tbuckley/cabot-search huggingface dataset:
A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug‐induced liver injury and postinjury inflammation in mice
Authors: Peter Lundbäck, Jonathan D. Lea, Agnieszka Sowinska, Lars Ottosson, Camilla Melin Fürst, Johanna Steen, Cecilia Aulin, Joanna I. Clarke, Anja Kipar, Lena Klevenvall, Huan Yang, Karin Palmblad, B. Kevin Park, Kevin J. Tracey, Anna M. Blom, Ulf Andersson, Daniel J. Antoine, Helena Erlandsson Harris
Journal: Hepatology (2016)

Acetaminophen (APAP) overdoses are of major clinical concern. Growing evidence underlines a pathogenic contribution of sterile postinjury inflammation in APAP‐induced acute liver injury (APAP‐ALI) and justifies development of anti‐inflammatory therapies with therapeutic efficacy beyond the therapeutic window of the only current treatment option, N ‐acetylcysteine (NAC). The inflammatory mediator, high mobility group box 1 (HMGB1), is a key regulator of a range of liver injury conditions and is elevated in clinical and preclinical APAP‐ALI. The anti‐HMGB1 antibody (m2G7) is therapeutically beneficial in multiple inflammatory conditions, and anti‐HMGB1 polyclonal antibody treatment improves survival in a model of APAP‐ALI. Herein, we developed and investigated the therapeutic efficacy of a partly humanized anti‐HMGB1 monoclonal antibody (mAb; h2G7) and identified its mechanism of action in preclinical APAP‐ALI. The mouse anti‐HMGB1 mAb (m2G7) was partly humanized (h2G7) by merging variable domains of m2G7 with human antibody‐Fc backbones. Effector function‐deficient variants of h2G7 were assessed in comparison with h2G7 in vitro and in preclinical APAP‐ALI. h2G7 retained identical antigen specificity and comparable affinity as m2G7. 2G7 treatments significantly attenuated APAP‐induced serum elevations of alanine aminotransferase and microRNA‐122 and completely abrogated markers of APAP‐induced inflammation (tumor necrosis factor, monocyte chemoattractant protein 1, and chemokine [C‐X‐C motif] ligand 1) with prolonged therapeutic efficacy as compared to NAC. Removal of complement and/or Fc receptor binding did not affect h2G7 efficacy. Conclusion: This is the first report describing the generation of a partly humanized HMGB1‐neutralizing antibody with validated therapeutic efficacy and with a prolonged therapeutic window, as compared to NAC, in APAP‐ALI. The therapeutic effect was mediated by HMGB1 neutralization and attenuation of postinjury inflammation. These results represent important progress toward clinical implementation of HMGB1‐specific therapy as a means to treat APAP‐ALI and other inflammatory conditions. (H epatology 2016;64:1699‐1710).
Abstract 1485: Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment
Authors: Luuk van Hooren, Maria Georganaki, Hua Huang, Sara Mangsbo, Anna Dimberg
Journal: Cancer Research (2016)

Abstract CD40-activating immunotherapy has potent anti-tumor effects due to its ability to activate dendritic cells and induce cytotoxic T-cell responses. However, its efficacy is limited by accumulation of immunosuppressive cells in the tumor and by endothelial anergy induced by pro-angiogenic growth factors. Here, we show that combining agonistic CD40 monoclonal antibody (mAb) therapy with vascular targeting using the tyrosine kinase inhibitor sunitinib significantly decrease tumor growth and improve survival in B16.F10 melanoma and T241 fibrosarcoma. Treatment of tumor-bearing mice with anti-CD40 mAb lead to increased activation of CD11c+ dendritic cells in the tumor draining lymph node, as evidenced by enhanced CD86 expression, while sunitinib treatment reduced vessel density. CD11b+Gr1+ myeloid derived suppressor cells accumulated in the tumor draining lymph nodes after anti-CD40 mAb treatment. This effect was reversed by co-treatment with sunitinib. Tumor endothelial expression of ICAM1 and VCAM1 adhesion molecules were increased only when anti-CD40 mAb treatment was combined with sunitinib. This was associated with enhanced tumoral infiltration of CD8+ T-lymphocytes. Our results show that combining CD40-stimulating immunotherapy with sunitinib treatment exert potent complementary antitumor effects mediated by dendritic cell activation, reduction in myeloid derived suppressor cells and increased endothelial activation, resulting in enhanced recruitment of cytotoxic T cells. Citation Format: Luuk van Hooren, Maria Georganaki, Hua Huang, Sara Mangsbo, Anna Dimberg. Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment. [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 1485.
Abstract 2234: Exploring the oncolytic potential of Newcastle Disease Virus
Authors: James A. Harper, Jon Travers, Ruth Franks, Shannon Burke, Christel Navarro, Cheng Xing, Weijia Wang, Qi Xu, Robert W. Wilkinson, Hong Jin, Danielle Carroll
Journal: Cancer Research (2016)

Abstract Oncolytic viruses are live, replication-competent viruses that infect and/or replicate selectively in tumour cells leading to the destruction of the infected cell. Cell death occurs as a natural consequence of the viral life cycle and newly produced virions can infect and kill neighbouring tumour cells leading to an amplified therapeutic effect. Oncolysis has the added benefit of potentially producing novel tumour antigens that can induce an immune-mediated therapeutic response. Newcastle Disease Virus (NDV) is an avian paramyxovirus, which has proven safety and demonstrated efficacy against a variety of mammalian cancers in PhI clinical studies. Using reverse genetics, we generated a recombinant strain of NDV that overcomes environmental and regulatory concerns uncoupling oncolytic potency and avian pathogenicity. We have additionally inserted the GM-CSF gene in order to maximize anti-tumour immune response and provide an in situ, patient/tumour- specific vaccine, combined with potent oncolysis. We have evaluated the biological characteristics of recNDVGM-CSF in vivo and in vitro. In vitro recNDVGM-CSF selectively replicates in and kills a wide variety of tumour cell types. In vivo, using a fibrosarcoma model that supports viral replication, a single administration (intra-tumoural or systemic) was able to cure 80% of tumour bearing mice. Additionally, following IV administration recNDVGM-CSF localises to and replicates within the tumour leading to a localised GM-CSF production within the tumour. The inherent properties of NDV (self-propagation, tumour-selective replication, immune activation) coupled with the ability to genetically engineer NDV to express therapeutic transgenes may provide a multi-modal attack on the tumour, delivering greater benefit to patients. Citation Format: James A. Harper, Jon Travers, Ruth Franks, Shannon Burke, Christel Navarro, Cheng Xing, Weijia Wang, Qi Xu, Robert W. Wilkinson, Hong Jin, Danielle Carroll. Exploring the oncolytic potential of Newcastle Disease Virus. [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 2234.
Multimodality therapy (MMT) for locoregionally (LR) advanced cancer of the esophagus and gastroesophageal junction (E/GEJ): The impact of clinical heterogeneity
Authors: T. W. Rice, D. J. Adelstein, L. A. Rybicki, J. P. Saxton, S. C. Murthy, M. A. Carroll
Journal: Journal of Clinical Oncology (2005)

4047 Background: MMT programs for LR advanced cancer of the E/GEJ are usually protracted, with results that are often difficult to interpret because of nonuniformity of the population studied. We report mature results from a phase II trial of accelerated MMT with a focus on the impact of this clinical heterogeneity. Methods: Eligibility required a diagnosis of E/GEJ cancer, and an esophageal ultrasound (EUS) stage of at least T3 or N1 or M1a (M1b excluded). Patients (pts) were given a 12 day induction of radiation (1.5 Gy b.i.d. to a dose of 30 Gy), concurrent with 4 day continuous intravenous infusions of cisplatin (20mg/m2/day) and 5-fluorouracil (1000mg/m2/day) beginning on day 1. Surgery followed in 4–6 weeks, followed 6–10 weeks later by a second identical 12-day course of chemoradiotherapy (CRT). Results: From 10/99–3/03, 93 pts were enrolled; 96% were white, 86% male, and 83% had adenocarcinoma (ACA). EUS stage was T3N0M0 in 31%; T2–3N1M0 in 49%; and T4 or M1a in 19%. Induction CRT was well tolerated with no induction death, and grade 3–4 mucositis/dysphagia in 14%. Neutropenia < 1000/mm3 occurred in 38% requiring hospitalization for fever in 17%. Resection was possible in 83 pts (89%) with 3 (3%) peri-operative deaths. Post-operative CRT was possible in 65 pts and was similarly tolerated. With a median follow-up of 35 (range 20–59) months, the 3-year projected overall survival (OS) is 26%, freedom from recurrence (FFR) is 30%, and distant metastatic control (DMC) is 30%. Locoregional control in the 83 resected pts is 89%. The 3 year FFR was significantly worse for pts with ACA vs. squamous cancer (21% vs. 72%, P=.02), for the GEJ ACA pts vs. pts with ACA elsewhere (13% vs. 34%, P=.07), for EUS stage T4 or M1a vs. T3 or N1 (0% vs. 34%, P=.012), and for pathologically staged T4 or M1 vs. N1 vs. N0 disease (0% vs. 19% vs. 54%, P<.001). Similar observations were made for OS and DMC. Conclusions: This accelerated MMT is safe and feasible. Tumor location, histology, clinical stage and post-treatment pathologic stage impact significantly on results making comparisons of non-randomized experiences problematic. Distant metastases remain the major challenge in this disease. No significant financial relationships to disclose.
Outcomes after Autologous Stem Cell Transplantation for Mantle Cell Lymphoma Based on Remission Status and Induction Chemotherapy Regimen.
Authors: Brian G. Till, Theodore A. Gooley, Nathan Crawford, Ajay K. Gopal, David G. Maloney, Stephen H. Petersdorf, John M. Pagel, Leona Holmberg, William Bensinger, Oliver W. Press
Journal: Blood (2007)
Screening for Dysglycemia: Connecting Supply and Demand to Slow Growth in Diabetes Incidence
Authors: Mohammed K. Ali, K. M. Venkat Narayan
Journal: PLoS Medicine (2016)

Diabetes is one of the most devastating and costly conditions worldwide, leading to substantial burdens of macro-and microvascular diseases, as well as other disorders.Armed with evidence from randomized controlled trials [1][2][3] and other data showing that progression to type 2 diabetes can be effectively [4] and cost-effectively [5] delayed among people at high risk, several countries have embarked on rolling out prevention programs to slow the growing incidence of diabetes.Such programs center on evidence-based behavior change interventions aimed at promoting healthy diets, appropriate physical activity, and modest weight loss.The most recent initiatives include the United States government's authorization for diabetes preventive services to be covered for Medicare beneficiaries [6] and the launch by the United Kingdom's National Health Service of a nationwide diabetes prevention program [7].However, for these endeavors to successfully mitigate growing diabetes burdens, several important barriers to implementation of prevention strategies need to be overcome (Fig 1), and screening for dysglycemia is a key part of this process to connect demand with a growing supply of preventive services.The principle that underlies screening for dysglycemia is to accurately identify risk of type 2 diabetes without causing physical or psychological harm and to motivate at-risk individuals to connect with appropriate health care and preventive services.While definitions of prediabetes vary, people with elevated fasting or 2-hour glucose, hemoglobin A1c, or any combination of these, albeit not in the diabetes range, have a 4-12 times higher annual likelihood of developing diabetes than the general, normoglycemic population [8].Screening is therefore pertinent to identify these persons, especially since nearly 47% of the 415 million people with diabetes worldwide, and a substantial yet unquantified proportion of those with prediabetes, remain unaware of their condition [9].Even in high-income countries like the US, over a quarter of the 29 million Americans with diabetes [10] and nearly 90% of the 86 million with prediabetes are not aware of their condition [11].These awareness gaps are likely to impede success of evidence-based interventions to prevent diabetes and its complications among adults with both prediabetes and diabetes.Although there are well-accepted, minimally-invasive glucose tests to accurately identify people with diabetes and prediabetes, and broad agreement that targeting persons at high risk for diabetes and offering glucose testing is more cost-effective and less harmful than universal testing [12], screening for dysglycemia has remained a contentious public health proposition for almost two decades.Debates about whether or not, and in whom, to encourage screening have led to disparate guidelines from influential expert committees [13,14], which may have
Weight Loss And Birth Rate in Obese Women
Authors: Anita Slomski
Journal: JAMA (2016)

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Non-specific binding and steric hindrance thresholds for penetration of particulate drug carriers within tumor tissue
Authors: Jimena G. Dancy, Aniket S. Wadajkar, Craig S. Schneider, Joseph R.H. Mauban, Olga G. Goloubeva, Graeme F. Woodworth, Jeffrey A. Winkles, Anthony J. Kim
Journal: Journal of Controlled Release (2016)
Dietary Guidelines for Americans—Eat Less Saturated Fat
Authors: Aaron P. Frank, Deborah J. Clegg
Journal: JAMA (2016)

New US dietary guidelines have been designed to help Americans choose and maintain a healthy diet.

The Dietary Guidelines for Americans were created by the US Departments of Health and Human Services and Agriculture and were updated in 2016. The guidelines are intended to help Americans make healthier food and beverage choices. This is important because 2 of every 3 Americans are either overweight or obese, and obesity is one of the most important causes of preventable diseases like heart attack and stroke. A summary of these guidelines was published in the February 2, 2016, issue of JAMA.
PWE-278 Does the length of time between diagnosis of colon cancer and undergoing a major resection affect the 2 year survival rate of patients?: Abstract PWE-278 Table 1
Authors: A Kuryba, K Walker, N Scott, J van der Meulen
Journal: Gut (2015)

<h3>Introduction</h3> Patients can be concerned that a delay of several weeks between colon cancer diagnosis and surgery might adversely affect their outcome. We investigated whether the length of time between diagnosis and major resection affected the 2 year all-cause mortality rate for patients with colon cancer. <h3>Method</h3> We used data from the National Bowel Cancer Audit to study patients who were diagnosed with colon cancer (excluding rectal cancer) in England between 1 April 2008 and 31 March 2011, who subsequently underwent an elective major resection within 8 weeks of this diagnosis. We derived patient/ tumour characteristics and time to procedure from audit data. Patient survival, mode of admission and co-morbidities were established via data linkage to HES (Hospital Episode Statistics). We calculated the observed and adjusted 2 year mortality rate for two week time bands (&lt;14 days, 14–27 days, 28–41 days, 42–55 days). Our risk adjustment model included year of surgical procedure, patient age, sex, tumour site, tumour stage (TNM), ASA grade, HES mode of hospital admission and patient co-morbidity. <h3>Results</h3> 17,854 patients were eligible for analysis: 2,972 (16.6%) died within 2 years of their major resection procedure. The overall observed 2 year mortality rate was 16.2% and was highest in the group of patients who underwent surgery within 14 days of diagnosis (20.1%). Those who underwent surgery within 28 to 41 days had the lowest observed mortality rate (13.8%). This trend in 2 year mortality was reduced but still present after risk adjustment, with the adjusted 2 year mortality rate ranging from 15.4% (28–41 day group) to 17.0% (&lt;14 day group). <h3>Conclusion</h3> Patients who underwent surgery within 2 weeks of diagnosis had a higher 2 year all-cause mortality rate than those who underwent surgery between 4 and 6 weeks after diagnosis. These results suggest that the scheduling of colonic cancer surgery for administrative reasons, 4 weeks and more after diagnosis does not appear to adversely affect outcome. <h3>Disclosure of interest</h3> None Declared.
ERCC1, class III β-tubulin, p53, and RRM1-tailored selection of personalized chemotherapy for stage IV NSCLC patients: A prospective study.
Authors: Huiqin Guo, Yu Zhao, Jiangyang Lu, Zejian Li
Journal: Journal of Clinical Oncology (2012)

e18087 Background: ERCC1, class III β-tubulin, p53, and RRM1 are predictive molecular biomarkers of platinum agents, taxel, vinorelbine and gemcitabine respectively in personalized therapies of NSCLC. Tailored therapy with several of these markers suggested patient benefit was reported previously. But there was no report about prospective study involving all of these biomarkers. Here we report a prospective study that patients were treated with the personalized therapy tailored by these 4 markers to assess this new therapy approach. Methods: From Feb. 2009 to Feb. 2011, in our single group at the thoracic surgical department of PUMC hospital, we identified 48 patients with previously untreated stage IV NSCLC, ECOG PS of 0-2, and at least 2 of the 4 low expression level markers were eligible. The expression level of ERCC1, class III β-tubulin, p53, and RRM1 was assayed by immunohistochemical (IHC) staining with the tissue samples obtained from bronchoscopy biopsy, percutaneous lung biopsy or operation. Patients with low ERCC1/low class III β-tubulin expression received cisplatin/taxel, patients with high ERCC1/low class III β-tubulin expression received gemcitabine(with low RRM1 level) or vinorelbine (with low p53 level)/taxel, patients with low ERCC1/high class III β-tubulin expression received cisplatin/gemcitabine(low RRM1) or vinorelbine (low p53), and patients with high ERCC1/high class IIIβ-tubulin expression received gemcitabine/vinorelbine. A follow-up CT was performed after every 2 cycles chemotherapy and every 3 months after chemotherapy. PFS and OS were estimated by the Kaplan-Meier method. Results: Follow-up period was 35 months till Jan. 2012. 16(33.3%) patients died within follow-up period, 32(66.7%) patients are still alive. The overall response(CR+PR) rate is 85.4% with 10CR, 31 PR, 5 SD and 2 PD. Median PFS is 14 months and median OS was 27 months. And 1-year OS was 88.3% Conclusions: Our study suggest ERCC1, class III β-tubulin, p53, and RRM1-tailored selection of personalized chemotherapy of NSCLC could dramatically raise response rate and improve survival over standard chemotherapy. It might be a promising treatment option in the future..
Abstract 4443: Investigation of the promoter methylation status of the FHIT (fragile histidine triad) gene in larynx cancer
Authors: Semra Demokan, Kubra Akalin, Cansu Ozkoklesen, Murat Ulusan, Necati Enver, Nejat Dalay
Journal: Cancer Research (2016)

Abstract Purpose: Development of carcinoma is associated with epigenetic modifications. Methylation of CpG islands in the promoter regions can participate in gene silencing and promote tumor aggressiveness. The Fragile histidine triad (FHIT) gene, localized on chromosome 3, is a tumor suppressor gene and the abnormal methylation of FHIT. The FHIT regulates the G2/M cell cycle check point and apoptotic pathwaysin various types of cancer. Inactivation of FHIT due to methylation has been shown in breast, cervical, gastric and colon carcinomas. In our study, we evaluated the FHIT gene promoter methylation in patients with larynx carcinoma (LC). Experimental Design: Methylation of FHIT was investigated by bisulfite modification/methylation-specific polymerase chain reaction in tumors and matched normal tissue samples from 57 Turkish patients with LC. Results: The promoter region of the FHIT was methylated in 96.49% and 29.82% of the primary tumors and the corresponding normal tissue samples, respectively [p = 0.0001, chi-square = 14.2105, OR(95%CI) = 64.7(14.4-296.07)]. A methylation rate (less than 10%) was observed in 3.51% (2/57) and 70.18% (40/57) of tumor and normal samples, respectively. Moderate methylation levels (10-25%) were found in 3.51% (2/57) of the tumors and 1.75% (1/57) of the adjacent normal tissues. High methylation levels (&amp;gt;25%) were observed in 92.98% (53/57) and 28.07% (16/57) in the tumor and normal tissues, respectively. Conclusion: Methylation may play an important role in LC carcinogenesis. Although we found that there was significant association between the methylation levels of tumor and adjacent normal tissues, high methylation levels of the FHIT was observed in the tumors when compared to the levels in normal tissue. These results suggest that the methylation rates of FHIT gene may provide a suitable biomarker in LC carcinogenesis. Our study is still in progress to include a larger cohort of patients. Citation Format: Semra Demokan, Kubra Akalin, Cansu Ozkoklesen, Murat Ulusan, Necati Enver, Nejat Dalay. Investigation of the promoter methylation status of the FHIT (fragile histidine triad) gene in larynx 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 4443.
Osteochondral Regeneration: Tuning Cell Differentiation into a 3D Scaffold Presenting a Pore Shape Gradient for Osteochondral Regeneration (Adv. Healthcare Mater. 14/2016)
Authors: Andrea Di Luca, Ivan Lorenzo‐Moldero, Carlos Mota, Antonio Lepedda, Dietmar Auhl, Clemens Van Blitterswijk, Lorenzo Moroni
Journal: Advanced Healthcare Materials (2016)

A combination of human mesenchymal stem cells with additive manufacturing technology for the fabrication of scaffolds with instructive properties is presented by Lorenzo Moroni and co-workers on page 1753. This new fiber deposition pattern allows the generation of pores of different shapes within the same construct. The most rhomboidal pore geometry sustained enhances alkaline phosphatase activity and osteogenic related genes expression with respect to the other gradient zones when the gradient scaffold is cultured in a medium supporting both osteogenic and chondrogenic differentiation. This may contribute to enhance osteochondral regeneration in orthopedic treatments.