tbuckley/cabot-search huggingface dataset:
Positioning SGLT2 Inhibitors/Incretin-Based Therapies in the Treatment Algorithm
Authors: John P.H. Wilding, Surya Panicker Rajeev, Ralph A. DeFronzo
Journal: Diabetes Care (2016)

Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are the most recent addition to the therapeutic options available for the treatment of type 2 diabetes and became available after the introduction of incretin-based therapies, dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs). These agents have potential advantages with regard to their weight loss–promoting effect, low risk of hypoglycemia, reduction in blood pressure, and reduction in cardiovascular events in high-risk patients (with empagliflozin). Apart from these clinically important outcomes, they may also correct core defects present in type 2 diabetes (i.e., improvement in β-cell function and insulin sensitivity). They do, however, have some adverse effects, notably, nausea with GLP-1 RAs and genital tract infections and potential for volume depletion with SGLT2i. Whether incretin-based therapies are associated with an increased risk of pancreatitis is unclear. Most recently, diabetic ketoacidosis has been reported with SGLT2i. Therefore, a key clinical question in relation to guidelines is whether these clinical advantages, in the context of the adverse effect profile, outweigh the additional cost compared with older, more established therapies. This article reviews the therapeutic rationale for the use of these newer drugs for diabetes treatment, considers their place in current guidelines, and discusses how this may change as new data emerge about their long-term efficacy and safety from ongoing outcome trials.
Abstract 1642: Calponin-3, acidic (CNN3) mediates EMT-related genes in human colorectal cancer metastasis
Authors: Soon-Chan Kim, Chang-Won Hong, Sang-Geun Jang, Yeh-Ah Kim, Seung-Yong Jung, Jea-Gab Park, Ja-Lok Ku
Journal: Cancer Research (2016)

Abstract (a) An introductory sentence indicating the purposes of the study Distant metastasis is the major cause of cancer-related death in colorectal cancer (CRC) patients. Although the Calponin family has emerged as a distinguishing feature in epithelial-to-mesenchymal transition (EMT) in human cancer, the role of CNN3 member in the metastatic CRC has not been investigated. (b) A brief description of pertinent experimental procedures. Three pairs of primary CRC and corresponding matched metastasis cell lines were analyzed for gene expression by microarray and western blotting. CNN3 was transduced to CRC cell line with lower CNN3 expression level (SW-480), and CNN3 with higher CNN3 expression CRC cell lines (SW-620, HCT-116) was suppressed by lentiviral-induced shRNA. Functional analysis of CNN3 overexpression and suppression was investigated in these CRC cell lines for proliferation and invasion. Expression of several potential CNN3 target genes (ERK1/2) and EMT markers (E-cadherin and vimentin) in primary CRC and matching metastasis CRC cell lines was validated. (c) A summary of the new, unpublished data. Global CNN3 expression levels were significantly higher in metastasis cell lines compared with the matched primary cell lines in both mRNA (FC = 2.3, p = 0.017) and protein levels. CRC cell lines with suppressed CNN3 showed decreased cell proliferation and reduced invasive behavior in CRC cell lines. Suppression of CNN3 in CRC cell lines with higher CNN3 expression resulted in increased E-cadherin and decreased vimentin. pERK1/2 were decreased in accordance with suppression of CNN3 in both SW-620 and HCT-116. Overexpression of CNN3 in CRC cell lines caused reduced E-cadherin in SW-480 and HT-29. (d) A statement of the conclusions CNN3 is involved in mediating EMT and metastatic behavior in the colon. Its expression is accordantly related to EMT markers, and CNN3 may serve as a possible diagnostic marker and therapeutic target for patients with CRC. Citation Format: Soon-Chan Kim, Chang-Won Hong, Sang-Geun Jang, Yeh-Ah Kim, Seung-Yong Jung, Jea-Gab Park, Ja-Lok Ku. Calponin-3, acidic (CNN3) mediates EMT-related genes in human colorectal cancer metastasis. [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 1642.
The Prostate Cancer Working Group 3 (PCWG3) consensus for trials in castration-resistant prostate cancer (CRPC).
Authors: Howard I. Scher, Michael J. Morris, Walter Michael Stadler, Celestia S. Higano, Susan Halabi, Matthew Raymond Smith, Ethan M. Basch, Karim Fizazi, Charles J. Ryan, Emmanuel S. Antonarakis, Paul Gettys Corn, Glenn Liu, Johann Sebastian De Bono, Lawrence H. Schwartz, Tomasz M. Beer, William Kevin Kelly, Maha Hussain, A. Oliver Sartor, Philip W. Kantoff, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2015)

5000 Background: The availability of new agents for men with CRPC, recognition of new disease phenotypes, and an evolving regulatory environment have created the need for new CRPC clinical trial guidelines to succeed PCWG2, published in 2008. Methods: Eight face-to-face meetings were convened over 3 years to create the PCWG3 guidelines, with subcommittees meeting more frequently. PCWG2 criteria were updated or revised based on new evidence from clinical trial data and validation studies of PCWG2 recommendations Results: PCWG3 distinguishes between prostate adeno- and non-adenocarcinomas; considers the sequence and number of prior systemic therapies in lieu of the pre- and post-taxane distinctions in PCWG2; encourages detailed reporting of disease subtypes based on distribution patterns; and defines endpoints for patients transitioning between non-metastatic and metastatic disease. For non-cytotoxic therapies, outcomes are focused on establishing proof-of-mechanism and determining the optimal biologic dose. The strength of association between patient-reported outcomes, radiographic progression-free survival, circulating tumor cell enumeration, and time to clinical events is emphasized rather than alterations in individual biomarkers. Similarly, PCWG3 underscores the distinction between first evidence of progression based on one disease manifestation in contrast to terminating treatment because the patient is no longer benefitting. We emphasize the importance of documenting progression in existing lesions as distinct from the development of new lesions. The revised guidelines highlight the importance of serial biologic profiling of the disease from biopsies and/or blood to understand treatment resistance and identify predictive biomarkers of sensitivity for use in prospective trials. Conclusions: PCWG3 updates the PCWG2 consensus criteria based on available new treatments and disease manifestations, and data validating biomarkers that were proposed in PCWG2. The revised criteria define the endpoints for the M0 to M1 transition. These recommendations will guide clinical trial design and conduct for therapeutics being tested in both M0 and M1 CRPC patient populations.
PXR variants: the impact on drug metabolism and therapeutic responses
Authors: C. Trent Brewer, Taosheng Chen
Journal: Acta Pharmaceutica Sinica B (2016)

The pregnane X receptor (PXR) plays an important and diverse role in mediating xenobiotic induction of drug-metabolizing enzymes and transporters. Several protein isoforms of PXR exist, and they have differential transcriptional activity upon target genes; transcript variants 3 (PXR3) and 4 (PXR4) do not induce target gene expression, whereas transcript variants 1 (PXR1) and 2 (PXR2) respond to agonist by activating target gene expression. PXR protein variants also display differences in protein-protein interactions; PXR1 interacts with p53, whereas PXR3 does not. Furthermore, the transcript variants of PXR that encode these protein isoforms are differentially regulated by methylation and deletions in the respective promoters of the variants, and their expression differs in various human cancers and also in cancerous tissue compared to adjacent normal tissues. PXR1 and PXR4 mRNA are downregulated by methylation in cancerous tissue and have divergent effects on cellular proliferation when ectopically overexpressed. Additional detailed and comparative mechanistic studies are required to predict the effect of PXR transcript variant expression on carcinogenesis, therapeutic response, and the development of toxicity.
Abstract MP59: Associations of Maternal Pre-pregnancy Body Mass Index and Gestational Weight Gain with Offspring Longitudinal Change in BMI
Authors: Gabriella M Lawrence, Shani Shulman, Hagit Hochner, Colleen Sitlani, Ayala Burger, Bella Savitsky, Einat Granot-Hershkovitz, Thomas Lumley, Daniel Enquobahrie, Pandora L Wander, Orly Manor, David S Siscovick, Yechiel Friedlander
Journal: Circulation (2013)

Introduction A number of studies have demonstrated significant associations between changes in obesity-related phenotypes and subsequent risk of CHD. While accumulating evidence suggests that maternal pre-pregnancy body mass index (mppBMI) and gestational weight gain (GWG) may impact adult offspring adiposity, no study has examined their associations with longitudinal changes in obesity. Changes in obesity are likely to reflect genetic-environmental interactions and may have important implications for understanding CHD risk. Objectives We examined the associations of mppBMI and GWG with longitudinal change in offspring’s BMI and assessed whether these associations are explained in part by genetic effects. Methods We used a birth cohort of 1400 young adults born in Jerusalem, with extensive archival data as well as clinical information at age 32, and longitudinal change in BMI based on two examinations at ages 17 and 32. Genotyping of mothers and offspring was carried out for 180 candidate genes related to cardio-metabolic outcomes. We created genetic propensity scores using a subset of 388 SNPs from 53 adiposity-related genes that were predictive of the exposures and outcome, and fit linear regression models both with and without genetic scores to examine the associations of mppBMI and GWG with offspring change in BMI. Analyses used inverse probability weighting to account for a stratified sampling scheme (i.e. oversampling of offspring with low and high birth weight as well as of overweight and obese mothers). Results mppBMI was positively associated with change in BMI over time (p&lt;0.001), independent of GWG and confounders; there was an increase of 0.21 kg/m 2 in BMI change per increase of one standard deviation (SD) in mppBMI. A one-SD change in GWG was associated with a 0.16 kg/m 2 BMI change, independent of mppBMI and confounders. These associations were maintained irrespective of offspring BMI at age 17. The association between mppBMI with offspring change in BMI was slightly attenuated with the addition of genetic scores in the model (b=0.213 vs. 0.187). In the GWG model, when adjusted for the genetic scores a substantial decrease of 28.2% in the coefficient for GWG was observed (b=0.163 vs. 0.117). Conclusions This study points to the strong relationship between maternal excess weight and weight gain in pregnancy with offspring change in body size from adolescence to adulthood. Our findings suggest that genetic factors account, in part, for the association between GWG and offspring longitudinal change in BMI. Mapping genes underlying these associations with longitudinal change in BMI may potentially lead to targeted intervention strategies to reduce CHD risk.
Favorable Outcomes for Older Adolescents and Young Adults (AYA) with Acute Lymphoblastic Leukemia (ALL): Early Results of U.S. Intergroup Trial C10403
Authors: Wendy Stock, Selina M. Luger, Anjali S. Advani, Susan Geyer, Richard C. Harvey, Charles G. Mullighan, Cheryl L. Willman, Greg Malnassy, Edy Parker, Kristina M Laumann, Ben Sanford, Guido Marcucci, Elisabeth M. Paietta, Michaela Liedtke, David F. Claxton, Matthew C. Foster, Frederick R. Appelbaum, Harry Erba, Mark R. Litzow, Martin S. Tallman, Richard M. Stone, Richard A. Larson
Journal: Blood (2014)
Abstract LB-129: Epigenetic regulators to predict docetaxel sensitivity; a guide for treatment choice
Authors: Zachary A. Gurard-Levin, Laurence OW Wilson, Vera Pancaldi, Sophie Postel-Vinay, Fabricio G. Sousa, Cecile Reyes, Elisabetta Marangoni, David Gentien, Alfonso Valencia, Yves Pommier, Paul Cottu, Genevieve Almouzni
Journal: Cancer Research (2016)

Abstract The limited capacity to predict the response of a given patient to cancer therapy is a major hurdle in cancer management. To date, many standard-of-care chemotherapy agents act by directly binding or modifying DNA or indirectly during processes that rely on chromatin architecture, as exemplified with docetaxel. Therefore, alterations in chromatin organization may impact resistance mechanisms for these drugs. Here, we explore the mis-regulation of chromatin regulators—factors involved in the establishment and maintenance of functional chromatin domains—as a tool to predict the response to docetaxel. For a series of chromatin regulators, we exploit Affymetrix microarray and NanoString gene expression data generated from breast cancer patient derived xenograft (PDX) models, colorectal cancer organoids, and breast cancer patient samples treated with docetaxel. Random Forest classification reveals a limited set of chromatin regulators that readily distinguish docetaxel responders from non-responders. Since the candidate predictive factors feature key subunits of the chromatin remodeler SWI/SNF complex, we then explore the behavior of SWI/SNF subunits in the response to docetaxel in the large NCI-60 dataset and in cultured cells. All together, our results showcase the predictive value of chromatin regulators and reveal that the SWI/SNF chromatin remodeler associates tightly with docetaxel response in several settings. Our findings open avenues for applications as biomarkers, but also as therapeutic targets to sensitize patients towards docetaxel. These approaches offer a means to potentially combat drug resistance. Citation Format: Zachary A. Gurard-Levin, Laurence OW Wilson, Vera Pancaldi, Sophie Postel-Vinay, Fabricio G. Sousa, Cecile Reyes, Elisabetta Marangoni, David Gentien, Alfonso Valencia, Yves Pommier, Paul Cottu, Genevieve Almouzni. Epigenetic regulators to predict docetaxel sensitivity; a guide for treatment choice. [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-129.
High attenuation areas on chest computed tomography in community-dwelling adults: the MESA study
Authors: Anna J. Podolanczuk, Elizabeth C. Oelsner, R. Graham Barr, Eric A. Hoffman, Hilary F. Armstrong, John H.M. Austin, Robert C. Basner, Matthew N. Bartels, Jason D. Christie, Paul L. Enright, Bernadette R. Gochuico, Karen Hinckley Stukovsky, Joel D. Kaufman, P. Hrudaya Nath, John D. Newell, Scott M. Palmer, Dan Rabinowitz, Ganesh Raghu, Jessica L. Sell, Jered Sieren, Sushil K. Sonavane, Russell P. Tracy, Jubal R. Watts, Kayleen Williams, Steven M. Kawut, David J. Lederer
Journal: European Respiratory Journal (2016)

Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking. We measured high attenuation areas (HAA; percentage of lung voxels between −600 and −250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis. HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3–11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8–13.0), lower forced vital capacity (FVC) (mean adjusted difference −82 mL, 95% CI −119–−44), lower 6-min walk distance (mean adjusted difference −40 m, 95% CI −1–−80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43–2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39–1.79). High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults.
KEYNOTE-006 study of pembrolizumab (pembro) versus ipilimumab (ipi) for advanced melanoma: Efficacy by PD-L1 expression and line of therapy.
Authors: Adil Daud, Christian U. Blank, Caroline Robert, Igor Puzanov, Erika Richtig, Kim Allyson Margolin, Steven O'Day, Marta Nyakas, Jose Lutzky, Ahmad A. Tarhini, Elaine McWhirter, Christian Caglevic, Peter Mohr, Michael Millward, Marcus O. Butler, Honghong Zhou, Kenneth Emancipator, Scot Ebbinghaus, Nageatte Ibrahim, Georgina V. Long
Journal: Journal of Clinical Oncology (2016)

9513 Background: In KEYNOTE-006 (NCT01866319), pembro (MK-3475) provided superior OS and PFS and a lower grade 3-5 treatment-related AE rate over ipi in patients (pts) with advanced melanoma and ≤ 1 prior therapy. We assessed the impact of PD-L1 expression and prior therapy on outcomes in KEYNOTE-006. Methods: Pts were randomized to pembro 10 mg/kg Q2W or Q3W or ipi 3 mg/kg Q3W. Pembro was given for 24 mo or until progression, intolerable toxicity, or investigator decision. Ipi was given for 4 cycles or until progression, intolerable toxicity, or investigator decision. PD-L1 was assessed by IHC using the 22C3 antibody; positivity was defined as ≥ 1% staining in tumor and adjacent immune cells. Response was assessed at wk 12, Q6W until wk 48, then Q12W. Survival follow-up was every 12 wk. Primary end points were OS and PFS (RECIST v1.1, central review). Data cutoff date was Mar 3, 2015. Pembro arms were pooled for this analysis. Results: Of the 834 pts enrolled, 80% were PD-L1+, 18% were PD-L1–, and 2% were PD-L1 unknown; 66% were treatment naive and 34% had 1 line of prior therapy. PFS and ORR were improved with pembro regardless of line of therapy or PD-L1 status (Table); OS was improved with pembro in all but PD-L1– pts, although the sample size was small and the CI was wide. For pembro, the best outcomes occurred in treatment-naive pts and those with PD-L1+tumors, with marginal additional benefit in pts with both characteristics (Table). There was a relationship between increasing PD-L1 expression and improved outcomes with pembro vs ipi when PD-L1 was scored as IHC 0 (0% staining), 1 ( < 1%), 2 (1-9%), 3 (10-32%), 4 (33-65%), and 5 ( ≥ 66%). Conclusions: Pembro provides benefit over ipi in pts with advanced melanoma, regardless of tumor PD-L1 expression or whether pts received prior therapy. Clinical trial information: NCT01866319.Pembro vs Ipi PD-L1+ PD-L1– Treatment Naive 1 Prior Therapy PD-L1+, Treatment Naive PFS 6-mo rate, % 51 vs 25 32 vs 28 52 vs 28 38 vs 23 55 vs 28 HR (95% CI) 0.52 (0.43-0.64) 0.83 (0.55-1.26) 0.55 (0.44-0.69) 0.74 (0.55-0.99) 0.49 (0.38-0.63) OS 6-mo rate, % 87 vs 74 81 vs 73 87 vs 76 83 vs 71 88 vs 75 HR (95% CI) 0.56 (0.43-0.73) 0.95 (0.56-1.62) 0.63 (0.46-0.85) 0.67 (0.45-0.98) 0.55 (0.39-0.78) ORR, % 39 vs 13 25 vs 13 40 vs 13 29 vs 12 43 vs 13
An unforeseeable adverse event during ERCP
Authors: Laura Maggino, Stefano Crinò, Laura Bernardoni, Giovanni Marchegiani, Giuseppe Malleo, Roberto Salvia, Armando Gabbrielli
Journal: Endoscopy (2016)

A 24-year-old previously healthy woman was involved in a bus accident in Nepal and sustained major blunt abdominal trauma with complete transection of the pancreatic neck. After 16 days of emergency stabilization in a local hospital, she was transferred to our center. Even though she appeared asymptomatic, abdominal imaging confirmed disconnected pancreatic duct syndrome with a 10-cm fluid collection ([Fig. 1]). After multidisciplinary consultation, endoscopic transpapillary drainage was proposed [1] [2].
Abstract 3239: Cancer-associated fibroblasts induce immunosuppressive macrophages in head and neck squamous cell carcinoma
Authors: Hideyuki Takahashi, Koichi Sakakura, Kazuaki Chikamatsu
Journal: Cancer Research (2016)

Abstract Background Cancer-associated fibroblasts (CAFs) are one of main elements in the tumor microenvironment (TME). Among the innate and adaptive immune cells in the TME, tumor-associated macrophages (TAMs) are particularly abundant and play a protumoral role. However, an interaction between CAFs and TAMs in head and neck squamous cell carcinoma (HNSCC) still remains unclear. In the present study, we investigated whether CAFs skewed macrophage function toward the immune suppressive phenotype. Materials and Methods In vitro assay: CAFs were prepared from surgical tissue of HNSCC patients, and culture supernatants of CAFs were collected. Using this supernatants and peripheral blood mononuclear cells collected from healthy donors, immunological interactions between CAFs and TAMs was investigated. In vivo assay: The immunohistochemistry (IHC) of 73 patients with HNSCC was performed. Anti-α-smooth muscle actin, CD68, and CD163 antibodies were used to identify CAFs and TAMs, respectively. The relationship between immunohistochemical parameters and clinical parameters was evaluated. Results The expression levels of CD68, CD163, CD14, CD80, CD86, and HLA-G were up-regulated in CD14+ cells co-cultured with the supernatants of CAFs (CAF-educated cells) compared with control cells. Moreover, the gene expressions of ARG1, IL6, IL10 and TGFB1 were also increased in CAF-educated cells. The CAF-educated cells suppressed T-cell proliferation more intensively than control cells, and neutralization of TGF-β and IL-10 led to significant restoration of T-cell proliferation. In IHC, the intensity of CAFs correlated with the number of CD68-positive macrophages, especially with CD163-positive macrophages. It also correlated with several clinical parameters such as lymphatic invasion, vascular invasion, nodal status, tumor stages and recurrence rate. Moreover, the high intensity of CAFs correlated with poor PFS and OS. The high intensity of CAFs and M2 macrophage infiltration were independent prognostic factors of PFS and OS in HNSCC. Conclusion The present study suggests that CAFs can induce an immunosuppressive phenotype of macrophages and contribute to establishing the immunosuppressive networks in TME, resulting poor prognosis in HNSCC patients. Citation Format: Hideyuki Takahashi, Koichi Sakakura, Kazuaki Chikamatsu. Cancer-associated fibroblasts induce immunosuppressive macrophages 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 3239.