shinsuke Kusakabe, Takafumi Yokota, Hirohiko Shibayama, Yoshiaki Tomiyama, Yuzuru Kanakura
Journal: Blood (2018)
Abstract P2-01-20: LAP2alpha, a novel tumor marker candidate is related to metastasis of breast cancer
Authors: Y Hu, J Qiu, M Zhou, X Li, Y Huang
Journal: Cancer Research (2019)

Abstract Background: To date, there is no suitable serum marker for diagnosis and prognosis of breast cancer. In our early research, a new tumor marker candidate of breast cancer whose molecular weight was 5.6 kDa was screened from serum using mass spectrometry technology. It was decoded to be a fragment of isoform alpha of lamina-associated polypeptide 2 (LAP2α). The survival analysis revealed that LAP2α was over-expressed in breast cancer patients and indicated poor prognosis. Materials and Methods: Immunohistochemistry (IHC) was utilized to evaluate LAP2α expression in paired primary breast tumor, metastasis of axillary lymph node and ipsilateral normal breast tissue of 29 breast cancer patients. An inhibition plasmid vector of LAP2α-small hairpin RNA (LAP2α-shRNA) was constructed and transfected into MCF-7 cells. The abilities of cell proliferation and metastasis were assessed both in vitro and in vivo. The association of LAP2α with epithelial-to-mesenchymal transition (EMT) was determined by western blot. Results: LAP2α expression of paired tissue descended in order of metastasis of axillary lymph node (21/29, 72.4%), primary breast tumor (11/29, 37.9%) and ipsilateral normal breast tissue (4/29, 13.8%) (P&amp;lt;0.05 in comparisons between each two groups). CCK-8 experiments on transfected and control cells showed that inhibition of LAP2α could not influence cell proliferation. Transwell and matrigel-transwell assays indicated that inhibition of LAP2α could significantly reduce cell migration and invasion abilities. In vivo experiments utilizing subcutaneous xenograft model and tail vein-injection mouse model revealed that the down-regulation of LAP2α might suppress tumorigenesis and metastasis of breast cancer. Western blot suggested that down regulation of LAP2α increased the E-cadherin expression level but repressed N-cadherin and vimentin expression levels. Conclusions: A novel tumor marker candidate, LAP2α is related to metastasis of breast cancer both in clinical samples and tissue culture experiments. Inhibition of LAP2α could suppress aggressiveness and metastasis of breast cancer probably via EMT suppression. Funding: The Natural Science Foundation of Zhejiang Province of China (No. LY14H160030 and LY13H160011), the National Program on Key Basic Research Project of China (973 Program; No. 2014CB542003), the National Natural Science Foundation of China (No. 30801341) and Zheng Shu Elite Scholarship for Clinical Medicine. Citation Format: Hu Y, Qiu J, Zhou M, Li X, Huang Y. LAP2alpha, a novel tumor marker candidate is related to metastasis of breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-20.
Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects
Authors: Amy P. Hsu, Agnes Donkó, Megan E. Arrington, Muthulekha Swamydas, Danielle Fink, Arundhoti Das, Omar Escobedo, Vincent Bonagura, Paul Szabolcs, Harry N. Steinberg, Jenna Bergerson, Amanda Skoskiewicz, Melanie Makhija, Joie Davis, Ladan Foruraghi, Cindy Palmer, Ramsay L. Fuleihan, Joseph A. Church, Avinash Bhandoola, Michail S. Lionakis, Sharon Campbell, Thomas L. Leto, Douglas B. Kuhns, Steven M. Holland
Journal: Blood (2019)
Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma
Authors: Junfei Zhao, Andrew X. Chen, Robyn D. Gartrell, Andrew M. Silverman, Luis Aparicio, Tim Chu, Darius Bordbar, David Shan, Jorge Samanamud, Aayushi Mahajan, Ioan Filip, Rose Orenbuch, Morgan Goetz, Jonathan T. Yamaguchi, Michael Cloney, Craig Horbinski, Rimas V. Lukas, Jeffrey Raizer, Ali I. Rae, Jinzhou Yuan, Peter Canoll, Jeffrey N. Bruce, Yvonne M. Saenger, Peter Sims, Fabio M. Iwamoto, Adam M. Sonabend, Raul Rabadan
Journal: Nature Medicine (2019)
Successful Administration of Yellow Fever Vaccine in Egg-allergic Patients
Authors: Clarissa Morais Busatto Gerhardt, Gislane S. Juliao, Bruna Pultrini Aquilante, Cristiane N. Santos, Mayra de Barros Dorna, Antonio Carlos Pastorino, Ana Paula Moschione Castro
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract P030: A Weight Loss Intervention Using a Commercial Mobile Application in Latino Americans - Adelgaza Trial
Authors: Yoshimi Fukuoka, Eric Vittinghoff, Julie Hooper
Journal: Circulation (2018)

Background: Latinos have the highest prevalence of overweight or obesity (77.1%) when compared with other racial/ethnic groups in the United States. More than half of Latino adults living in the United States are expected to develop type 2-diabetes in their lifetime. Despite the growing interest in smartphone use for weight-loss and diabetes prevention, relatively few clinical trials have evaluated the efficacy of mobile app -based interventions in Latino populations. Purpose: To evaluate the potential efficacy of an in-person weight loss intervention in conjunction with a commercially available Fitbit app in a Latino sample at risk for type 2 diabetes and explore significant predictors associated with weight loss. Methods: After the run-in period, 54 self-identified Latinos with Body Mass Index (BMI) &gt; 24.9 kg/m 2 were enrolled in an 8-week uncontrolled pilot study, and received a Fitbit Zip, its app and two in-person weight loss sessions adapted from the Diabetes Prevention Program. Results: Mean age was 45.3 (SD ± 10.8) years, 61.1% were born in the U.S, and mean BMI was 31.4 (SD ± 4.1) kg/m 2 . Overall, participants lost an average of 3.3 (SD ± 3.4) % of their body weight (p &lt;.0005), corresponding to an average change of -2.4 kg (-5.3 lb) (p&lt;.0005), respectively. We also observed statistically significant reductions in hip and waist circumferences, and systolic and diastolic blood pressure (p &lt; 0.001). After controlling for demographic factors, use of the mobile app weight diary at least twice a week (p = 0.01) and change in the International Physical Activity Questionnaire score (P=0.033) were associated with change in percent body weight. Conclusions: The intervention showed the potential efficacy of this intervention, which should be formally evaluated in a randomized controlled trial.
Characterising variations in perceptual decision making
Authors: Johannes Schultz, René Hurlemann
Journal: Behavioral and Brain Sciences (2018)

Abstract Current perspectives propose that observer models accounting for both optimal and suboptimal behaviour may yield real progress in understanding perception. We propose that such models could, in addition, be very useful for precisely characterising the variation in perception across healthy participants and those affected by psychiatric disorders, as well as the effects of neuromodulators such as oxytocin.
Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting
Authors: Maarten van der Kroef, Monica Castellucci, Michal Mokry, Marta Cossu, Marianna Garonzi, Lara M Bossini-Castillo, Eleni Chouri, Catharina G K Wichers, Lorenzo Beretta, Elena Trombetta, Sandra Silva-Cardoso, Nadia Vazirpanah, Tiago Carvalheiro, Chiara Angiolilli, Cornelis P J Bekker, Alsya J Affandi, Kris A Reedquist, Femke Bonte-Mineur, Els J M Zirkzee, Flavia Bazzoni, Timothy R D J Radstake, Marzia Rossato
Journal: Annals of the Rheumatic Diseases (2019)

Background and objective Systemic sclerosis (SSc) is a severe autoimmune disease, in which the pathogenesis is dependent on both genetic and epigenetic factors. Altered gene expression in SSc monocytes, particularly of interferon (IFN)-responsive genes, suggests their involvement in SSc development. We investigated the correlation between epigenetic histone marks and gene expression in SSc monocytes. Methods Chromatin immunoprecipitation followed by sequencing (ChIPseq) for histone marks H3K4me3 and H3K27ac was performed on monocytes of nine healthy controls and 14 patients with SSc. RNA sequencing was performed in parallel to identify aberrantly expressed genes and their correlation with the levels of H3K4me3 and H3K27ac located nearby their transcription start sites. ChIP-qPCR assays were used to verify the role of bromodomain proteins, H3K27ac and STATs on IFN-responsive gene expression. Results 1046 and 534 genomic loci showed aberrant H3K4me3 and H3K27ac marks, respectively, in SSc monocytes. The expression of 381 genes was directly and significantly proportional to the levels of such chromatin marks present near their transcription start site. Genes correlated to altered histone marks were enriched for immune, IFN and antiviral pathways and presented with recurrent binding sites for IRF and STAT transcription factors at their promoters. IFNα induced the binding of STAT1 and STAT2 at the promoter of two of these genes, while blocking acetylation readers using the bromodomain BET family inhibitor JQ1 suppressed their expression. Conclusion SSc monocytes have altered chromatin marks correlating with their IFN signature. Enzymes modulating these reversible marks may provide interesting therapeutic targets to restore monocyte homeostasis to treat or even prevent SSc.
Reaction thresholds in in peanut-allergic adults and the influence of exercise and sleep deprivation: a randomised controlled trial
Authors: Shelley Dua, Monica Ruiz Garcia, Simon Bond, Stephen R. Durham, Ian Kimber, Clare Mills, Graham Roberts, Isabel J. Skypala, James Wason, Pamela W. Ewan, Robert J. Boyle, Andrew T. Clark
Journal: Journal of Allergy and Clinical Immunology (2019)
Disruption of Endolysosomal RAB5/7 Efficiently Eliminates Colorectal Cancer Stem Cells
Authors: Mitsunobu Takeda, Jun Koseki, Hidekazu Takahashi, Norikatsu Miyoshi, Naohiro Nishida, Junichi Nishimura, Taishi Hata, Chu Matsuda, Tsunekazu Mizushima, Hirofumi Yamamoto, Hideshi Ishii, Yuichiro Doki, Masaki Mori, Naotsugu Haraguchi
Journal: Cancer Research (2019)

Given that cancer stem cells (CSC) play a key role in drug resistance and relapse, targeting CSCs remains promising in cancer therapy. Here we show that RAB5/7, which are involved in the endolysosomal pathway, play key roles in the maintenance of CSC survival via regulation of the mitophagic pathway. Inhibition of RAB5/7 efficiently eliminated colorectal CSCs and disrupted cancer foci. In addition, we identified mefloquine hydrochloride, an antimalarial drug, as a novel RAB5/7 inhibitor and promising colorectal CSC-targeting drug. Endolysosomal RAB5/7 and LAMP1/2 mediated parkin-dependent mitochondrial clearance and modulated mitophagy through lysosomal dynamics. In a patient-derived xenograft (PDX) model of colon cancer, treatment with mefloquine resulted in suppression of mitophagic PINK1/PARKIN and increased mitochondrial disorder and mitochondria-induced apoptosis without apparent side effects. These results suggest that the combination of mefloquine with chemotherapeutic agents in the PDX model potentially disrupts the hierarchy of colorectal cancer cells and identify endolysosomal RAB5/7 and LAMP1/2 as promising therapeutic targets in CSCs. SIGNIFICANCE: These findings show that endosomal/lysosomal RAB5 and RAB7, which regulate mitophagy, are essential for the survival of colon cancer stem cells.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1426/F1.large.jpg.
Abstract 19074: Clinical Predictors of Short and Long Term Mortality in Patients With Heart Failure Preserved Ejection Fraction
Authors: Kalyani A Boralkar, Yukari Kobayashi, Mirela Tuzovic, Kegan J Moneghetti, Vedant S Pargaonkar, Nadia Ouazani, Bojan Vrtovec, Matthew Wheeler, Dipanjan Banerjee, Paul Heidenreich, Francois Haddad
Journal: Circulation (2016)

Introduction: A number of studies have reported predictors of adverse outcomes in patients with heart failure preserved ejection fraction (HFpEF), but few studies have reported long term outcomes a...