tbuckley/cabot-search huggingface dataset:
Abstract 5050: The significance of the expression of E-cadherin and CD44 in patients with unresectable metastatic colorectal cancer
Authors: Yasuhito Iseki, Masatsune Shibutani, Kiyoshi Maeda, Hisashi Nagahara, Tatsuro Tamura, Go Ohira, Sadaaki Yamazoe, Katsunobu Sakurai, Kenjiro Kimura, Takahiro Toyokawa, Ryosuke Amano, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira, Kosei Hirakawa
Journal: Cancer Research (2016)

Abstract The loss of the adhesion molecules is reported to correlate with tumor invasion and metastasis in patients with various cancers. E-cadherin is an important molecule for cell-to-cell adhesion. While, CD44 is important for cell-to-extra cellular matrix adhesion. The aim of the present study is to evaluate the significance of the expression of E-cadherin and CD44 in patients with the unresectable metastatic colorectal cancer who are undergoing palliative chemotherapy. Formalin-fixed, paraffin-embedded samples were obtained from 49 patients who underwent primary tumor resection and who were receiving palliative chemotherapy for unresectable metastatic colorectal cancer. We evaluated the expression of E-cadherin and CD44 by immunohistochemistry. The expression of E-cadherin was not significantly associated with progression-free survival (PFS) or overall survival (OS). Although, the expression of CD44 did not correlate with PFS, it tended to correlate with the OS (p = 0.0699). According to the combination of CD44 and E-cadherin, both low expression group showed a significant poor PFS (p = 0.0101) and OS (p = 0.0009). Objective response rate and disease control rate were significantly decreased in both low expression group (p = 0.0076 and p = 0.0294, respectively). A univariate analysis to determine the variables that were associated with PFS indicated that the both low expression of E-cadherin and CD44 (p = 0.0474) and gender (p = 0.0330) were significantly associated with decreased survival. A multivariate analysis showed that the both low expression of E-cadherin and CD44 was an independent risk factor for decreased PFS (hazard ratio [HR]: 8.276, 95% confidence interval [CI]: 1.383-43.311; p = 0.0227). According to OS, the both low expression of E-cadherin and CD44 expression was revealed a prognostic factor by univariate and multivariate analysis(HR:15.118, 95%CI: 2.645-77.490; p = 0.0039). This study suggested that the combined low expression of both E-cadherin and CD44 was a strong independent predictor of decreased chemotherapeutic outcome and survival in patients with unresectable metastatic colorectal cancer. Citation Format: Yasuhito Iseki, Masatsune Shibutani, Kiyoshi Maeda, Hisashi Nagahara, Tatsuro Tamura, Go Ohira, Sadaaki Yamazoe, Katsunobu Sakurai, Kenjiro Kimura, Takahiro Toyokawa, Ryosuke Amano, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira, Kosei Hirakawa. The significance of the expression of E-cadherin and CD44 in patients with unresectable metastatic colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5050.
Polycythemia vera. II. Hypersensitivity of bone marrow erythroid, granulocyte-macrophage, and megakaryocyte progenitor cells to interleukin-3 and granulocyte-macrophage colony-stimulating factor
Authors: CH Dai, SB Krantz, EN Dessypris, RT Jr Means, ST Horn, HS Gilbert
Journal: Blood (1992)
Ammonium Production and Glutamine-Addiction of Myeloma Cells: New Attractive Targets in Multiple Myeloma
Authors: Fabrizio Accardi, Martina Chiu, Marina Bolzoni, Paola Storti, Katia Todoerti, Luca Agnelli, Massimiliano Ferrari, Gabriele Missale, Franco Aversa, Ovidio Bussolati, Nicola Giuliani
Journal: Blood (2014)
A 71-Year-Old Man With Complicated Myocardial Infarction
Authors: Vinod Namana, Ram Balasubramanian, Gerald Hollander
Journal: JAMA Cardiology (2016)

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Preliminary results from a phase II study of ARQ 197 in patients with microphthalmia transcription factor family (MiT)-associated tumors
Authors: J. Goldberg, G. D. Demetri, E. Choy, L. Rosen, A. Pappo, S. Dubois, J. Geller, F. Chai, D. Ferrari, A. J. Wagner
Journal: Journal of Clinical Oncology (2009)

10502 Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. The drug has demonstrated a favorable safety profile and preliminary anti-cancer activity in three phase 1 studies. MiT tumors include clear cell sarcoma (CCS), alveolar soft part sarcoma (ASPS), and translocation-associated renal cell carcinoma (TLA RCC) and are linked biologically by a shared activated transcriptional mechanism which directly upregulates c-Met. Tumors with this type of chromosomal abnormality are generally resistant to all approved therapies and, in the absence of complete surgical resection, prove invariably fatal. Methods: This is a multi-center, single arm, two-stage phase 2 trial in patients (pts) 13 years of age or older with MiT tumors. Initially pts received 120 mg ARQ 197 orally twice daily (bid). The protocol was amended in August 2008 to increase the dose to 360 mg bid. If either a complete response (CR) or a partial response (PR) were to be observed in the 23 pts in stage 1, the study would be advanced to stage 2 where 16 additional patients will be enrolled. Tumor responses are measured in 8-week intervals per RECIST criteria. Results: To date, 28 pts (19 females, 9 males; median age = 21; 7 CCS, 17 ASPS, 4 RCC) have been treated. One pt with CCS demonstrated a confirmed PR, 15 pts (10 ASPS, 2 CCS, 3 RCC) demonstrated stable disease (SD) for durations up to 29+ weeks, and 4 pts progressed. An overall response rate of 5% and a disease control rate (CR+PR+SD) of 80% were demonstrated among 20 pts who were evaluable for efficacy. The most common drug-related adverse events (AEs) have been fatigue (35.7%), nausea (35.7%), vomiting (21.4%), decreased hemoglobin (10.7%). and cough (10.7%). To date, only 3 drug-related Grade 3 or 4 AEs have been reported including anemia (2) and decreased neutrophil count (1). No drug-related serious AEs or deaths have been reported. Conclusions: To date, ARQ 197 has demonstrated an extremely favorable safety profile and preliminary evidence of anti-cancer activity in these young pts. The criterion for advancing the study from stage 1 to stage 2 has been met. Stage 2 enrollment is ongoing. Updated data on both dose levels will be presented. [Table: see text]
Abstract 4475: SMYD2 inhibitor BAY-598 reveals the giant scaffold AHNAK as a novel multi-methylated substrate
Authors: Erik Eggert, Timo Stellfeld, Daniel Korr, Carlo Stresemann
Journal: Cancer Research (2016)

Abstract The SET and MYND domain-containing protein 2 (SMYD2) has been reported to mono-methylate several lysine residues on histone and non-histone proteins. Overexpression of SMYD2 has been reported in cancer cell lines as well as in esophageal squamous cell carcinoma (ESCC), bladder carcinoma, gastric cancer and pediatric acute lymphoblastic leukemia patients and correlates with lower survival rates. Although several studies uncovered important roles of SMYD2 in promoting tumorgenesis by protein methylation of key proteins (e.g. p53, PTEN, Rb, PARP), the biology of SMYD2 and its possible role in cancer biology is still far from being fully understood. Therefore, we employed the SMYD2 inhibitor BAY-598 (AACR-2015 abstract 2829, publication in preparation), and used proteomics to find novel substrates of SMYD2 in cancer cells. We confirmed with both BAY-598 and by knockdown experiments that the giant scaffold protein AHNAK is a novel major substrate of SMYD2. Different studies have tried to decipher the function of AHNAK in normal and diseased tissues. AHNAK forms multi-protein complexes acting as a structural scaffold involved in different processes, including calcium channel regulation, cell contact signaling, migration, and tumor metastasis. Interestingly, we found AHNAK to be mono-methylated by SMYD2 on multiple sites in its central repeated domain as well as on its C-terminal domain. BAY-598 potently inhibited methylation at these sites on AHNAK. To further determine the prevalence of AHNAK methylation, we analyzed different cancer cell lines and tissues from mice. AHNAK methylation correlated with SMYD2 expression, but not with AHNAK expression, suggesting tissue-specific regulation of AHNAK methylation by SMYD2. In summary, the novel finding of AHNAK regulation by methylation further complements the understanding of the roles of SMYD2 in cancer biology and underlines the utility of using probe inhibitors like BAY-598 to explore potential therapeutic targets in cancer. Citation Format: Erik Eggert, Timo Stellfeld, Daniel Korr, Carlo Stresemann. SMYD2 inhibitor BAY-598 reveals the giant scaffold AHNAK as a novel multi-methylated substrate. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4475.
Abstract LB-270: Inhibition of the stromal p38MAPK pathway abrogates breast cancer metastases
Authors: Sheila A. Stewart, Bhavna Murali, Xinming Su, Kevin Flanagan, Jasmin Sponagel, Xianmin Luo, Yujie Fu, Elise Alspach, Kathleen Leahy, Joseph Monahan, Katherine Weilbeacher
Journal: Cancer Research (2016)

Abstract Bone metastasis is a devastating and fatal complication of breast cancer for which we lack effective therapies. Thus, identifying therapies that effectively limit metastases will significantly reduce comorbidities and improve long-term survival. Recently we demonstrated that the p38MAPK pathway sustains the pro-tumorigenic senescence-associated secretory phenotype (SASP) and targeting this pathway limits the tumor-promoting capabilities of senescent cells and cancer-associated fibroblasts (CAFs). Because we found that a significant percentage of p38MAPK-dependent SASP factors are expressed in the stroma associated with breast cancer lesions, we asked whether targeting p38MAPK could limit primary and metastatic breast cancer growth. While p38MAPK inhibition modestly limited primary tumor growth, we found that this inhibition significantly reduced breast cancer bone metastases by targeting the stromal compartment. Further, p38MAPK inhibition was as effective as paclitaxel at limiting tumor growth in the bone but in contrast to paclitaxel, which failed to protect from cancer-induced bone loss, p38MAPK inhibition also protected against devastating bone loss. This contrasts our p38MAPK approach from zoledronic acid, which limits bone loss but fails to slow tumor growth in already engrafted tumors. Analysis of the mechanism(s) responsible for this reduced metastasis suggests that p38MAPK inhibition specifically targets reactive and/or senescent osteoblasts within the bones of animals harboring metastatic lesions. Because we find that senescent osteoblasts are present in human bone, we postulate that they promote metastatic outgrowth and thus p38MAPK inhibition limits the pro-metastatic activities of these cells. Finally, we will present recent data from our clinically relevant preclinical model that demonstrates that inhibition of the p38MAPK pathway can drastically reduce metastasis from the primary site. We propose that p38MAPK is an important stromal-specific therapy for breast cancer metastasis to the bone. Citation Format: Sheila A. Stewart, Bhavna Murali, Xinming Su, Kevin Flanagan, Jasmin Sponagel, Xianmin Luo, Yujie Fu, Elise Alspach, Kathleen Leahy, Joseph Monahan, Katherine Weilbeacher. Inhibition of the stromal p38MAPK pathway abrogates breast cancer metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-270.
Abstract 4419: Exploration of alternative pathways mediated by IFNL4 and related to cell proliferation and death in a hepatoma cell line
Authors: Fang Wang, Olusegun O. Onabajo, Nina Rao, Ludmila Prokunina-Olsson
Journal: Cancer Research (2016)

Abstract The ability to generate interferon lambda 4 (IFNL4), the most recently discovered member of the type-III interferon family, has been associated with impaired clearance of hepatitis C virus (HCV). IFNL4 signals through an IFNL receptor complex that serves all type-III interferons and consists of receptors IFNLR1 and IL10R2. Signaling through IFNL receptor complex leads to activation of the JAK-STAT pathway and transcriptional activation of interferon-stimulated genes (ISG). Intracellular expression of IFNL4 also causes reduced proliferation and increased cell death in human hepatic cells but it remains unclear if this is a result of JAK-STAT signaling through IFNL receptor complex or through some other alternative mechanisms. To address this question, we used CRISPR-CAS9 system to knock-out IFNLR1 in a hepatoma HepG2 cells. We designed and tested six guide RNAs (gRNAs) for IFNLR1 exons. CAS9 protein and gRNAs that most efficiently induced mutations in IFNLR1 were introduced into HepG2 cells to generate stable cell lines. No obvious defects were observed in IFNLR1-KO-HepG2 cells, indicating that loss of IFNLR1 had no deleterious effects on cell viability. We selected three stable clones which had sequencing-confirmed inactivating IFNLR1 mutations and Western blot-confirmed lack of IFNLR1 protein expression. Compared to the parental HepG2 cells the IFNLR1-KO-HepG2 cells were deficient in the ability to induce the luciferase-tagged interferon-stimulated response element (ISRE-Luc) reporter after treatment with recombinant IFNL4 and IFNL3 proteins, which signal through the same receptor complex. At the same time, response to IFNa treatment was not affected because IFNa signals through its own receptor complex. These results indicate that, as other type-III interferons, IFNL4 induces ISRE signaling through IFNL receptor complex. INFLR1-KO-HepG2 cells provide a highly efficient model for studies of factors involved in signaling of type-III interferons, including IFNL4. Next, we will investigate alternative pathways involved in anti-proliferative and cell death-related phenotypes induced by IFNL4 in HepG2 cell. We will perform RNA-seq on parental and IFNLR1-KO-HepG2 cells treated with or without IFNL4, IFNL3 and IFNa. These results will contribute to a better understanding of IFNL4 function, which can be relevant for viral infections and cancer. Citation Format: Fang Wang, Olusegun O. Onabajo, Nina Rao, Ludmila Prokunina-Olsson. Exploration of alternative pathways mediated by IFNL4 and related to cell proliferation and death in a hepatoma cell line. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4419.
First in Human Single-Ascending Dose Study: Safety, Biomarker, Pharmacokinetics and Exposure-Response Relationships of ALXN1210, a Humanized Monoclonal Antibody to C5, with Marked Half-Life Extension and Potential for Significantly Longer Dosing Intervals
Authors: Leonardo Sahelijo, Arshad Mujeebuddin, David Mitchell, Richard Larouche, Zhao-Xue Yu, Yuchun Zhang, Rekha Patel, Melissa Lasaro, Keith Bouchard, Bruce Andrien, Yi Wang, Paul Tamburini, Susan Macdonald, Douglas Sheridan, Paresh Soni
Journal: Blood (2015)
Blood neutrophil to lymphocyte ratio as a predictor of response to chemotherapy in head and neck cancer.
Authors: Kambiz Novin, Mohammad Hashemi Bahremani, Nafiseh Mortazavi, Ameri Ahmad, Zahra Razaghi, Pedram Fadavi
Journal: Journal of Clinical Oncology (2016)

e23078 Background: To investigate whether pre-treatment blood neutrophil to lymphocyte ratio (NLR) could serve as a bio-predictor of response to chemotherapy for head and neck cancers (HNCs). Methods: Patients with newly diagnosed epithelial HNC were consecutively enrolled in the study. The pre-treatment percent of neutrophils and lymphocytes in the peripheral blood smear slides and NLR for each patient was calculated. For patients that received chemotherapy, response rates and treatment toxicities were analysed due to pre-treatment mean NLR. Results: Of total 46 included patients, 38 were men and 8 were women with mean age of 54 years (27 to 82 years). Mean NLR of the whole patients was 2.8. The overall response rate (complete response plus partial response) was 86%. Mean NLR was significantly lower in the group with higher response compared to no response group (2.5 and 5.8 respectively; P=0.027). The differences were also significant for percent of neutrophil and lymphocyte between these groups (Table). There was no correlation between NLR and treatment toxicities. Conclusions: Our study proposed that pre-treatment NLR might predict response to chemotherapy in epithelial HNCs. Comparison of mean NLR, neutrophil and lymphocyte percent between different patient, tumor and treatment related groups. No Mean NLR P- value MeanNeut (%) P- value MeanLymph (%) P- value Sex - - 0.723 - 0.421 - 0.518 Male 38 2.7 64 31 Female 8 3 67 28 Age Group - - 0.538 - 0.576 - 0.813 <=50 years 17 3 65 30 > 50 years 29 2.7 63 31 Primary Tumor Site - - 0.231 - 0.583 - 0.684 Nasopharynx 14 3.4 66 29 Non-Nasopharynx 32 2.5 64 31 T-stage Group - - 0.079 - 0.184 - 0.148 T1/T2 20 2.2 62 33 T3/T4 25 3.3 66 28 N-stage Group - - 0.057 - 0.090 - 0.066 N0/N1 18 2.2 61 34 N2/N3 24 3.5 68 27 Chemotherapy Regimen - - 0.582 - 0.974 - 0.655 wTC 16 3.2 65 29 DCF/CF 23 2.8 65 30 Response to Treatment - - 0.027 - 0.024 - 0.030 CR/PR 30 2.5 63 32 SD/PD 5 5.8 77 19 Total 35 2.9 65 30 Abbreviations: T-stage, tumor stage; N-stage, lymph node stage; Diff, differentiated; wTC, weekly paclitaxel plus carboplatin; DCF, docetaxel plus cisplatin plus 5-fluorouracil; CF, cisplatin plus 5-fluorouracil; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
Implications of Intraoperative Vascular Surgery Assistance for Hospitals and Vascular Surgery Trainees
Authors: Tadaki M. Tomita, Heron E. Rodriguez, Andrew W. Hoel, Karen J. Ho, William H. Pearce, Mark K. Eskandari
Journal: JAMA Surgery (2016)

<h3>Importance</h3> Vascular surgeons possess a skill set that allows them to assist nonvascular surgeons in the operating room. Existing studies on this topic are limited in their scope to specific procedures or clinical settings. <h3>Objective</h3> To describe the broad spectrum of cases that require intraoperative vascular surgery assistance. <h3>Design, Setting, and Participants</h3> A retrospective medical record review of patients undergoing nonvascular surgery procedures that required intraoperative vascular surgery assistance between January 2010 and June 2014 at a single urban academic medical center (Northwestern Memorial Hospital, Chicago, Illinois). Trauma patients and inferior vena cava filter placements were excluded. <h3>Exposures</h3> Intraoperative vascular surgery assistance stratified by need for vascular reconstruction, anatomic location, urgency of consultation, and timing of consultation. <h3>Main Outcomes and Measures</h3> A composite primary end point of death, myocardial infarction, or unplanned return to the operating room within 30 days of the index operation. <h3>Results</h3> We identified 299 patients involving 12 different surgical subspecialties that met the study criteria. The cohort included 148 men (49.5%) and had a mean (SD) age of 56.4 (15) years. Most consultations occurred preoperatively (n = 224; 74.9%; odds ratio, 0.04; 95% CI, 0.02-0.08;<i>P</i> &lt; .001) and were elective (n = 212; 70.9%; odds ratio, 0.06; 95% CI, 0.03-0.12;<i>P</i> &lt; .001 ). The indications for vascular surgery assistance were 156 spine exposure (52%), 43 vascular control without hemorrhage (14.4%), 43 control of hemorrhage (14.4%), and 57 vascular reconstruction (19%). Vascular repairs consisted of 13 bypasses (4.3%), 18 patch angioplasties (6.0%), and 79 primary repairs (26.4%). All procedures required open surgical exposure by the vascular surgeon. The incidence of death, myocardial infarction, or unplanned return to the operating room was 11.4% for the cohort with a mortality rate of 1.7%. Patients who required vascular repair had a higher incidence of death, myocardial infarction, or unplanned return to the operating room (17.4% vs 7.9%;<i>P</i> = .01). These cases resulted in an additional 1371.46 work relative value units per year. <h3>Conclusions and Relevance</h3> Vascular surgeons provide crucial operative support across multiple specialties. Although vascular reconstruction is not needed in most patients, it may be associated with increased risk of death, myocardial infarction, or unplanned return to the operating room. The high proportion of emergent cases that require vascular repair demonstrates the importance of having vascular surgeons immediately available at the hospital. To continue providing this valuable service, vascular surgery trainees need to continue to learn the full breadth of open anatomic exposures and vascular reconstruction.