tbuckley/cabot-search huggingface dataset:
Abstract 3226: Patient-derived xenograft (PDX) models for triple negative breast cancer (TNBC): A pre-clinical platform for drug discovery
Authors: Jayant Thatte, Miguel Meza, Jill Ricono, Cyrus Mirsaidi, Thomas Broudy
Journal: Cancer Research (2015)

Abstract In the United States, TNBC comprises 15-20% of breast cancers and are characterized by the lack of expression of estrogen receptor, progesterone receptor and receptor tyrosine protein kinase ERBB2 or Her-2/neu oncogene amplification. As a result, this type of breast cancer is difficult to treat as most of the chemotherapies target these 3 receptors. TNBC is highly aggressive and is associated with high morbidity, mortality and shorter disease-free survival. Given its heterogeneous clinical presentation, histology and response to therapy, prognosis and management of TNBC is complicated. In this study, we report development and characterization of the TNBC PDX model. We used patient derived TNBC tissues to generate 5 new TNBC models in NOD-SCID mice. Patient tumors were pre-screened for their ER, PR and Her-2/Neu expression by IHC, prior to inoculation in mice. Efficacy of two standard of care drugs, Cisplatin and Vinorelbine in the TNBC PDX model demonstrates the potential utility of the TNBC model in drug discovery effort in oncology for treatment of TNBC. Citation Format: Jayant Thatte, Miguel Meza, Jill Ricono, Cyrus Mirsaidi, Thomas Broudy. Patient-derived xenograft (PDX) models for triple negative breast cancer (TNBC): A pre-clinical platform for drug discovery. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3226. doi:10.1158/1538-7445.AM2015-3226
Effectiveness of intraoperative histologic assessment of surgical margins for breast-conserving surgery
Authors: Naoki Aomatsu, Seika Tei, Soichiro Hiramatsu, En Wang, Takehiko Iwauchi, Takafumi Nishii, Junya Morimoto, Kinshi Kosaka, Yasutake Uchima, Kazuhiro Takeuchi
Journal: Annals of Oncology (2015)
Management of direct antiviral agent failures
Authors: María Buti, Rafael Esteban
Journal: Clinical and Molecular Hepatology (2016)

The current standard of care for patients with chronic hepatitis C virus (HCV) infection is a combination of direct-acting antiviral agents (DAAs). Most HCV patients treated with these drugs achieve viral elimination, but 1% to 15% fail to attain this objective. Treatment failures are usually related to relapse, and less often to on-treatment viral breakthrough. HCV drug resistant associated substitutions are detected in most patients who do not eliminate the virus. The risk of developing these variants depends on host- and virus-related factors, the properties of the drugs used, and the treatment strategies applied. Patients who carry Resistant Associated Substitutions (RASs) may not obtain benefits from treatment, and are at a risk of disease progression. Whether HCV RASs persist depends on their type: NS3-4A variants often disappear gradually after DAA therapy is stopped, whereas NS5A variants tend to persist for more than 2 years. The best way to prevent emergence of resistant variants is to eliminate the virus at the first treatment using highly potent DAAs with genetic barriers to resistance. For those who fail an NS5A inhibitor, deferral of treatment is recommended pending the availability of additional data if they do not have cirrhosis or reasons for urgent re-treatment. If re-treatment is needed, the most commonly used strategy is sofosbuvir as backbone therapy plus a drug from a class other than that previously used, for 24 weeks. Unless it is contraindicated, weight-based ribavirin should also be added. If available, nucleotide-based (eg, sofosbuvir) triple or quadruple DAA regimens may be considered. The optimal treatment for patients who fail an NS5A inhibitor and those with multidrug-resistant variants remains to be defined, and research efforts should continue to focus on treatment for these patients. Keywords: Hepatitis C virus; Direct-acting antivirals; Resistant associated substitutions
Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor
Authors: Greta Hultqvist, Stina Syvänen, Xiaotian T Fang, Lars Lannfelt, Dag Sehlin
Journal: Theranostics (2016)

The blood-brain barrier (BBB) is an obstacle for antibody passage into the brain, impeding the development of immunotherapy and antibody-based diagnostics for brain disorders. In the present study, we have developed a brain shuttle for active transport of antibodies across the BBB by receptor-mediated transcytosis. We have thus recombinantly fused two single-chain variable fragments (scFv) of the transferrin receptor (TfR) antibody 8D3 to the light chains of mAb158, an antibody selectively binding to Aβ protofibrils, which are involved in the pathogenesis of Alzheimer's disease (AD). Despite the two TfR binders, a monovalent interaction with TfR was achieved due to the short linkers that sterically hinder bivalent binding to the TfR dimer. The design enabled efficient receptor-mediated brain uptake of the fusion protein. Two hours after administration, brain concentrations were 2-3% of the injected dose per gram brain, comparable to small molecular drugs and 80-fold higher than unmodified mAb158. After three days, fusion protein concentrations in AD transgenic mouse brains were 9-fold higher than in wild type mice, demonstrating high in vivo specificity. Thus, our innovative recombinant design markedly increases mAb158 brain uptake, which makes it a strong candidate for improved Aβ immunotherapy and as a PET radioligand for early diagnosis and evaluation of treatment effect in AD. Moreover, this approach could be applied to any target within the brain.
Abstract 17232: Comparison of Methods for the Measurement of Cholesterol Efflux Capacity of Plasma HDL With J774 Mouse Macrophages Reveals Superiority of the Radioactive Cholesterol Method over the BODIPY-Cholesterol-2 Method
Authors: David Rhainds, Renaud Julien, Boulé Marie, Denis Maxime, Rhéaume Eric, Tardif Jean-Claude
Journal: Circulation (2015)

Recent clinical studies suggest that raising HDL-cholesterol (HDL-C) concentration is insufficient to lower cardiovascular risk and that protection derives from other characteristics of HDL particles. One such characteristic that can be measured in vitro is the cholesterol efflux capacity of plasma, an assay where HDL accepts labelled cholesterol from macrophages. Recently, a method for the measurement of cholesterol efflux with a fluorescent tracer, BODIPY-cholesterol-2 (BC2), has been proposed as an alternative to the radioactive method. We undertook a systematic comparison of BC2 and 3H-cholesterol methods with J774 macrophages in basal and cAMP-stimulated conditions with purified acceptors, plasma from healthy volunteers and patients with myocardial infarction of the Montreal Heart Institute Biobank. Dose-response curves show higher affinity of BC2 vs. 3H cholesterol with apoA-I, HDL and apoB-depleted plasma (all p&lt;0.01) and a higher maximal efflux for HDL and depleted plasma (both p&lt;0.001) in stimulated conditions. This was reflected in a faster kinetics of BC2 efflux compared to 3H-cholesterol efflux (time for half-maximal efflux 4.1h vs. 10.2 h) and resulted in a 2.5-fold increase of BC2 maximal efflux (p&lt;0.01). With 50 normolipidemic plasmas (2.8%, 4h efflux), the two methods were not correlated in basal conditions (r2=0.079) and strongly correlated in stimulated conditions (r2=0.830). BC2 values did not correlate with HDL-C in all conditions, contrary to 3H cholesterol values (p&lt;0.01). Using more complex samples from patients with MI (n=115), the correlations were modest in basal (r2=0.219) and stimulated (r2=0.400) conditions. Differences between controls and MI cases showed reduced significance with BC-2 compared to 3H cholesterol. Lastly, in macrophages examined under the confocal microscope, BC2 labels vesicular structures colocalized with filipin, a free cholesterol marker, suggesting endosomal loading of BC2. Thus, the BC2 method is not equivalent to the classic 3H cholesterol method for cholesterol efflux measurement.
Anti-Myeloma Activity of Selective PI-3K/PDK/mTOR Inhibitor BEZ235.
Authors: Douglas W. McMillin, Joseph Negri, Jake Delmore, Patrick Hayden, Nicholas Mitsiades, Paul G. Richardson, Nikhil C. Munshi, Robert Schlossman, Saveur-Michel Maira, Carlos García-Echeverría, Kenneth C. Anderson, Constantine S. Mitsiades
Journal: Blood (2007)
Activity of the cancer metabolism inhibitor MPC-9528 in xenograft models: Comparison of different dosing schedules.
Authors: V. R. Baichwal, J. A. Willardsen, J. W. Lockman, B. R. Murphy, R. Gordillo, T. C. Fleischer, C. Bradford, D. I. Papac, G. G. Mather, R. O. Carlson
Journal: Journal of Clinical Oncology (2011)

10529 Background: MPC‐9528 is a potent, selective, orally bioavailable inhibitor of nicotinamide phosphoribosyltransferase (Nampt) that catalyzes the rate-limiting step in NAD biosynthesis from nicotinamide. Nampt inhibition results in NAD depletion, inhibition of ATP synthesis and cell death. MPC-9528 has potent tumoricidal activity against cancer cell lines of diverse origin and induces regressions in xenograft models. Here we explore determinants of MPC-9528 activity in xenografts by comparing tumor NAD depletion and survival with alternate dosing schedules. Methods: HT1080 human fibrosarcoma cells were implanted subcutaneously into athymic mice (nu/nu) for xenograft studies. MPC-9528 was dosed orally, once weekly or once or twice daily, for two or three weeks. NAD concentration in xenografts and mouse organs was determined by LC-MS/MS. Results: MPC-9528 (75 mg/kg) dosed weekly for three weeks resulted in 75% xenograft regression 8 days after the last dose. ED50 with this schedule was 44 mg/kg and doses at or below 35 mg/kg showed no activity. All doses were well-tolerated with <10% change in median body weight. A dose of 10 mg/kg once daily, 3 mg/kg twice daily or 4 mg/kg twice daily for 14 days resulted in 91%, 92% and 100% tumor regression, respectively, by the end of dosing. Two of 10 animals in the 10 mg/kg and 3 mg/kg groups, and 9 in the 4 mg/kg group had no detectable tumors at the end of dosing. In the 10, 3 and 4 mg/kg groups, 40%, 50% and 70% of the mice, respectively, were tumor free thirty-four days after the last dose. Pharmacokinetic profiles of a 3, 10 or 75 mg/kg dose of MPC-9528 indicated that anti-tumor activity was not dependent on maximal plasma concentration or total absorbed dose but on maintenance of compound concentration above a specific efficacious concentration threshold. MPC-9528 also caused a rapid and sustained reduction of NAD in tumors with the magnitude and kinetics of NAD change dependent on the dose and schedule. Conclusions: MPC-9528 induces regression of xenografts when its plasma concentration is maintained above a threshold efficacious concentration. It shows comparable activity when given intermittently, once weekly, or continuously on a once or twice daily schedule.
351. Gene Electrotransfer of pVEGF in a Porcine Model to Induce Angiogenesis and Improve Cardiac Function
Authors: Richard Heller, Anna Bulysheva, Cathryn Lundberg, Niculina Burcua, Len Murray, Barbara Hargrave
Journal: Molecular Therapy (2015)

Nonviral gene therapy is an attractive method for treating cardiovascular disease; however, achieving appropriate gene expression levels is often problematic. Gene electro transfer (GET) can be safely used to enhance expression. We have previously reported on establishing GET protocols to safely and effectively delivering plasmids encoding luciferase, green fluorescent protein or VEGFA directly to the heart in a porcine model. In the current study, we tested whether gene delivery of VEGF via GET could induce angiogenesis and improve cardiac function in a porcine ischemic model. Domestic farm pigs were anesthetized and intubated followed by median sternotomy to expose the heart. The left anterior descending coronary artery was partially tied off to induce localized ischemia. Animals received no treatment, injection of pVEGF or injection of pVEGF with electro transfer. Treatment was performed at four sites surrounding the ischemic region on the border of viable and ischemic myocardium. A SPY Intraoperative Perfusion Assessment System was utilized to determine the area of ischemia and quantify the approximate reduction in perfusion and to identify the area of ischemia before treatment. The animals were followed for seven weeks. Ultrasound evaluation and arteriograms were performed prior to surgery, post treatment, 2 weeks post treatment and 7 weeks post treatment. Arteriograms suggest the growth of blood vessels as early as 2 weeks. Spy analysis revealed significant increase in perfusion within the ischemic zone in animals treated with pVEGF +GET compared to controls. Echography showed improved cardiac output was significantly greater (p<0.03) 14 days post-infarct in GET treated animals compared to values immediately after surgery. Based on these results, gene delivery to the heart can be successfully accomplished using in vivo GET and evidence suggests the potential for a therapeutic effect.
Abstract 1981: Regulation of NF-kB signaling pathway by glucocorticoid in breast cancer cells
Authors: Zenaida Lopez-Dee, Jun Ling
Journal: Cancer Research (2015)

Abstract Steroid hormone signaling through nuclear receptors plays critical roles in every stage of breast cancer development. Although estrogen receptor (ER) and progesterone receptor (PR) are well studied, due to the high heterogeneity of breast cancer, therapies targeting these nuclear receptors are still not effective enough or generate inconsistent and even controversial results. In this study, we focused on the glucocorticoid (GC)/ glucocorticoid receptor (GR) signaling to investigate how it regulates NFkB activity that leads to differential outcomes in different subtypes of breast cancer. A qRT-PCR array containing a curated NF-kB responsive gene set (84 genes) was utilized in this study to analyze the effect of GC/GR on basal and luminal subtypes of breast cancer cells. It was identified that MDA-MB-231 cells (basal subtype) were more responsive than MCF7 cells (luminal subtype) to GC treatment as the former showed more down- or up-regulated NF-kB target genes. Negative regulation of the NF-kB target genes was more prevalent in both cells, which is consistent with the general rule of trans-repression of NF-kB by GR. However, there were also a number of NF-kB target genes up-regulated by GC in both subtypes of breast cancer cells, suggesting that the trans-activation of NF-kB by GR may also play an important role in breast cancer cell growth and pathological behaviors. Among the differentially expressed genes in both cell types, genes with functions in cell migration and adhesion are highly regulated, such as CXCL1, CCL2, ICAM1, VCAM1, BIRC3 and SNAP25, implying that GC may mainly regulate the invasion and metastasis of breast cancer cells via NF-kB signaling. Biochemical studies identified that GR was activated by GC differently in MDA-MB-231 and MCF7 cells; the interaction between GR and various NF-kB subunits were also different in these cells, thus elucidating part of mechanisms underlying the differential regulation of NF-kB by GC in different subtypes of breast cancer cells. Citation Format: Zenaida Lopez-Dee, Jun Ling. Regulation of NF-kB signaling pathway by glucocorticoid in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1981. doi:10.1158/1538-7445.AM2015-1981
Colombia sees fourfold increase in microcephaly cases in a year
Authors: Claudia Collucci
Journal: BMJ (2016)

The number of babies born with microcephaly in Colombia increased fourfold between 2015 and 2016, coinciding with a widespread outbreak of Zika virus in the country, a report from the US Centers for Disease Control and Prevention (CDC) and the Colombian health department has shown.1

There were 476 cases of microcephaly recorded in Colombia between March and November this year, compared with 110 cases in the same period in 2015, showing an increase in prevalence from 2.1 cases for every 10 000 live births to 9.6 cases per 10 000.

At its peak in July, microcephaly cases in Colombia were nine times higher …
Successful Retransplantation of Bone Marrow Cells Following Failure of Initial Engraftment in 4 Patients with SCN
Authors: Shiho Nishimura, Yoko Mizoguchi, Shuhei Karakawa, Keita Tomioka, Mizuka Miki, Hiroshi Kawaguchi, Kazuhiro Nakamura, Masao Kobayashi
Journal: Blood (2014)
Outcome of Aurora Kinase Inhibition of Acute Myeloid Leukemia by AT9283 Is Dependent upon the Presence or Absence of Mutations in Type 1 Oncogenic Kinase Signalling Pathways.
Authors: John Goodall, Matthew S Squires, Vicky Lock, Farhad Ravandi, Hagop M Kantarjian, James Foran, Neil T Thompson, John F Lyons
Journal: Blood (2008)
The ascending pathophysiology of cholestatic liver disease
Authors: Peter L.M. Jansen, Ahmed Ghallab, Nachiket Vartak, Raymond Reif, Frank G. Schaap, Jochen Hampe, Jan G. Hengstler
Journal: Hepatology (2016)

In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending course of the disease process. The first and early lesions are in “downstream” bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)–mediated toxic injury of the “upstream” liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom‐poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%‐60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more “tailored” use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium‐dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis–suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti‐inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor‐ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end‐stage disease. These are arguments to consider a step‐wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage–defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (H epatology 2017;65:722‐738).
Vimentin expression of esophageal squamous cell carcinoma and its aggressive potential for lymph node metastasis.
Authors: H. Jin, H. Kawasaki, K. Hakamada, H. Kijima
Journal: Journal of Clinical Oncology (2011)

e14566 Background: Esophageal squamous cell carcinoma (ESCC) has been generally considered as one of the most aggressive cancers with poor prognosis. Vimentin has been regarded as a marker of epithelial-mesenchymal transition (EMT). However, little is known about ESCC with vimentin expression as a marker of EMT. In this study, we analyzed vimentin expression of ESCC and its aggressive behavior. Methods: One hundred and twenty-nine ESCC were surgically resected at Hirosaki University Hospital from 1996 to 2008. All the patients underwent operations including subtotal esophagectomy and dissection of lymph nodes. No patients received radiotherapy or chemotherapy before operation. In each patient, one representative histological specimen at the deepest invaded area of an esophageal cancer lesion was selected, and immunohistochemical examination of Vimentin and α-smooth muscle actine (α-SMA) was performed. In addition, in cases of lymph node metastasis, the largest metastatic carcinoma specimen was selected, and the same immunohistochemical examination of vimentin was performed. Results: Vimentin expression was identified in 96 of the 129 cases (74.4%). The cases with vimentin-positive carcinoma cells showed a significantly higher incidence of lymph node metastasis (P=0.001). Carcinomas with vimentin expression were more advanced in terms of tumor status and lymphatic invasion (P=0.001, P=0.009, respectively), and associated with stronger stromal α-SMA expression (P<0.001). Vimentin expression was also associated with distant metastasis, including distant node metastasis (P=0.014). Vimentin expression in both primary and metastatic carcinomas was found in 68.6% (48/70) of the cases, while no vimentin expression in both primary and metastatic carcinomas comprised 92.3% of the cases (12/13) (P<0.001). Finally, Vimentin expression in ESCC is an independent predictor of lymph node metastasis (multivariate analysis, P=0.014, odds ratio: 3.314, 95% confidence interval: 1.276-8.605). Conclusions: Vimentin expression in ESCC is an independent predictor of lymph node metastasis. In addition, vimentin expression was frequently retained in metastatic carcinoma of the lymph node.