tbuckley/cabot-search huggingface dataset:
The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non–Small Cell Lung Cancer
Authors: Tina Cascone, Li Xu, Heather Y. Lin, Wenbin Liu, Hai T. Tran, Yuan Liu, Kathryn Howells, Vincent Haddad, Emer Hanrahan, Monique B. Nilsson, Maria A. Cortez, Uma Giri, Humam Kadara, Babita Saigal, Yun-Yong Park, Weiyi Peng, Ju-Seog Lee, Anderson J. Ryan, Juliane M. Jüergensmeier, Roy S. Herbst, Jing Wang, Robert R. Langley, Ignacio I. Wistuba, Jack J. Lee, John V. Heymach
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Resistance to VEGFR inhibitors is a major obstacle in the treatment of non–small cell lung cancer (NSCLC). We investigated the cellular mechanisms mediating resistance of NSCLCs to VEGFR tyrosine kinase inhibitors. Experimental Design: We generated murine models of human NSCLC and performed targeted inhibition studies with the VEGFR TKIs cediranib and vandetanib. We used species-specific hybridization of microarrays to compare cancer (human) and stromal (mouse) cell transcriptomes of TKI-sensitive and -resistant tumors. We measured tumor microvascular density and vessel tortuosity to characterize the effects of therapy on the tumor vascular bed. Circulating cytokine and angiogenic factor levels in patients enrolled in VEGFR TKI trials were correlated with clinical outcomes. Results: Murine xenograft models of human lung adenocarcinoma were initially sensitive to VEGFR TKIs, but developed resistance to treatment. Species-specific microarray analysis identified increased expression of stromal-derived hepatocyte growth factor (HGF) as a candidate mediator of TKI resistance and its receptor, c-MET, was activated in cancer cells and tumor-associated stroma. A transient increase in hypoxia-regulated molecules in the initial response phase was followed by adaptive changes resulting in a more tortuous vasculature. Forced HGF expression in cancer cells reduced tumor sensitivity to VEGFR TKIs and produced tumors with tortuous blood vessels. Dual VEGFR/c-MET signaling inhibition delayed the onset of the resistant phenotype and prevented the vascular morphology alterations. In patients with cancer receiving VEGFR TKIs, high pretreatment HGF plasma levels correlated with poorer survival. Conclusions: HGF/c-MET pathway mediates VEGFR inhibitor resistance and vascular remodeling in NSCLC. Clin Cancer Res; 23(18); 5489–501. ©2017 AACR.
Drug-Bearing Supramolecular Filament Hydrogels as Anti-Inflammatory Agents
Authors: Zhipeng Chen, Lei Xing, Qin Fan, Andrew G. Cheetham, Ran Lin, Barbara Holt, Liwen Chen, Yanyu Xiao, Honggang Cui
Journal: Theranostics (2017)

We report here on the covalent conversion of the anti-inflammatory agent ketoprofen into self-assembling prodrugs that enable the effective purification of ketoprofen enantiomers, the improved selectivity and potency of ketoprofen, as well as the formation of one-component drug-bearing supramolecular hydrogels.We found that the ketoprofen hydrogelator could exhibit much-enhanced selectivity for cyclooxygenase 2 (COX-2) over COX-1, reduce the concentration of inflammatory cytokines (IL-1 and TNFα), and induce apoptosis in fibroblast-like synoviocytes while maintaining biocompatibility with healthy chondrocytes.In addition, these anti-inflammatory agent-containing hydrogels demonstrated the ability to retain the therapeutic within a joint cavity after intra-articular injection, exhibiting a slow, steady release into the plasma.We believe that upon further optimization these drug-based injectable supramolecular hydrogels could provide the basis for a local treatment strategy for rheumatoid arthritis and similar conditions.
Searching for unity: Real-world versus item-based visual search in age-related eye disease
Authors: David P. Crabb, Deanna J. Taylor
Journal: Behavioral and Brain Sciences (2017)

When studying visual search, item-based approaches using synthetic targets and distractors limit the real-world applicability of results. Everyday visual search can be impaired in patients with common eye diseases like glaucoma and age-related macular degeneration. We highlight some results in the literature that suggest assessment of real-word search tasks in these patients could be clinically useful.
Celiac plexus block in patients with nonpancreatic GI malignancies: Experience from a single institution.
Authors: Shejal B Patel, James Edward Shaw
Journal: Journal of Clinical Oncology (2012)

e19551 Background: Celiac plexus block (CPB) has been well described in the treatment of pancreatic cancer pain. A recent Cochrane Library review of the subject concluded that CPB often resulted in fewer adverse effects when compared to chronic opioid use. CPB has not been well described in non-pancreatic GI malignancies. This study sought to determine the effectiveness of CPB in non-pancreatic GI malignancies. Methods: The Virginia Commonwealth University Massey Cancer Center database was queried for all patients who had undergone celiac plexus block, 2001-2010, using specific CPT billing codes. In addition, VCU Radiology Department records were also examined. Diagnosis, physician assessment of effectiveness, pre and post procedure pain scores, complications of procedure, and pain medication dosage pre and post procedure were all assessed. Results: 68 total patients were identified. 12 patients underwent a CPB for non-pancreatic GI malignancies and 56 for pancreatic cancer patients. The most common non-pancreatic GI malignancies were colorectal cancer (50%), hepatocellular carcinoma (8%), carcinoid (8%), duodenal cancer (8%), and gastric cancer (8%). By study criteria, 7 of the 12 patients had sufficient data for exploratory analysis. By physician assessment, CPB resulted in pain relief in 5 (71%) of 7 patients. Furthermore, the post procedure pain score improved but the usage of pain medications did not change. By comparison, 26 of 56 patients with pancreatic CA had sufficient data and 15(58%) has pain relief by physician assessment. Conclusions: CPB appears to provide some pain relief for patients with non-pancreatic GI malignancies. However, the retrospective design revealed missing data including: pre and post procedure pain scores, complications of procedure and patient assessments of pain. A prospective study is being considered.
Second- and third-line treatment of EGFR wild-type non-small cell lung cancer (NSCLC): A retrospective real-world practice review of the use of tyrosine kinase inhibitors at a single tertiary care center.
Authors: Kim Anh Ma, Victor Cohen, Goulnar Kasymjanova, Jason Scott Agulnik
Journal: Journal of Clinical Oncology (2014)

e19147 Background: Wild-type NSCLC constitutes the large majority of lung cancers, but treatment is limited. Current standard for second-line treatment are pemetrexed, docetaxel or erlotinib. Few trials have compared these treatments, although there is evidence for better overall survival (OS) with docetaxel vs. erlonitib. Nevertheless, data on the use of TKI in real-life clinical setting remains limited. We performed a retrospective practice review of TKI use in second and third line treatment of EGFR wild-type NSCLC at a single tertiary care center, and compared clinical outcomes of TKI and single agent taxotere as second-line treatment. Methods: This retrospective cohort study includes pts (patients) with advanced NSCLC EGFR wild-type treated at the Jewish General Hospital (Montreal, Canada) between 2003 and 2010. Pts received a TKI as second- or third-line treatment. A control group of pts received taxotere as second-line therapy. Both groups were compared for age, sex, smoking and ECOG status. Outcomes analyzed include OS from time of diagnosis of advanced disease, response rate (RR) measured by first available imaging, and time to clinical progression measured by duration of treatment. Timing of imaging and treatment duration were left to the clinician’s discretion. Results: The TKI group includes 115 pts, 76 receiving TKI secod-line and 39 as third-line. In the control group, 49 pts received taxotere as second-line. OS of TKI in second- and third-line treatment combined was 10.9 months. Median time to clinical progression was 3.1 months. Only 9 patients discontinued TKI due to side effects. When comparing second line treatments, in the TKI and taxotere groups, median age was 63 vs. 58 years, male pts constituted 53% vs. 45%, 74% vs. 94% of pts had a smoking history, and 78% vs. 84% had an ECOG 0-1. RR for TKI and taxotere were 34.5% vs. 26.5% (p=0.241), and OS was 15.5 vs. 13.9 months (p=0.858). Conclusions: In our study population, TKI was efficacious and well tolerated, and there was no significant difference in OS, and RR when comparing TKI to taxotere in second-line therapy. Hence, our real-life data supports a role for TKI in the second-line treatment of EGFR wild-type NSCLC.
Shining the light of hope
Authors: Michael Day
Journal: BMJ (2017)

A doctor who cares for 750 000 people, seven days a week, in Sudan’s war ravaged Nuba Mountains has scooped a $1m (£777 000; €894 000) humanitarian prize that was set up to mark the Armenian genocide. The $1m will go to charities of the winner’s choice.

Tom Catena, a Catholic missionary from the US, is the only medic in the remote, violence plagued region and can see as many as 400 patients a day. He regularly has to dive into makeshift, dug-out bomb shelters along with patients, for whom he provides everything from paediatrics and general surgery to psychiatric care.

Accepting the Aurora prize for awakening humanity in the …
The impact of mandatory helmet use on career length in the national hockey league (nhl)
Authors: Claus Reinsberger, Bernd Frick
Journal: British Journal of Sports Medicine (2017)

Objective In 1979, the National Hockey League (NHL) announced that helmets would become mandatory for incoming players. The objective of this study is to evaluate, whether the mandatory use of helmets has a positive impact on the career length in NHL players. Design A public database (www.hockeydb.com) was utilised to extract career lengths of NHL players before and after 1979. Since the rule allowed players who signed professional contracts prior to June 1, 1979 to continue not to wear a helmet, career lengths of all players entering the NHL via the draft in ten seasons before (1969–1978) and ten seasons after (1979–1988) the introduction of the helmet rule was compared. Main results In the 20 years analysed, 3952 players were selected by NHL teams of which 1818 eventually appeared in at least one match and were considered for further analysis. Controlling for draft round, draft number, individual players’ performance (games played per season, number of goals and assists per game, number of penalty minutes per game), year of entry and team picking the player, players during the era of mandatory helmet use had significantly longer careers (approximately 2.5 years, cox regression z=−0.768, p&lt;0.01). Defenders and forwards benefit to the same extent from wearing a helmet. Conclusions The introduction of mandatory use of helmets in the NHL was associated with an increase in career length. Protection of head and brain together with associated conditions may be contributing to this observation. Competing interests None.
Adoptive immunotherapy (AIT) of established tumors with tumor antigen peptide-sensitized T cells
Authors: Catriona T. Miller, Laura J. Graham, Harry D. Bear
Journal: Cancer Research (2004)

5474  Recent cancer immunotherapy approaches have focused on immunization with defined peptide epitopes. AH1 (SPSYVYHQF), a class I (H-2Ld) restricted peptide derived from the murine leukemia virus gp70, has been reported to be the immunodominant epitope of T cell responses to murine CT26 colon carcinoma and 4T1 mammary carcinoma. We have shown that amplification of weak anti-tumor immunity, via AIT with bryostatin/ionomycin (B/I)-activated antigen-sensitized T cells, can mediate tumor regression. We hypothesized that vaccination with dendritic cells pulsed with the optimized AH1-A5 (DC:AH1-A5) peptide could protect against tumor challenge and that AIT with B/I activated AH1-sensitized T cells could induce tumor regression. Methods: BALB/c mice were vaccinated X 3 with DC:AH1-A5 or once with transfected whole tumor cell vaccines: 4T07-IL2 or CT26-B7. Vaccinated mice were challenged with 4T1 or CT26 tumors. Tumor-specific T cell responses were assayed in vitro by measuring interferon-γ release and cytolytic activity. After restimulation in culture, AH1-specific CD8+ T cells in vaccine draining lymph nodes (V-DLN) were enumerated by Ld:Ig/AH1 dimer staining and flow cytometry. AIT of 4 day established 4T1 or CT26 tumors was performed by transfer of V-DLN cells activated ex vivo with B/I and expanded in IL-2. Results: DC:AH1:A5 vaccination protected against CT26 tumor growth, but not 4T1 tumor challenge. The transfected tumor cell vaccines were protective against tumor challenge with their respective wild-type (WT) tumor cells. All 3 methods of vaccination induced similar levels of Ld:Ig/AH1 binding T cells: 37.4% of the CD8+ cells for DC:AH1-A5, 32% for CT26-B7, and 29.2% for 4T07-IL2. Splenocytes from mice immunized with DC:AH1-A5 released IFN-γ in response to peptide, but not to tumor cells; CT26-B7 or 4T07-IL2 sensitized splenocytes released IFN-γ in response to peptide, 4T1, and CT26 cells. Splenocytes from DC:AH1-A5-vaccinated mice lysed CT26 (63% specific release) and 4T1 (31.1%) cells, but tumor-cell vaccinated splenocytes had low cytolytic activity. Despite these results, AIT with DC:AH1-A5 sensitized lymphocytes was ineffective at inducing regression of WT CT26 or 4T1 tumors, while AIT with CT26-B7 or 4T07-IL2-sensitized T cells induced regression of their corresponding WT tumors. Conclusions: Vaccination with a single peptide induced strong AH1 and tumor-reactive T cell responses, as measured in vitro, and was effective at preventing CT26 tumor growth, but not 4T1 tumor growth. AIT with tumor cell-sensitized T cells was effective at inducing regression of established tumors, while AIT with AH1-sensitized T cells was not. We have shown that while a defined single tumor antigen peptide may be a powerful tool for tracking tumor-specific T cell responses, T cells sensitized against a single tumor antigen peptide are ineffective as a treatment for established tumors, even with AIT amplification.
Preparation and evaluation of poly( l -histidine) based pH-sensitive micelles for intracellular delivery of doxorubicin against MCF-7/ADR cells
Authors: Nan Jia, Yuqing Ye, Qi Wang, Xiuli Zhao, Haiyang Hu, Dawei Chen, Mingxi Qiao
Journal: Asian Journal of Pharmaceutical Sciences (2017)

In this study, a pH-sensitive micelle self-assembled from poly(l-histidine) based triblock copolymers of poly(ethylene glycol)-poly(d,l-lactide)-poly(l-histidine) (mPEG-PLA-PHis) was prepared and used as the intracellular doxorubicin (Dox) delivery for cancer chemotherapy. Dox was loaded into the micelles by thin-film hydration method and a Box-Behnken design for three factors at three levels was used to optimize the preparations. The optimized mPEG-PLA-Phis/Dox micelles exhibited good encapsulation efficiency of 91.12%, a mean diameter of 45 nm and narrow size distribution with polydispersity index of 0.256. In vitro drug release studies demonstrated that Dox was released from the micelles in a pH-dependent manner. Furthermore, the cellular evaluation of Dox loaded micelles displayed that the micelles possessed high antitumor activity in vitro with an IC50 of 35.30 µg/ml against MCF-7/ADR cells. The confocal microscopy and flow cytometry experiments indicated that mPEG-PLA-Phis micelles mediated efficient cytoplasmic delivery of Dox with the aid of poly(l-histidine) mediated endosomal escape. In addition, blank mPEG-PLA-Phis micelles were shown to be nontoxic to MCF-7/ADR cells even at a high concentration of 200 µg/ml. The pH-sensitive mPEG-PLA-PHis micelles have been demonstrated to be a promising nanosystem for the intracellular delivery of Dox for MDR reversal.
Brief Report: Remission Rates With Tofacitinib Treatment in Rheumatoid Arthritis: A Comparison of Various Remission Criteria
Authors: Josef S. Smolen, Daniel Aletaha, David Gruben, Samuel H. Zwillich, Sriram Krishnaswami, Charles Mebus
Journal: Arthritis & Rheumatology (2016)

Tofacitinib is an oral JAK inhibitor that is used for the treatment of rheumatoid arthritis (RA). In previous clinical trials of tofacitinib, a Disease Activity Score in 28 joints (DAS28)-based analysis was used to assess outcomes. In this study, remission rates according to various remission criteria were evaluated across 5 phase III randomized controlled studies.In all 5 studies, tofacitinib was administered at a dosage of 5 mg twice daily or 10 mg twice daily, either as monotherapy or with background methotrexate or other conventional synthetic disease-modifying antirheumatic drugs. One of the studies included adalimumab 40 mg once every 2 weeks. In addition to the 4-variable DAS28 using the erythrocyte sedimentation rate (DAS28-4[ESR]), a primary efficacy variable used in the phase III studies, disease activity was assessed post hoc by the 4-variable DAS28 using the C-reactive protein level (DAS28-4[CRP]), the Clinical Disease Activity Index (CDAI), the Simplified Disease Activity Index (SDAI), and Boolean-based assessment.A total of 3,306 patients were analyzed (1,213 of these patients received tofacitinib 5 mg twice daily, 1,212 received tofacitinib 10 mg twice daily, 679 received placebo, and 202 received adalimumab 40 mg every 2 weeks). Remission rates varied according to the criteria used, with higher rates in the active-treatment groups for the DAS28-4(CRP) than for other scores. At month 3, remission rates with tofacitinib 5 mg twice daily were 18-22% using the DAS28-4(CRP), 5-10% using the DAS28-4(ESR), 4-7% using the SDAI, 5-6% using the CDAI, and 2-7% using the Boolean-based method. In contrast, the remission rates with placebo varied from 0% to 7%, with small differences between the DAS28-4(ESR) and the DAS28-4(CRP).Although tofacitinib at dosages of 5 mg twice daily and 10 mg twice daily was effective compared with placebo in achieving disease remission, regardless of the disease activity measure, remission rates were substantially higher when the DAS28-4(CRP) was used. The presence or absence and type of acute-phase reactants in remission criteria were significant contributors to remission rates across treatment groups. This finding has important consequences for trial design and clinical practice.
DIPG-05. COMBINATION OF SYNTHETIC RETINOID FENRETINIDE WITH RECEPTOR TYROSINE KINASE INHIBITOR PONATINIB AS A POTENTIAL NEW APPROACH AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Maria Tsoli, Nicole Yeung, Santosh Valvi, Swapna Joshi, Laura Franshaw, Han Shen, Jie Liu, David Ziegler
Journal: Neuro-Oncology (2017)

Diffuse Intrinsic Pontine Gliomas (DIPGs) are the most devastating of all brain tumours. They mostly affect young children and, as there are no effective treatments, almost all will die of their tumour within 12 months. We performed a high throughput screen (HTS) of 3500 clinically available compounds, which identified fenretinide among the top 33 most active agents against DIPG. In an attempt to find novel combination therapies, which could enhance the cytotoxic efficacy of fenretinde we performed a combination HTS based on the remaining 32 agents together with 50 chemotherapeutic agents against fenretinide. This approach identified drugs that enhanced fenretinide activity including Ion channel inhibitors (ivermectin, halofantrine, diphenylhydantoin), neurotransmitter receptor antagonist (GR-127935), receptor tyrosine kinases (RTKs) inhibitors (ponatinib, pazopanib) and histone deacetylase (HDAC) inhibitor saha. These promising 7 combinations were selected for further investigation in vitro using cytotoxicity assays, colony formation assays, while the best combination was further validated by flow cytometry assessing apoptotic events and western blotting to elucidate mechanisms of action. When tested against a panel of four neurosphere forming DIPG cultures, only ponatinib was found to uniformly enhance the anti-proliferative effects of fenretinide. Colony formation assays showed that fenretinide combined with ponatinib, pazopanib, GR127935, and diphenylhydantoin led to significantly reduced colony formation both with and without irradiation. Flow cytometric analysis enhanced apoptotic events in the combination treated cells. Furthermore we found that although fenretinide combination inhibited the PDGFR/PI3K pathway, these effects didn’t appear to be mediated at the gene expression level. In vivo experiments examining the therapeutic efficacy of fenretinide/irradiation and ponatinib combinations are currently undergoing using an orthotopic model of DIPG. Preliminary results indicate that delivery of fenretinide with irradiation could extend the survival of mice. This novel and potentially effective DIPG treatment strategy is readily translatable to clinical trial.
Confusing Terminology—Neuroleptic Malignant Syndrome vs Malignant Hyperthermia
Authors: Ronald S. Litman
Journal: JAMA Neurology (2017)

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