tbuckley/cabot-search huggingface dataset:
Abstract 1486: Pharmacodynamic response to HER2/CD3 bispecific antibody (HER2-TDB): evidence of T-cell recruitment and further rationale for combination treatment with anti-PD-L1
Authors: Ji Li, Maria Hristopoulos, Robyn Clark, Jennifer Johnston, Dion Slaga, Bu-Er Wang, Rafael Cubas, Klara Totpal, Melissa R. Junttila, Teemu T. Junttila
Journal: Cancer Research (2016)

Abstract Based on the recent clinical success of tumor immunotherapies that block immune suppressive mechanisms to restore T cell function, there is a profound interest in the clinical development of T cell targeted therapies. We have produced a trastuzumab-based HER2 T cell dependent bispecific antibody (HER2/CD3; HER2-TDB; Junttila et al Cancer Res 2014, 74:5561) that conditionally activates T cells resulting in lysis of HER2 expressing cancer cells at low picomolar concentrations. In vivo, HER2/CD3 can inhibit growth of established mammary tumors in mice at doses as low as 0,01 mg/kg. Due to its unique mechanism of action, which is unrelated to HER2 signaling or sensitivity to chemotherapeutic agents, HER2/CD3 can eliminate cells refractory to currently approved HER2 therapies and inhibit growth of Kadcyla insensitive mammary tumor models. Treatment with HER2-TDBs also results in tumor regression as a second line treatment for Kadcyla relapsed mammary tumors in mice. Spontaneous mammary tumors arising in MMTV-huHER2 transgenic animals are poorly immunogenic or “immunological deserts” due to their low mutational load and low T cell infiltration. Despite these attributes, HER2/CD3 shows remarkable activity in this model characterized by a robust increase in the number of infiltrating lymphocytes and CD8+ T cells as well as a significant enhancement of tumor CD8+ cytotoxic effector function as measured by increased IFNg production. In addition to inducing T cell proliferation, we further show that HER2/CD3 strongly recruits new T cells from the periphery and this leads to significantly increased T cell numbers in the mammary tumor tissue. Another notable feature of the response to HER2/CD3 treatment is a significant upregulation of PD-1 expression on tumor infiltrating CD8+ T cells. This observation adds a strong rationale for combining HER2/CD3 with anti-PDL1 treatment. Our in vitro experiments further demonstrate that PD-1/PD-L1 signaling can inhibit killing mediated by CD3 bispecific antibodies and that combining two immune therapies - direct polyclonal recruitment of T cell activity together with inhibiting the T cell suppressive PD-1/PD-L1 axis results in enhanced and durable long term responses in vivo. Citation Format: Ji Li, Maria Hristopoulos, Robyn Clark, Jennifer Johnston, Dion Slaga, Bu-Er Wang, Rafael Cubas, Klara Totpal, Melissa R. Junttila, Teemu T. Junttila. Pharmacodynamic response to HER2/CD3 bispecific antibody (HER2-TDB): evidence of T-cell recruitment and further rationale for combination treatment with anti-PD-L1. [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 1486.
Abstract 118: A comprehensive profile of the genomic architecture of curable prostate cancer
Authors: Michael E. Fraser, Theodorus van der Kwast, John McPherson, Colin C. Collins, Yves Fradet, Bernard Tetu, Alain Bergeron, Rob G. Bristow, Paul C. Boutros
Journal: Cancer Research (2016)

Abstract There is an urgent need to develop novel biomarkers of treatment response for precision medicine in prostate cancer, particularly in the setting of localized, non-indolent disease, which represents the vast majority of cases at initial clinical presentation. The Canadian Prostate Cancer Genome Network (CPC-GENE) - a member of the International Cancer Genome Consortium - aims to identify multi-modal prognostic and predictive signatures of therapeutic outcome based on intrinsic tumour genomics, transcriptomics, and epigenomics, which are being incorporated into novel clinical trials of treatment escalation/de-escalation for image-guided radiotherapy and/or radical prostatectomy. Herein we report the results of the largest prostate cancer whole-genome sequencing study to date, consisting of 194 patients and whole-exome sequencing of 479 patients with localized, potentially curable disease; a sample size that allows for saturating discovery of genes mutated at ≥1% frequency. We show that tumours treated by curative local therapy have a paucity of clinically-actionable mutations relative to high-risk localized or metastatic disease, but instead harbor a significant number of recurrent non-coding aberrations and genomic rearrangements, including a novel inversion - and an associated reduction in gene expression - of the PTEN tumour suppressor gene on chromosome 10. The median tumour contains three distinct driver mutations, with &amp;gt;86% of tumours possessing at least one known driver. Importantly, multiple driver aberrations are associated with patient outcome, including copy number aberrations and methylation events, but notably excluding well-described recurrent events such as TMPRSS2:ERG fusions and SPOP point mutations. Localized hypermutation events (e.g. kataegis) were detected in &amp;gt;20% of tumours, and were strongly enriched for aggressive disease. Taken together, these data provide a comprehensive analysis of the genomic landscape of localized, non-indolent prostate cancer. Moreover, our results strongly suggest that specific molecular aberrations may serve as useful biomarkers for improved pre-treatment stratification of patients with localized, low/intermediate risk disease into escalation/de-escalation protocols, and support the development of clinical trials to assess this hypothesis, based on patient-specific molecular profiles. Citation Format: Michael E. Fraser, Theodorus van der Kwast, John McPherson, Colin C. Collins, Yves Fradet, Bernard Tetu, Alain Bergeron, Rob G. Bristow, Paul C. Boutros. A comprehensive profile of the genomic architecture of curable prostate 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 118.
Clinical Considerations on the Duration of Left Ventricular Systoles
Authors: Yoshiaki Hishimoto, Tohru Matsuura, Toshiaki Kiriyama, Masakazu Ochiai, Hiroshi Kunishige, Susumu Marumoto, Isao Niki, Naoto Endo
Journal: Circulation (1968)

Tension period, isometric contraction time and ejection time were measured in 20 normal subjects and 72 patients with nonvalvular heart disease to evaluate the usefulness of the duration of left ventricular systoles as an index of the ventricular performance. Left ventricular function could not be manifested with only one of those durations. The ratio of ejection time to isometric contraction time demonstrated a parallelism to changes in left ventricular performance. Serial observations of this ratio offer a convenient detection for the changes in left ventricular per-formance.
Abstract 4859: Identifying high quality, potent and selective inhibitors of ATM kinase: Discovery of AZD0156
Authors: Kurt G. Pike
Journal: Cancer Research (2016)

Abstract Ataxia telangiectasia mutant (ATM) is a serine/threonine protein kinase from the phosphatidylinositol 3-kinase-related kinase (PIKK) family of protein kinases (also comprising ATR, DNA-PKcs, mTOR etc.) and plays a crucial role in the cellular DNA damage response signalling activated by DNA double strand breaks (DSB). Activated ATM promotes DNA repair and S/G1-cell cycle checkpoints to prevent premature mitosis, maintain genomic integrity and promote appropriate cell survival or death pathways. DSBs arise intrinsically through the collapse of stalled replication forks, which are induced by a wide range of chemotherapies, or extrinsically through exposure to ionizing radiation. Therefore, ATM inhibition represents an exciting clinical opportunity as a target to hyper-sensitize tumors to chemo/radiotherapy. Herein, we describe our efforts to identify multiple, novel series of ATM inhibitors. We will describe our optimization efforts with particular attention given to improving the potency of the compounds in cellular systems and the selectivity of the compounds over other closely related proteins (e.g. ATR, mTOR etc.). We will also describe our efforts to optimize both the physicochemical properties of the molecules as well as the pharmacokinetic profile to enable low dose, oral administration in the clinic. These efforts culminated in the discovery of the clinical candidate AZD0156, a first in class orally available ATM inhibitor. AZD0156 shows sub-nanomolar potency in cell based assays of ATM inhibition with selectivities of greater than 1000 fold over other members of the PIKK family of enzymes. AZD0156 is a permeable, highly soluble compound with excellent preclinical pharmacokinetic properties including oral bioavailability. AZD0156 shows robust efficacy in mouse xenograft models after oral administration when combined with DSB inducing agents. AZD0156 is currently undergoing early clinical assessment. Citation Format: Kurt G. Pike. Identifying high quality, potent and selective inhibitors of ATM kinase: Discovery of AZD0156. [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 4859.
Expression of C1ql3 in Discrete Neuronal Populations Controls Efferent Synapse Numbers and Diverse Behaviors
Authors: David C. Martinelli, Kylie S. Chew, Astrid Rohlmann, Matthew Y. Lum, Susanne Ressl, Samer Hattar, Axel T. Brunger, Markus Missler, Thomas C. Südhof
Journal: Neuron (2016)
PTU-069 Predictors of hepatitis C treatment outcome in genotype 1 patients in a “real world” setting
Authors: C Sieberhagen, A S M Brown, D G Demuth, J A Livingstone, M E Cramp
Journal: Gut (2010)

<h3>Introduction</h3> Many factors affect treatment outcomes in Hepatitis C genotype 1 patients, some of which may differentiate between those achieving sustained viral response (SVR) and those who don9t. Several variables were studied in unselected patients to look at predictive factors for achieving SVR. <h3>Methods</h3> Medical records of 438 patients treated with PEG-IFN α-2b and Ribavirin from 20 UK centres were studied to better understand factors predicting successful treatment outcome in the “real world” outside clinical trials. Data included patient demographics, SVR rates, early viral response (EVR), rapid viral response (RVR), methadone and other medication use and lab assay data. This study was supported by Schering-Plough. <h3>Results</h3> HCV was contracted from injection drug use (61%), blood/blood products (13%) or other source (26%). 55% (243/438) of patients achieved SVR. As expected, male sex, high viral load and cirrhosis were all associated with failure to achieve SVR. 78% (341/438) had a liver biopsy prior to treatment, 12% were cirrhotic. The use of methadone / buprenorphine (65/438) or antidepressants (102/438) did not affect SVR negatively. EPO and GCSF were used in a small number of cases (2%). Higher doses and longer duration use was associated with greater chance of achieving SVR. Younger age (40 vs 46 years, p&lt;0.001) and starting treatment sooner (28 vs 40 months, SVR vs non-SVR, P&lt;0.05) were important factors in achieving SVR. ALT level at baseline was significantly higher in patients achieving SVR (p&lt;0.05). Early normalisation of ALT (week 4) was significantly associated with achieving SVR (p&lt;0.001). GGT levels were significantly higher in patients not achieving SVR (p&lt;0.05). 130 patients had an early viral response. These were divided into two groups – EVR with HCV RNA undetectable (EVR-U, n=73), and those that had &gt;2 log drop in HCV RNA but RNA still detectable at 12 weeks (EVR-D, n=57). EVR-U patients were more likely to achieve SVR when compared to EVR-D patients (p&lt;0.001). 18 patients had a rapid viral response (treatment week 4) with 89% achieving SVR. <h3>Conclusion</h3> Treatment outcomes in UK real world patients mirror results of registration trials, despite treatment of significant numbers on opiate substitutes and antidepressants. Early normalisation of ALT on treatment strongly predicted achieving SVR and may be useful in encouraging adherence. Interestingly, a high GGT appears to be associated with a poorer outcome.
Abstract 2837: The CDK4/6 inhibitor has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma
Authors: Bo Mi Ku, Jiae Koh, Yeon-Hee Bae, Jong-Mu Sun, Se-hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
Journal: Cancer Research (2016)

Abstract Head and neck squamous cell carcinoma (HNSCC) is a rare lethal human malignancy with no effective therapy. It is critical to identify new therapeutic strategies for NHSCC. Deregulation of CDKN2A (p16) or CCND1 (cyclin D1) occurs commonly in HNSCC and induces sustained cyclin-dependent kinase (CDK) 4/6 activation. The selective CDK4/6 inhibitor, LY2835219 inhibited CDK4/6-dependent Ser780 phosphorylation in retinoblastoma (RB) and induced cell cycle arrest and growth inhibition. In an animal xenograft model of HNSCC, LY2835219 treatment led to reduced tumor growth. However, because single-agent treatment with LY2835219 showed a limited effect in HNSCC, a combinational strategy is necessary for effective therapy. At the molecular level, we found that LY2835219 inhibited activation of AKT and ERK, but not mTOR. The combination of LY2835219 with mTOR inhibitor was found to be more effective than either drug alone in vitro and in vivo. Taken together, our findings suggest that a combination treatment with LY2835219 and mTOR inhibitor is a promising therapeutic approach for HNSCC. Citation Format: Bo Mi Ku, Jiae Koh, Yeon-Hee Bae, Jong-Mu Sun, Se-hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn. The CDK4/6 inhibitor has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma. [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 2837.
Abstract 1981: Histone demethyalase JMJD1A promotes the DNA damage response of prostate cancer cells
Authors: Lingling Fan, Guihong Peng, Natasha Sahgal, Ladan Fazli, Martin Gleave, Yuji Zhang, Arif Hussain, Feyruz Rassool, Jianfei Qi
Journal: Cancer Research (2016)

Abstract DNA damage is a common feature of prostate cancer (PCa) therapies (e.g. radio-, chemo- and androgen deprivation therapies). Thus, the DNA damage response (DDR) is a key factor in determining the therapeutic response of PCa patients. JMJD1A regulates gene expression by demethylating H3K9. Here, we identified a new role for JMJD1A in the DDR of PCa cells. Inhibition of JMJD1A led to increased r-H2AX foci (marker for the double strand DNA breaks) in the non-irradiated cells, and the delayed clearance of r-H2AX foci in the irradiated cells. JMJD1A knockdown in PCa cells inhibited the DNA strand break repair in the reporter assays. We further found that phosphorylation and ubiquitination were key modifications that regulate the activity of JMJD1A in the DDR. Ectopic expression of the mutant JMJD1A at the phosphorylation or ubiquitination site attenuated the expression of DNA repair factors, DNA strand break repair, and PCa cell proliferation under irradiation and androgen deprivation conditions. Our results suggest that targeting JMJD1A may sensitize the response of PCa to the major anti-PCa therapies. Citation Format: Lingling Fan, Guihong Peng, Natasha Sahgal, Ladan Fazli, Martin Gleave, Yuji Zhang, Arif Hussain, Feyruz Rassool, Jianfei Qi. Histone demethyalase JMJD1A promotes the DNA damage response of prostate cancer cells. [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 1981.
Unique pathology of colonic spirochaetosis characterised by mucosal eosinophilia is linked to diarrhoea and IBS
Authors: Thomas M Goodsall, Nicholas J Talley, Loui Rassam, Nicola K Wood, Alkesh Zala, Mike Jones, Marjorie M Walker
Journal: Gut (2016)

Dear Sir,

We read with interest the commentary of Raes1 on the growing clinical role of microbiome-based companion diagnostics. We agree that the future of microbiome in medical practice will be in using markers for diagnosis as well as predicting and personalising treatment. We report here new observations on a colonic bacteria that, while traditionally considered a commensal, may be important in chronic diarrhoea and IBS.

Colonisation of the colon by Brachyspira aalborgi and B. pilosicoli is characterised by the histological finding of extensive, densely packed, end-on attachment of spirochaetes to the mucosal wall, which is visible on HE bacterial colonisation is dramatically demonstrated by Warthin-Starry staining like Helicobacter pylori (figure 1).2 ,3 The significance of this finding and its role in human disease has been debated in the literature and generally colonic spirochaetosis (CS) is considered to be a …
Out of Hospital Treatment of Acute Pulmonary Embolism in Patients with a Low NT-ProBNP Level.
Authors: Mariette J Agterof, Roger E.G. Schutgens, Repke J Snijder, G. Epping, Henny G Peltenburg, Ward Posthuma, J. A. Hardeman, Rene Van der Griend, Ted Koster, Martin Prins, Douwe Biesma
Journal: Blood (2009)
Bladder cancer risk: Use of PLCO and NLST to identify a suitable screening cohort.
Authors: Laura-Maria Krabbe, Robert Scott Svatek, Shahrokh F. Shariat, Edward M. Messing, Yair Lotan
Journal: Journal of Clinical Oncology (2014)

4546 Background: Bladder cancer (BC) screening is not accepted in part due to low overall incidence. We utilized the PLCO and NLST to identify optimal high-risk populations most likely benefit from screening. Methods: Data were extracted from PLCO and NLST to stratify risk of BC by overall population, gender, race, age at inclusion and smoking status. Incidence rates between groups were compared using chi-square test. Results: BC was identified in 1430/154,898 in PLCO and 439/53,173 in NLST. BCs were grades III/IV in 36.8% and 41.3%, respectively. Incidence rates were significantly higher in men than women (PLCO: 1.4 vs. 0.31/1000 person-years, NLST: 1.84 vs. 0.6/1000 person-years, both p<0.0001). In proportional hazards models, male sex, higher age, duration and intensity of smoking were associated with higher risk of BC (all p<0.0001). In men >70 with smoking exposure of 30 pack years (PY) and more, incidence rates were as high as 11.92 (PLCO) and 5.23 (NLST) (per 1000 person-years). In current high intensity smokers (≥50 PY) the gender disparity in incidence persists in both trials (0.78 vs. 2.99 per 1000 person-years in PLCO and 1.12 vs. 2.65 per 1000 person years in NLST). Conclusions: Men over 60 years with a smoking history of >30 PY generate incidence rates over 2/1000 person-years, which could serve as an excellent population for screening trials. Gender differences in BC incidence cannot be readily explained by differences in exposure to tobacco, since in PLCO and NLST the gender disparity persisted regardless of smoking intensity.
Telephone prompting to increase attendance at a Psychiatric Outpatient Clinic
Authors: R W Burgoyne, F X Acosta, J Yamamoto
Journal: American Journal of Psychiatry (1983)

Although it has been commonly taught and has been reported elsewhere that telephone prompting increases the rate at which patients keep their first outpatient clinic appointment, this study indicated that the increased rate at which patients kept their first appointment was more likely related to socioeconomic factors (such as having a telephone) than to telephone prompting. The authors conclude that measures to improve services to patients need to be carefully scrutinized before one can assume that results following initiation of a new procedure are in fact due to that procedure.
Abstract 2205: Exosomal encapsulation of doxorubicin reduces the cardiac toxicity of mice
Authors: Flavio Rizzolio, Mohamad Hadla, Giuseppe Corona, Isabella Caligiuri, Stefano Palazzolo, Sabrina Semeraro, Amelia Gamini, Vincenzo Canzonieri, Giuseppe Toffoli
Journal: Cancer Research (2016)

Abstract Exosomes are nanovesicles produced by cells embedded of cellular information and represent a formidable natural cargo for communication. The name “FedExosomes” denotes the general idea that exosomes could deliver cargo that conveniently manipulated could be of help for patient therapy. Up to now, a few papers demonstrated that modified exosomes could deliver drugs specifically to cancer cells and many laboratories are now studying their properties and compositions. Differently from previously published papers that focused on the efficacy of the doxorubicin encapsulated in exosomes (exoDOX), for the first time, we demonstrated that unmodified exosomes loaded with DOX are less toxic than free DOX by altering the biodistribution of the drug. The heart tissue of mice treated with a toxic dosage of DOX exhibited scattered cytoplasmic paranuclear vacuoles and focal intense eosinophilic cytoplasm, devoid of their transversal striations with moderate disarrangement of cardiomyocytes. The heart tissue of exoDOX treated mice at the same dosage appeared normal. Mass spectrometry studies confirmed that although the quantity of exoDOX in the blood was the same compared to DOX, accumulation in the heart was reduced of about forty percent. Maximum tolerated dose of exoDOX treated mice is double than free DOX. Mice treated at double concentration of exoDOX vs DOX have reduced tumor burden compared to free DOX without observable toxicity. We demonstrated that exoDOX increased the therapeutic index of DOX by reducing toxic side effects and envisage a similar mechanism for others chemotherapeutic drugs. Since the exosomes could be prepared directly from the patients, our preclinical approach could have a possible immediately application in the clinic. Citation Format: Flavio Rizzolio, Mohamad Hadla, Giuseppe Corona, Isabella Caligiuri, Stefano Palazzolo, Sabrina Semeraro, Amelia Gamini, Vincenzo Canzonieri, Giuseppe Toffoli. Exosomal encapsulation of doxorubicin reduces the cardiac toxicity of mice. [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 2205.
Genome-Wide Association Analyses Identify Susceptibility Loci For Vincristine-Induced Peripheral Neuropathy In Children With Acute Lymphoblastic Leukemia
Authors: Barthelemy Diouf, Kristine Crews, Glen Lew, Deqing Pei, Cheng Cheng, Ju Bao, Jie Zheng, Wenjian Yang, Yiping Fan, Steven W. Paugh, Joseph Robert McCorkle, Xiaomin Lu, Naomi J. Winick, William L. Carroll, Mignon L. Loh, Stephen P. Hunger, Meenakshi Devidas, Ching-Hon Pui, Mary V. Relling, William E. Evans
Journal: Blood (2013)
THE ROLE OF BILIARY CHOLESTEROL AND PHOSPHOLIPIDS IN THE REGULATION OF PLASMA-LIPID LEVELS - STUDIES IN MDR2 TRANSGENIC MICE
Authors: F Kuipers, Jjm Smit, Rpjo Elferink, R Ottenhof, Ah Schinkel, Hj Verkade, Rj Vonk, P Borst, Ak Groen
Journal: Circulation (1994)