tbuckley/cabot-search huggingface dataset:
High-dose combination alkylating agents with bone marrow support as initial treatment for metastatic breast cancer.
Authors: W P Peters, E J Shpall, R B Jones, G A Olsen, R C Bast, J P Gockerman, J O Moore
Journal: Journal of Clinical Oncology (1988)

To evaluate the effect of high-dose chemotherapy in the treatment of metastatic breast cancer, we performed a phase II trial of a single treatment with high-dose cyclophosphamide (5,625 mg/m2), cisplatin (165 mg/m2), and carmustine (600 mg/m2), or melphalan (40 mg/m2) and bone marrow support as the initial chemotherapy for metastatic breast cancer. Twenty-two premenopausal patients with estrogen receptor negative, measurable metastatic disease were treated. Twelve of 22 patients (54%) obtained a complete response at a median 18 days. The overall response rate is 73% (complete and partial response). Median duration of response in the patients achieving complete response was 9.0 months with a median duration of survival for complete responders that is currently undefined. Relapse occurred predominantly at sites of pretreatment bulk disease or within areas of previous radiation therapy. Toxicity was frequent and five patients died of therapy-related complications. The results indicate that a single treatment with intensive combination alkylating agents with bone marrow support can produce more rapid and frequent complete responses than conventional chemotherapy when used as initial chemotherapy for metastatic breast cancer, although median disease-free and overall survival is not improved. Three patients (14%) remain in unmaintained remission beyond 16 months.
P1177 : Risk factors for hepatic decompensation in primary biliary cirrhosis - results of an international follow up study of 2326 patients
Authors: M.H. Harms, W.J. Lammers, P. Invernizzi, P.M. Battezzati, A. Floreani, A. Pares, F. Nevens, D. Thorburn, A.L. Mason, K.V. Kowdley, C. Ponsioen, C. Corpechot, H.L. Janssen, G.M. Hirschfield, M. Mayo, N.F. LaRusso, A. Lleo, N. Cazzagon, I. Franceschet, L. Caballeria, R. Poupon, A. Cheung, P. Trivedi, K. Lindor, H.R. van Buuren, B.E. Hansen
Journal: Journal of Hepatology (2015)
Preclinical rationale for therapeutic targeting of mTOR by CC-I779 and rapamycin in Hodgkin lymphoma
Authors: G. V. Georgakis, V. Y. Yazbeck, Y. Li, A. Younes
Journal: Journal of Clinical Oncology (2006)

10070 Background: Although conventional chemotherapy has been the golden standard for the treatment of Hodgkin Lymphoma (HL), significant long-term toxicities necessitate the need for development of targeted therapy that is potentially less toxic to normal cells. We and others have recently reported that the PI3K/AKT pathway is aberrantly activated in primary and cultured HL cells, and its inhibition induces apoptosis and cell cycle arrest. Because only mTOR inhibitors are currently being evaluated in clinical trials, we examined the biologic and molecular activity of two mTOR inhibitors CCI-779 and rapamycin in HL cell lines, and determined the molecular mechanisms of their activity. Methods: Three HL-derived cell lines were used (HD-LM2, L-428, and KM-H2). Cell viability was determined by the MTS assay. Cell cycle arrest was determined by propidium iodide staining and FACS analysis. Autophagy was determined by staining of intracellular organelles with Acridine Orange and FACS analysis. Molecular changes were determined by western blot. Results: The antiproliferative effect of CCI-779 and rapamycin in all HL cell lines was evident as early as 24 hour and was time- and dose-dependent. CCI-779 induced cell cycle arrest in all cell lines at the G0/G1 phase. CCI-779 and rapamycin were equally effective in HL cell lines. Cell cycle arrest was not followed by apoptosis but rather by autophagy, as evident by the increase of acidic autophagic intracellular organelles. On the molecular level, mTOR inhibition by CCI-779 dephosphorylated the downstream ribosomal S6 in all HL cell lines, but had no significant effect on AKT or phospho AKT. Cell cycle arrest was attributed to the upregulation of p27, but cyclin D1 remained unchanged. CCI-779 also enhanced the antiproliferative effect of the PI3K inhibitor LY294002, but did not change the effect of doxorubicin chemotherapy. Conclusions: Inhibition of mTOR by CCI-779 or rapamycin in HL cell lines has antiproliferative effect, by inducing cell cycle arrest followed by autophagy. CCI-779 enhances the activity of PI3K inhibitor LY294002. These data suggest that CCI-779 may have a therapeutic value in patients with HL. No significant financial relationships to disclose.
Frontotemporal dementia: insights into the biological underpinnings of disease through gene co-expression network analysis
Authors: Raffaele Ferrari, Paola Forabosco, Jana Vandrovcova, Juan A. Botía, Sebastian Guelfi, Jason D. Warren, Parastoo Momeni, Michael E. Weale, Mina Ryten, John Hardy
Journal: Molecular Neurodegeneration (2016)

In frontotemporal dementia (FTD) there is a critical lack in the understanding of biological and molecular mechanisms involved in disease pathogenesis. The heterogeneous genetic features associated with FTD suggest that multiple disease-mechanisms are likely to contribute to the development of this neurodegenerative condition. We here present a systems biology approach with the scope of i) shedding light on the biological processes potentially implicated in the pathogenesis of FTD and ii) identifying novel potential risk factors for FTD. We performed a gene co-expression network analysis of microarray expression data from 101 individuals without neurodegenerative diseases to explore regional-specific co-expression patterns in the frontal and temporal cortices for 12 genes (MAPT, GRN, CHMP2B, CTSC, HLA-DRA, TMEM106B, C9orf72, VCP, UBQLN2, OPTN, TARDBP and FUS) associated with FTD and we then carried out gene set enrichment and pathway analyses, and investigated known protein-protein interactors (PPIs) of FTD-genes products. Gene co-expression networks revealed that several FTD-genes (such as MAPT and GRN, CTSC and HLA-DRA, TMEM106B, and C9orf72, VCP, UBQLN2 and OPTN) were clustering in modules of relevance in the frontal and temporal cortices. Functional annotation and pathway analyses of such modules indicated enrichment for: i) DNA metabolism, i.e. transcription regulation, DNA protection and chromatin remodelling (MAPT and GRN modules); ii) immune and lysosomal processes (CTSC and HLA-DRA modules), and; iii) protein meta/catabolism (C9orf72, VCP, UBQLN2 and OPTN, and TMEM106B modules). PPI analysis supported the results of the functional annotation and pathway analyses. This work further characterizes known FTD-genes and elaborates on their biological relevance to disease: not only do we indicate likely impacted regional-specific biological processes driven by FTD-genes containing modules, but also do we suggest novel potential risk factors among the FTD-genes interactors as targets for further mechanistic characterization in hypothesis driven cell biology work.
Her2-targeted pegylated stealth liposomal doxorubicin (PLD) retains its specific targeting ability to Her2-expressing tumor cells after in vivo circulation and extravasation to mouse malignant ascites
Authors: H. Shmeeda, D. Tzemach, L. Mac, A. Najafi, K. Hjortsvang, A. Gabizon
Journal: Journal of Clinical Oncology (2006)

13097 Background: Receptor-directed targeting of ligand-bearing liposomes to tumor cells may enhance therapeutic efficacy by intracellular delivery of a concentrated payload of liposomal drug. The goal of this study was to assess whether Her2-targeted PLD retains its binding ability to Her2-expressing target cells through circulation in the blood and extravasation to the ascitic fluid of mice with malignant ascites. Methods: PLD was grafted with a pegylated lipophilic conjugate of an anti-Her2 scFv antibody fragment (F5) at a ratio of 15 ligands per liposome. BALB/c mice were injected with J6456 lymphoma cells into the peritoneal cavity to generate malignant ascites. When abdominal swelling developed, Her2-targeted PLD and nontargeted PLD were injected into the mice i.v. at a dose of 15 mg/kg. The ascitic fluid was collected 48 hr later, ascitic tumor cells were removed, and the doxorubicin levels in the cell-free ascitic fluid and plasma were determined. Binding of the liposome-containing ascitic fluid was tested in vitro against Her2-expressing human tumor cell lines (N87, SKBR-3) and compared to the binding of shelf formulations (not passaged in vivo) of Her2-PLD and PLD, using as parameter the amount of cell-associated doxorubicin. Results: Plasma and ascitic fluid levels of Her2-PLD were only slightly below those of PLD indicating that the Her2 ligand did not cause any significant change in the clearance rate of PLD. Her2-PLD and PLD bound to an equal extent to J6456 cells in vivo. The in vitro binding of Her2-PLD from ascites to Her2- expressing cells was increased 10 to 20-fold above that of PLD from ascites, similarly to the 20-fold difference in binding between shelf Her2-PLD and PLD. Conclusions: Her2-targeted PLD demonstrates similar circulation time to that of nontargeted PLD. After in vivo passage, the targeted liposome retains most of its original binding capacity to Her2 expressing cells indicating that the ligand is stably maintained in association with the doxorubicin liposomal carrier. Targeting of PLD using this Her2 antibody fragment should provide an important means of selective drug delivery to tumors expressing the Her2 receptor. [Table: see text]
Tidal breathing flow-volume curves with impedance pneumography during expiratory loading
Authors: Ville-Pekka Seppä, Marko Uitto, Jari Viik
Journal: European Respiratory Journal (2013)

Introduction: Diagnosis of asthma in the preschool children is difficult due to the lack of objective lung function tests suitable for this age group. Impedance pneumography (IP) is a mode of measurement that could enable ambulatory 24h recording of tidal flow indices. IP can provide accurate flow signal in freely breathing subjects (Seppa et al. Eur Respir J. 2011;38(55 Suppl):219s), but tidal breathing flow-volume curves (TBFVC) or difficult respiratory conditions have not been demonstrated.  Objectives: To induce changes in breathing control and mechanics and study the ability of IP to reproduce the TBFVC and track its changes under difficult conditions.  Methods: TBFVCs were obtained from 17 lung-healthy subjects simultaneously with a direct mouth pneumotachograph (PNT) and IP during free breathing and expiratory loading (15 cmH20.l/s). The TBFVC were normalized in flow and volume and the largest distance between the PNT and IP curves was found for each subject as d max .  Results: The agreement of PNT and IP normalized TBFVCs was found excellent having d max  of 7.2 %±3.1 % and 7.3%±4.2 % during free and loaded breathing, respectively. Intense expiratory loading did not degrade the agreement.  Conclusion: We conclude that by using correct electrode placement and proper cardiac filtering, IP was able to accurately reproduce and track changes in normalized TBFVCs under free and loaded respiration in healthy subjects.
Variability in mortality following caesarean delivery, appendectomy, and groin hernia repair in low-income and middle-income countries: a systematic review and analysis of published data
Authors: Tarsicio Uribe-Leitz, Joshua Jaramillo, Lydia Maurer, Rui Fu, Micaela M Esquivel, Atul A Gawande, Alex B Haynes, Thomas G Weiser
Journal: The Lancet Global Health (2016)

Surgical interventions occur at lower rates in resource-poor settings, and complication and death rates following surgery are probably substantial but have not been well quantified. A deeper understanding of outcomes is a crucial step to ensure that high quality accompanies increased global access to surgical care. We aimed to assess surgical mortality following three common surgical procedures--caesarean delivery, appendectomy, and groin (inguinal and femoral) hernia repair--to quantify the potential risks of expanding access without simultaneously addressing issues of quality and safety.We collected demographic, health, and economic data for 113 countries classified as low income or lower-middle income by the World Bank in 2005. We did a systematic review of Ovid, MEDLINE, PubMed, and Scopus from Jan 1, 2000, to Jan 15, 2015, to identify studies in these countries reporting all-cause mortality following the three commonly undertaken operations. Reports from governmental and other agencies were also identified and included. We modelled surgical mortality rates for countries without reported data using a two-step multiple imputation method. We first used a fully conditional specification (FCS) multiple imputation method to establish complete datasets for all missing variables that we considered potentially predictive of surgical mortality. We then used regression-based predictive mean matching imputation methods, specified within the multiple imputation FCS method, for selected predictors for each operation using the completed dataset to predict mortality rates along with confidence intervals for countries without reported mortality data. To account for variability in data availability, we aggregated results by subregion and estimated surgical mortality rates.From an initial 1302 articles and reports identified, 247 full-text articles met our inclusion criteria, and 124 provided data for surgical mortality for at least one of the three selected operations. We identified 42 countries with mortality data for at least one of the three procedures. Median reported mortality was 7·9 per 1000 operations for caesarean delivery (IQR 2·8-19·9), 2·2 per 1000 operations for appendectomy (0·0-17·2), and 4·9 per 1000 operations for groin hernia (0·0-11·7). Perioperative mortality estimates by subregion ranged from 2·8 (South Asia) to 50·2 (East Asia) per 1000 caesarean deliveries, 2·4 (South Asia) to 54·0 (Central sub-Saharan Africa) per 1000 appendectomies, and 0·3 (Andean Latin America) to 25·5 (Southern sub-Saharan Africa) per 1000 hernia repairs.All-cause postoperative mortality rates are exceedingly variable within resource-constrained environments. Efforts to expand surgical access and provision of services must include a strong commitment to improve the safety and quality of care.None.
Correlation between docetaxel-induced skin toxicity and the use of steroids and H<sub>2</sub> blockers: A multi-institution survey
Authors: K. Kawaguchi, H. Ishiguro, S. Morita, S. Nakamura, S. Ohno, N. Masuda, H. Iwata, K. Aogi, K. Kuroi, M. Toi
Journal: Journal of Clinical Oncology (2009)

9536 Background: Docetaxel is a standard drug used for adjuvant or neoadjuvant chemotherapeutic treatment of early breast cancer. With appropriate management of chemotherapy-induced bone marrow toxicity, skin toxicities such as hand-foot syndrome (HFS) and facial erythema (FE) have become dose-limiting. Steroids and H 2 blockers are commonly used to provide supportive care to patients being treated with taxane-containing chemotherapeutic regimens, but their effects on skin toxicity are poorly understood. Methods: We asked institutions belonging to the JBCRG to complete a questionnaire regarding the occurrence of grade 2 or higher HFS and FE among patients treated with docetaxel as an adjuvant or neoadjuvant chemotherapeutic treatment for breast cancer between April 2007 and March 2008. Data collected were docetaxel dose, other chemotherapeutic agents administered, dosage regimens for the steroids and H 2 blockers (if used), and incidences of grade 2 or higher HFS or FE. Statistical analyses were performed using the chi-squared test. Results: We obtained data for 989 patients from 22 institutions. Most patients received docetaxel at a dose of 75 mg/m 2 and 852 patients were treated with docetaxel monotherapy. HFS and FE occurred in 18% and 13% of patients, respectively. The relationships between the incidence of skin toxicity and (i) chemotherapy regimen and (ii) use of H 2 blockers are shown below ( Table ). Conclusions: Our data suggest that use of H 2 blockers as premedication in breast cancer patients treated with docetaxel significantly increases the risk of both HFS and FE. [Table: see text] [Table: see text]
Different expression of somatostatin receptor subtypes in human prostate cancer
Authors: A. Gernone, S. Trabucco, V. Pagliarulo, G. Troccoli
Journal: Journal of Clinical Oncology (2008)

16148 Background: Neuroendocrine (NE) differentiation of prostate carcinoma correlates with poor prognosis and tumor progression. The aim of our study was to evaluate the expression of somatostatin receptor (SSTR) 1, 2, 3, 4, 5 subtypes by immunohistochemistry in primary tumors with NE pattern. Patients and Methods: Prostate cancer tissues were obtained from 24 pts who had undergone biopsy or radical prostatectomy for previously untreated advanced or metastatic prostate cancer. All samples expressed chromogranin A (CgA), a marker of NE differentiation. The median age was 68 years (range 45–83), median baseline PSA: 70 ng/ml (range 0.3–200), median ECOG Performance Status: 1 (range 0–2), Gleason score ≥ 7. Serum levels of CgA were increased in 18 pts (75%) and normal in 6 pts (25%). Results: Immunohistochemical analysis demonstrated the presence of SSTR1 in 4 samples, SSTR 5 in 2 samples, both SSTR1 and SSTR5 were found in 6 samples. SSTR 1–5 were undetectable in 12 pts with more aggressive clinical course. Receptor subtypes 2, 3 an 4 were not detected in all samples. Conclusions: The present study demonstrates the presence of SSTR 1 and 5 in 12/24 pts with NE prostate cancer, whereas SSTR 2, 3, 4 were not detectable. The absence of SSTR 1 and 5 could represent a growth advantage in NE prostate cancer. SSTRs and somatostatin analogs are potential targets for prostate cancer treatment. No significant financial relationships to disclose.
Myeloid-Derived Suppressor Cells Express Bruton's Tyrosine Kinase and Can Be Depleted in Tumor-Bearing Hosts by Ibrutinib Treatment
Authors: Andrew Stiff, Prashant Trikha, Robert Wesolowski, Kari Kendra, Vincent Hsu, Sarvani Uppati, Elizabeth McMichael, Megan Duggan, Amanda Campbell, Karen Keller, Ian Landi, Yiming Zhong, Jason Dubovsky, John Harrison Howard, Lianbo Yu, Bonnie Harrington, Matthew Old, Sean Reiff, Thomas Mace, Susheela Tridandapani, Natarajan Muthusamy, Michael A. Caligiuri, John C. Byrd, William E. Carson
Journal: Cancer Research (2016)

Abstract Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immature myeloid cells that expand in tumor-bearing hosts in response to soluble factors produced by tumor and stromal cells. MDSC expansion has been linked to loss of immune effector cell function and reduced efficacy of immune-based cancer therapies, highlighting the MDSC population as an attractive therapeutic target. Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL2-inducible T-cell kinase (ITK), is in clinical use for the treatment of B-cell malignancies. Here, we report that BTK is expressed by murine and human MDSCs, and that ibrutinib is able to inhibit BTK phosphorylation in these cells. Treatment of MDSCs with ibrutinib significantly impaired nitric oxide production and cell migration. In addition, ibrutinib inhibited in vitro generation of human MDSCs and reduced mRNA expression of indolamine 2,3-dioxygenase, an immunosuppressive factor. Treatment of mice bearing EMT6 mammary tumors with ibrutinib resulted in reduced frequency of MDSCs in both the spleen and tumor. Ibrutinib treatment also resulted in a significant reduction of MDSCs in wild-type mice bearing B16F10 melanoma tumors, but not in X-linked immunodeficiency mice (XID) harboring a BTK mutation, suggesting that BTK inhibition plays an important role in the observed reduction of MDSCs in vivo. Finally, ibrutinib significantly enhanced the efficacy of anti-PD-L1 (CD274) therapy in a murine breast cancer model. Together, these results demonstrate that ibrutinib modulates MDSC function and generation, revealing a potential strategy for enhancing immune-based therapies in solid malignancies. Cancer Res; 76(8); 2125–36. ©2016 AACR.
Abstract 244: Cytoprotective Effect of Growth Hormone Releasing Hormone Agonist in Cardiac Stem Cells
Authors: Victoria Florea, Sonia S Majid, Rosemeire M Kanashiro-Takeuchi, Norman L Block, Andrew V Schally, Joshua M Hare, Claudia O Rodrigues
Journal: Circulation Research (2014)

Background: Our group has previously shown that growth hormone releasing hormone receptor agonists (GHRHR-A) improve cardiac performance in heart failure models and reverse remodeling. This effect was associated with an increase in the number of c-kit+ cardiac stem cells (CSCs), suggesting that this agonist might have an effect on these cells. Methods and Results: We investigated the expression of GHRH receptor (GHRHR) in CSCs of different species by flow cytometry analysis. GHRH-R is expressed in 96-98% of CSCs isolated from mouse, rat and porcine. Results were compared to GHRHR expression in HeLa and MCF7, and T47D cell lines, positive and negative controls, respectively. To determine if GHRHR activation can improve CSCs self-renewal, we tested the effect of agonists on porcine CSCs proliferation. The rate of cell division was increased 2-fold with JI38 (GHRHR-A) treatment (3.4 ± 0.7) vs. vehicle control (1.7 ± 0.2) (p&lt;0.05). Pre-treatment of CSCs with the GHRHR antagonist MIA-602, showed a trend toward reversal of the JI38 agonistic effect on proliferation rate (2.2 ± 0.6). These studies were further extended to other GHRHR agonists. In addition to JI38, MR356 and MR409, both of which showed significant increase in CSCs proliferation relative to vehicle control, by 20 ± 5.7%, 37 ± 8.5% and 36 ± 12.2%, respectively (p&lt;0.05). The protective effect of JI38 on porcine CSCs survival was determined under oxidative stress generated by hydrogen peroxide exposure. Pre-treatment of CSCs with JI38 prior to peroxide exposure significantly reduced cell death by 33 ± 2.2% (p&lt;0.02). Similar effects were observed for MR356, which decreased cell death by 12 ± 8.6% (p&lt;0.03). Furthermore, we found that the effect of GHRHR-A on CSCs proliferation was completely reversed by inhibitors of the ERK, PI3K and Akt pathways (p&lt;0.05). Conclusion: These findings confirm for the first time the expression of GHRHR in CSCs. GHRHR-A promotes CSCs proliferation and enhance survival. GHRHR-A effects on CSCs proliferation are mediated through activation of ERK, PI3K and AKT pathways. Accordingly, activation of GHRHR signaling pathways represents a novel therapeutic approach to protect and stimulate endogenous CSC population, promoting cardiac repair.