tbuckley/cabot-search huggingface dataset:
Retrospective analysis of the difference of prognosis between unresectable and recurrent biliary tract cancer: Kansai Hepatobiliary Oncology Group (KHBO) 1001.
Authors: Masashi Kanai, Kenji Ikezawa, Tetsuo Ajiki, Tadashi Tsukamoto, Hideyoshi Toyokawa, Hiroaki Terajima, Hiroaki Furuyama, Hiroaki Nagano, Iwao Ikai, Nobukazu Kuroda, Hiroaki Awane, Toshiya Ochiai, Shigekazu Takemura, Atsushi Miyamoto, Makoto Kume, Masao Ogawa, Yutaka Takeda, Kaoru Taira, Tatsuya Ioka
Journal: Journal of Clinical Oncology (2012)

e14518 Background: The difference of prognosis between patients (pts) with unresectable and recurrent biliary tract cancer (BTC) receiving chemotherapy has not been clarified although some studies reported prognostic factors of BTC. In this study, we aimed to compare the prognosis of unresectable BTC with that of recurrent BTC. We also evaluated other prognostic factors of BTC. Methods: This study retrospectively reviewed the data of 403 consecutive pts with pathologically proven unresectable or recurrent BTC who received palliative chemotherapy from 18 hospitals in Japan between April 2006 and March 2009. The 1-year survival rate and overall survival (OS) and patient characteristics were compared between unresectable and recurrent cases. Univariate and multivariate analyses were performed to identify prognostic factors. Results: 380 pts (94.3%) received chemotherapy using gemcitabine and/or S-1. The 1-year survival rate and OS were significantly better in 192 pts with recurrent BTC than 211 pts with unresectable BTC (1-year survival 57.3% vs. 43.1%, p=0.005; OS 398 days [95% confidence interval (CI) 365-430] vs. 323 days [95% CI 282-364], p=0.004). In baseline characteristics, the proportion of pts who had distant metastasis was significantly greater in recurrent BTC than unresectable BTC (77.1% vs. 66.8%, p&lt;0.001). In contrast, lymph node involvement, biliary intervention and elevated tumor marker levels (CEA and CA19-9) were more common in pts with unresectable BTC (p&lt;0.001). After the multivariate analysis, unresectable BTC group still demonstrated a significantly worse survival than recurrent BTC group (hazard ratio [HR] 1.44, 95% CI 1.15-1.80, p=0.002). Other statistically significant prognostic factors were ECOG PS (HR 1.49, 95% CI 1.18-1.87, p&lt;0.001), metastatic disease (HR 1.53, 95% CI 1.20-1.97, p&lt;0.001) and higher CEA (≥5 ng/ml) (HR 1.71, 95% CI 1.36-2.15, p&lt;0.001). Conclusions: The status of unresectable/recurrent disease is identified as one of the prognostic factors for pts with BTC receiving chemotherapy and recommended to be used as a stratification factor in the clinical trials.
P084 Salivary gland epithelial cells from sjÖgrens’ patients increase B lymphocytes survival and activation
Authors: E Rivière, J Pascaud, A Virone, B Ly, A Paoletti, J Rohmer, S Bitoun, G Nocturne, X Mariette
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Student for a master or a PhD. <h3>Introduction</h3> Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder characterized by lymphocytic infiltrates and destruction of the salivary glands (SG). Several lines of evidence support the hypothesis that SG epithelial cells (SGECs) are not only the target of autoimmunity in pSS but may also play a role for its initiation and maintenance. <h3>Objectives</h3> To study the survival and the activation of B lymphocytes cocultured with SGECs from pSS patients compared to controls. <h3>Methods</h3> Primary cultures of SGECS were established from minor SG biopsies. Patients had pSS according to 2016 EULAR/ACR criteria and controls had sicca symptoms without any antibodies and with normal SG biopsies. The coculture involved B lymphocytes isolated by CD19 magnetic bead positive selection from healthy donors' blood (purity &gt;80%). Several conditions of stimulation were tested: IFNa 2400 U/mL, IFNg 5 ng/mL, Poly(IC) 10 µg/mL or 30 µg/mL. After 5 days, the viability, the activation (CD38) and the differentiation (CD27) of B lymphocytes were assessed by flow cytometry. Mann-Whitney (unpaired data) and Wilcoxon (paired data) were used for statistical analysis. <h3>Results</h3> A significant increase of B lymphocytes survival was observed when cocultured with SGECs compared to B lymphocytes cultured alone, in all conditions of stimulation (p&lt;0.05). The survival of B lymphocytes (percentage of alive cocultured B lymphocytes–percentage of alive cultured alone B lymphocytes) was increased when the cocultures were performed with SGECs from pSS patients (n=5) compared to SGECs from controls (n=5), in all conditions of stimulation (p&lt;0.05), except IFNg. Moreover, there was a trend for an increase of B lymphocytes activation, assessed by higher percentages of CD38+ B lymphocytes when the cocultures were performed with SGECs from pSS patients compared to SGECs from controls. This difference was statistically significant (p&lt;0.05) in the condition stimulated with TLR3 agonist (Poly(IC) 10 µ/mL). The percentage of CD27+ B lymphocytes was not affected by the cocultures and no difference between pSS and controls SGECs was observed. <h3>Conclusions</h3> This coculture model showed a differential effect of SGECs from pSS compared to controls on B lymphocytes survival. Interestingly, there was also a trend for a higher activation level of B lymphocytes when cocultured with SGECs from pSS compared to controls. These results suggest that SGECs could play a major role in pSS pathophysiology through B lymphocytes support and activation. <h3>Disclosure of Interest</h3> None declared.
Simultaneous targeting of DNA replication and homologous recombination in glioblastoma with a polyether ionophore
Authors: Yi Chieh Lim, Kathleen S Ensbey, Carolin Offenhäuser, Rochelle C J D’souza, Jason K Cullen, Brett W Stringer, Hazel Quek, Zara C Bruce, Amanda Kijas, Valentina Cianfanelli, Bijan Mahboubi, Fiona Smith, Rosalind L Jeffree, Lisa Wiesmüeller, Adrian P Wiegmans, Amanda Bain, Fanny J Lombard, Tara L Roberts, Kum Kum Khanna, Martin F Lavin, Baek Kim, Petra Hamerlik, Terrance G Johns, Mark J Coster, Andrew W Boyd, Bryan W Day
Journal: Neuro-Oncology (2019)

Despite significant endeavor having been applied to identify effective therapies to treat glioblastoma (GBM), survival outcomes remain intractable. The greatest nonsurgical benefit arises from radiotherapy, though tumors typically recur due to robust DNA repair. Patients could therefore benefit from therapies with the potential to prevent DNA repair and synergize with radiotherapy. In this work, we investigated the potential of salinomycin to enhance radiotherapy and further uncover novel dual functions of this ionophore to induce DNA damage and prevent repair.In vitro primary GBM models and ex vivo GBM patient explants were used to determine the mechanism of action of salinomycin by immunoblot, flow cytometry, immunofluorescence, immunohistochemistry, and mass spectrometry. In vivo efficacy studies were performed using orthotopic GBM animal xenograft models. Salinomycin derivatives were synthesized to increase drug efficacy and explore structure-activity relationships.Here we report novel dual functions of salinomycin. Salinomycin induces toxic DNA lesions and prevents subsequent recovery by targeting homologous recombination (HR) repair. Salinomycin appears to target the more radioresistant GBM stem cell-like population and synergizes with radiotherapy to significantly delay tumor formation in vivo. We further developed salinomycin derivatives which display greater efficacy in vivo while retaining the same beneficial mechanisms of action.Our findings highlight the potential of salinomycin to induce DNA lesions and inhibit HR to greatly enhance the effect of radiotherapy. Importantly, first-generation salinomycin derivatives display greater efficacy and may pave the way for clinical testing of these agents.
The changing landscape of research funding: challenges for mid-career researchers
Authors: Nick Wong
Journal: Genome biology (2019)

Funding research is a challenge faced by most scientists around the world. Genome Biology has invited four scientists based in three different countries to share their own experience and opinions regarding funding, the difficulties young scientists must overcome, and how the process of securing funding can be improved. In this part, Nick Wong shares his experience in securing funding for his research in Australia.
P169 Effect of macrophage migration inhibitory factor on human macrophages from arthritis patients
Authors: T Rakovich, C Cunningham, S Ansboro, T McGarry, DJ Veale, U Fearon
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Post-doctoral fellow. <h3>Introduction</h3> Macrophage migration inhibitory factor (MIF) is a key regulator of pro-inflammatory cytokines and has been implicated in angiogenesis and pathogenesis of several diseases such as rheumatoid arthritis (RA). Macrophages are considered to be one of the key players in the hyperplastic synovial tissue that invades and degrades adjacent cartilage and bone in patients with inflammatory arthritis. <h3>Objectives</h3> In this study a comparative analysis was performed to examine the expression of MIF, and the effect it has on the macrophage polarisation and on the angiogenic and inflammatory mechanisms of macrophages in patients with RA, Psoriatic Arthritis (PsA), Osteoarthritis (OA) and in Arthralgia patients. <h3>Methods</h3> PBMCs (Peripheral Blood Mononuclear Cells) were isolated from healthy donors, and patients with OA, RA, PsA and Arthralgia. Primary macrophages (Mfs) were subsequently differentiated and polarised from circulating CD14+ monocytes into M1 and M2 phenotypes. The levels of MIF expression in PBMC, Mf and Synovial tissue was evaluated by real-time-PCR (RT-PCR) and Immunohistochemistry (IHC). The effect of MIF on polarisation of Mfs was investigated by examining M1 and M2 Mf specific markers by RT-PCR and Flow Cytometry. Polarised Mf supernatants were harvested and assayed for soluble MIF by ELISA. The effect of MIF on angiogenic and inflammatory markers (MCP-1, IL-6, IL-8, Ang-2, VEGF, Hif1a, PDGF-B, bFGF, RANTES and ICAM-1) of polarised Mfs was investigated by Real-PCR, Western blot and ELISA. <h3>Results</h3> MIF expression was significantly increased in RA tissue compared to OA and PsA. In contrast MIF expression in RA PBMCs was significantly decreased when compared to HC, Arthralgia, and PsA. RA tissue biopsies demonstrated significantly higher MIF expression when compared to PsA, OA, and Arthralgia. In polarised macrophages MIF expression was found to be increased in RA and PsA compared to healthy controls. Addition of rhMIF activated pro-inflammatory and angiogenic responses in unpolarised and polarised HC Mfs with increases in gene expression levels of IL-1β, IL-6, MCP-1, ICAM-1, Hey-1, VEGF and Hif1a. Soluble IL-6 expression was also elevated in M0 macrophages. <h3>Conclusions</h3> MIF may have a key role in promoting pathogenesis of RA and has a good potential as a therapeutic for RA. <h3>Acknowledgements</h3> Author would like to thank Arthritis Ireland for funding this project. <h3>Disclosure of Interest</h3> None declared.
Differential response of mTORC1 and mTORC2 to rapamycin in rapamycin-sensitive and -resistant tumor xenograft models
Authors: Jim Gamez, Sophie Peng, Heather Raymon, Rama Krishna Narla
Journal: Cancer Research (2008)

1425  Mammalian target of rapamycin (mTOR) is a large protein kinase that exists in two different complexes, mTORC1 and mTORC2. Rapamycin exhibits antitumor activity by inhibiting several processes including cell proliferation, cell survival and angiogenesis. The antitumor activity of rapamycin is variable and tumor type specific. The factors contributing to this differential activity are not known. Several in vitro studies have suggested that rapamycin universally inhibits mTORC1 (raptor complex) preventing the phosphorylation of down stream targets such as S6K. The response of mTORC2 (rictor complex) is tumor type specific. Furthermore, inhibition of mTORC1 alone leads to the activation of AKT via a feedback loop, which may protect cells from apoptosis. To understand the kinetic response of mTORC1 and mTORC2 to rapamycin in vivo, we analyzed phospho-S6 (pS6) and phospho-AKT (pAKT) expression in rapamycin-sensitive and -resistant tumor xenograft models including glioblastoma (U-87 MG), prostate (PC-3), non-small cell lung (NCI-H460) and colorectal (HCT 116) cancers. In rapamycin-sensitive PC-3 and U-87 MG xenograft models, rapamycin showed profound antitumor activity with a T/C ratio of 27% and 1.2%, respectively. In a refractory HCT 116 xenograft model, a moderate inhibition of tumor growth was observed with a T/C ratio of 51%. Response of tumor biomarkers was measured using western blots, Meso Scale Discovery (MSD) platform and immunohistochemistry. Robust endogenous expression of pS6 and pAKT was observed in all sensitive tumor types. In rapamycin-resistant HCT 116 model, tumor pAKT level was relatively low. Significant inhibition of pS6 was observed within 1 h after a single dose of rapamycin in all models and continued up to 48 h. In sensitive tumors, inhibition of pAKT was observed only after 24 h of rapamycin administration. In the HCT 116 model however, inhibition of pAKT was not observed at any time point studied even with multiple doses of rapamycin. Results from western blots correlated well with MSD analysis. Ease of quantification and the dynamic range of MSD makes it the preferable method of analysis. Immunohistochemical localization of total and phospho proteins of S6 and AKT revealed that the expression of phospho proteins was not uniform throughout the tumor. The expression was patchy and localized more in the peripheral zones of the tumor lobules. The expression of AKT was more abundant than S6 in terms of number of cells expressing the protein. Rapamycin significantly inhibited pS6 and pAKT in tumor cells but did not effect the expression of total S6 and AKT. Together these data suggest that a single dose of rapamycin treatment exerts a profound effect on mTORC1 in sensitive and resistant tumor types in vivo. Sustained activation of mTORC2/AKT even after chronic treatment may partially explain the modest growth inhibition of HCT 116 tumors.
Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study
Authors: Owen A. O’Connor, Lorenzo Falchi, Jennifer K. Lue, Enrica Marchi, Cristina Kinahan, Ahmed Sawas, Changchun Deng, Francesca Montanari, Jennifer E. Amengual, Hye A. Kim, Aishling M. Rada, Karen Khan, Alice T. Jacob, Michelle Malanga, Mark M. Francescone, Renu Nandakumar, Craig R. Soderquist, David C. Park, Govind Bhagat, Bin Cheng, Alberto Risueño, Daniel Menezes, Andrei R. Shustov, Lubomir Sokol, Luigi Scotto
Journal: Blood (2019)
Working together in cancer care: An academic community partnership for a diverse patient population.
Authors: Naomi Ko, Mayah Burgess, Lindsay Demers, Vaishali Sanchorawala, Gretchen Gignac, Frederick Thurston Drake, Michael Ryan Cassidy, Emily Baiyee, Stephanie Lee, Beverly Moy
Journal: Journal of Clinical Oncology (2019)

10525 Background: The Massachusetts General Hospital Cancer Care Equity Program conducted a qualitative survey health assessment in the inner-city communities of Boston to study Black Bostonian patients’ perceptions of the barriers to cancer care. Findings revealed a level of mistrust toward large cancer centers and a request for more interactions with their trusted community health providers. At a subsequent community forum geared toward soliciting solutions to improve relationships with academic medical centers, community members recommended that academic oncologists increase engagement with their community health center (CHC) clinicians with a cancer lecture series. Methods: Academic oncologists from Massachusetts General Hospital and Boston Medical Center met with the leadership at two CHCs prior to the creation of the cancer lecture series. Feedback on how to best support CHC providers was established and a cancer care lecture series was created with continuing medical education (CME) credit provided. Five in-person lectures were given at each CHC. Topics included: Consultative Hematology, Breast Cancer, Prostate Cancer, Thyroid Cancer, Colon Cancer and Adrenal Masses. Survey evaluations (summative and formative) were distributed to all participants. An online portal was established to provide ongoing CME to providers. Results: Six academic physicians specializing in cancer care provided lectures at two CHCs. Currently, we have 176 surveys completed from both CHCs. Thus far, 98.3% surveys have indicated that the lectures have been “Excellent” or “Above Average,” and all participants have responded that the objectives of each presentation have been met. We have developed a website to provide ongoing CME for the lectures that were given: http://bucme.org/cancercare . Conclusions: This project aims to improve cancer care education and communication between providers from academic cancer centers and primary care providers at CHCs that care for a diverse and vulnerable patient population.
Impacts of epidermal growth factor receptor, HER2, and mTOR status on outcomes of patients with gastric cancer.
Authors: Kubra Aydin, Kerem Okutur, Mustafa Bozkurt, Esat Namal, Akin Ozturk, Kezban Nur Planci, Zafer Akcali, Coskun Tecimer, Gokhan Demir
Journal: Journal of Clinical Oncology (2012)

e14698 Background: Expression of EGFR, Her-2 and mTOR have been linked to clinical outcomes in several solid tumors. However clinical significance of these biomarkers in gastric cancer remain unclear. This study was designed to detect the clinical implications of these three biomarkers in Turkish population. Methods: Paraffin-embedded tissue microarray blocks containing gastric cancer tissue obtained from 30 patients were constructed. Expression of mTOR, EGFR were detected by immunohistochemistry. Her-2 gene ampflication was detected by FISH. The correlation of these biomarkers to clinicopathologic features and survival of patients with gastric cancer was studied. Results: The overall rates of positive mTOR, EGFR and Her-2 status were 36.7%, 63.3% and 23.3% respectively. The EGFR expression(any grade) was significantly correlated with better OS(Overall Survival)(p=0.01). Median survival time is 34.7 months in EGFR +patients and 10.6 months in EGFR - patients. There was no significant correlation with Her-2 status and survival. But 5 of these 7 Her-2 positive patients have already took trastuzumab treatment. Also we find that her-2 pozitive tumors significantly metastasized much more frequently to liver than her-2 negative tumors.(p= 0.043) In Contrast, her-2 positive tumors significantly metastasized less commonly to periton, over, omentum as seeding than her-2 negative tumors.(p=0.009). There was no association was noted between the expression of mTOR and survival time. Conclusions: EGFR is good prognostic marker in gastric cancer patients.
Atrophic Annular Plaques on the Breasts Following Augmentation Surgery
Authors: Jessica G. Labadie, Samantha Conrad, Joaquin C. Brieva
Journal: JAMA Dermatology (2019)

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Association of Primary Care Clinic Appointment Time With Opioid Prescribing
Authors: Hannah T. Neprash, Michael L. Barnett
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Time pressure to provide a quick fix is commonly cited as a reason why opioids are frequently prescribed in the United States, but there is little evidence of an association between appointment timing and clinical decision-making. As the workday progresses and appointments run behind schedule, physicians may be more likely to prescribe opioids. <h3>Objective</h3> To estimate whether characteristics of appointment timing are associated with clinical decision-making about pain treatment. <h3>Design, Setting, and Participants</h3> This cross-sectional study of physician behavior used data from electronic health record systems in primary care offices in the United States to analyze primary care appointments occurring in 2017 for patients with a new painful condition who had not received an opioid prescription within the past year. <h3>Main Outcomes and Measures</h3> The association between treatment decisions and 2 dimensions of appointment timing (order of appointment occurrence and delay relative to scheduled start time) were assessed. The rates of opioid prescribing were measured and compared with rates of nonopioid pain medication (ie, nonsteroidal anti-inflammatory drugs) prescribing and referral to physical therapy. All rates were estimated within the same physician using physician fixed effects, adjusting for patient, appointment, and seasonal characteristics. <h3>Results</h3> Among 678 319 primary care appointments (642 262 patients; 392 422 [61.1%] women) with 5603 primary care physicians, the likelihood that an appointment resulted in an opioid prescription increased by 33% as the workday progressed (1st to 3rd appointment, 4.0% [95% CI, 3.9%-4.1%] vs 19th to 21st appointment, 5.3% [95% CI. 5.1%-5.6%];<i>P</i> &lt; .001) and by 17% as appointments ran behind schedule (0-9 minutes late, 4.4% [95% CI, 4.3%-4.6%] vs ≥60 minutes late, 5.2% [95% CI, 5.0%-5.4%];<i>P</i> &lt; .001). Prescribing of nonsteroidal anti-inflammatory drugs and referral to physical therapy did not display similar patterns. <h3>Conclusions and Relevance</h3> These findings suggest that, even within an individual physician's schedule, clinical decision-making for opioid prescribing varies by the timing and lateness of appointments.