tbuckley/cabot-search huggingface dataset:
Abstract 2611: Comparison of 3D culture conditions to develop an in vitro model for breast cancer cell emboli formation
Authors: Ariana Vitale, Esta Sterneck, Balamurugan Kuppusamy
Journal: Cancer Research (2020)

Abstract Inflammatory breast cancer (IBC) is a rare type of breast cancer accounting for 2-4% of all breast cancer patients, but accounts for 7-10% of breast cancer related mortality. IBC is characterized by extensive skin invasion and the formation of tumor cell emboli within the breast and dermal lymphatic system. Characteristics of emboli include cell to cell adhesions mediated by E-cadherin, encoded by the gene CDH1. Studies from our laboratory show that CEBPD is expressed in IBC patient emboli and promotes emboli formation in vitro. Mechanistically we found that CEBPD promotes cell-cell adhesion within emboli at least in part by supporting the expression of E-cadherin adhesion complex proteins. In this study, we compared an in vitro model for intra-lymphatic emboli formation with conditions of tumor sphere formation to begin to address the role of fluid shear in emboli formation and emboli-specific molecular events, if any. We conducted experiments under slow rocking and non-rocking culture conditions with 4 different culture media. We found that the mechanical shear forces (achieved by low speed rocking) generated large, well-compacted emboli-like structures within 24 hours of suspension culture. In the absence of fluid shear, the cells assembled into smaller and more irregular aggregates. In agreement with this, our preliminary data suggest that E-cadherin expression is modestly higher under fluid shear conditions in addition to overall increase under 3D conditions. We are now validating the mechanisms for higher expression of emboli in 3D culture conditions and are designing experiments to address the functional relevance of the pathways for IBC emboli biology. Understanding the molecular mechanisms of emboli formation may provide valuable insights into the uniquely aggressive nature of IBC. Citation Format: Ariana Vitale, Esta Sterneck, Balamurugan Kuppusamy. Comparison of 3D culture conditions to develop an in vitro model for breast cancer cell emboli formation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2611.
Gastrointestinal synthetic epithelial linings
Authors: Junwei Li, Thomas Wang, Ameya R. Kirtane, Yunhua Shi, Alexis Jones, Zaina Moussa, Aaron Lopes, Joy Collins, Siddartha M. Tamang, Kaitlyn Hess, Rameen Shakur, Paramesh Karandikar, Jung Seung Lee, Hen-Wei Huang, Alison Hayward, Giovanni Traverso
Journal: Science Translational Medicine (2020)

A targeted coating of polydopamine polymerized in situ in the small intestine enables drug delivery and modulation of nutrient absorption in pigs.
Abstract 4666: Cigarette smoking and opium use in relation to the oral microbiome in Iran
Authors: Zeni Wu
Journal: Cancer Research (2020)

Abstract Background: Cigarette smoking and opium use are associated with periodontal disease, which is linked to the changes in oral microbiome. We aimed to study the association between cigarette and/or opium use with the oral microbiome. Methods: A total of 558 subjects included in the present analysis were from a case-control study of pancreatic cancer in Tehran, Iran conducted from 2011 to 2015. A questionnaire ascertained demographic, cigarette and opium use history, and lifestyle characteristics, and participants provided saliva samples. DNA was extracted using the DSP DNA Virus Pathogen kit and 16S rRNA gene sequencing was performed on the MiSeq. Sequences were clustered into amplicon sequence variants (ASVs) using QIIME2 and taxonomy was assigned against the Human Oral Microbiome Database. Logistic regression, MiRKAT and zero-inflated β regression models were calculated with adjustment for age, sex, body mass index, and case status. Results: The average number of observed ASVs for users of cigarette only (82.13 ± 38.55), opium only (76.19 ± 40.71), or both cigarette and opium users (77.80 ± 42.83) were significantly lower than never cigarette/opium users (95.10 ± 44.03). Similar trends were observed for the Shannon index. The microbial communities appeared to differ by cigarette and opium use as indicated by the MiRKAT models from the three beta diversity matrices. Four phylum level relative abundances were associated with cigarette and opium use, while the presence/absence of nine genera was associated with users of both cigarette and opium in the zero-inflated β regression models. The phylum Firmicutes and class Bacilla (Firmicutes) were significantly associated with opium only use, which showed marginally significant adjusted P values in users of both cigarettes and opium. No taxa were specifically associated with cigarette use only. Conclusion: Cigarette and/or opium use were related to overall oral microbiome community composition and the presence/absence as well as relative abundance of multiple taxa. Further studies are needed to investigate the impact of the changes to the oral microbiome through cigarette and/or opium use on human health and disease status. Citation Format: Zeni Wu. Cigarette smoking and opium use in relation to the oral microbiome in Iran [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4666.
Concentration-dependent Early Antivascular and Antitumor Effects of Itraconazole in Non–Small Cell Lung Cancer
Authors: David E. Gerber, William C. Putnam, Farjana J. Fattah, Kemp H. Kernstine, Rolf A. Brekken, Ivan Pedrosa, Rachael Skelton, Jessica M. Saltarski, Robert E. Lenkinski, Richard D. Leff, Chul Ahn, Chyndhri Padmanabhan, Vaidehi Chembukar, Sahba Kasiri, Raja Reddy Kallem, Indhumathy Subramaniyan, Qing Yuan, Quyen N. Do, Yin Xi, Scott I. Reznik, Lorraine Pelosof, Brandon Faubert, Ralph J. DeBerardinis, James Kim
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Itraconazole has been repurposed as an anticancer therapeutic agent for multiple malignancies. In preclinical models, itraconazole has antiangiogenic properties and inhibits Hedgehog pathway activity. We performed a window-of-opportunity trial to determine the biologic effects of itraconazole in human patients. Experimental Design: Patients with non–small cell lung cancer (NSCLC) who had planned for surgical resection were administered with itraconazole 300 mg orally twice daily for 10–14 days. Patients underwent dynamic contrast-enhanced MRI and plasma collection for pharmacokinetic and pharmacodynamic analyses. Tissues from pretreatment biopsy, surgical resection, and skin biopsies were analyzed for itraconazole and hydroxyitraconazole concentration, and vascular and Hedgehog pathway biomarkers. Results: Thirteen patients were enrolled in this study. Itraconazole was well-tolerated. Steady-state plasma concentrations of itraconazole and hydroxyitraconazole demonstrated a 6-fold difference across patients. Tumor itraconazole concentrations trended with and exceeded those of plasma. Greater itraconazole levels were significantly and meaningfully associated with reduction in tumor volume (Spearman correlation, −0.71; P = 0.05) and tumor perfusion (Ktrans; Spearman correlation, −0.71; P = 0.01), decrease in the proangiogenic cytokines IL1b (Spearman correlation, −0.73; P = 0.01) and GM-CSF (Spearman correlation, −1.00; P &amp;lt; 0.001), and reduction in tumor microvessel density (Spearman correlation, −0.69; P = 0.03). Itraconazole-treated tumors also demonstrated distinct metabolic profiles. Itraconazole treatment did not alter transcription of GLI1 and PTCH1 mRNA. Patient size, renal function, and hepatic function did not predict itraconazole concentrations. Conclusions: Itraconazole demonstrates concentration-dependent early antivascular, metabolic, and antitumor effects in patients with NSCLC. As the number of fixed dose cancer therapies increases, attention to interpatient pharmacokinetics and pharmacodynamics differences may be warranted.
Modifying macronutrients is superior to microbiome transplantation in treating nonalcoholic fatty liver disease
Authors: Fontini Tania Mitsinikos, Denise Chac, Nicholas Schillingford, R. William DePaolo
Journal: Gut Microbes (2020)

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver injury and liver transplantation in Western countries. The pathogenesis of NAFLD includes overnutrition-associated metabolic syndrome or the improper consumption of dietary macro- and micro-nutrients that either support or prevent disease development. This altered nutrient landscape has been linked to shifts within the gut microbiota which can exacerbate liver pathology and the progression of NAFLD. Treatment goals for NAFLD target lifestyle and dietary modifications that restrict calories and adjust macronutrient content. It is not well understood how different macronutrients alter the microbiota and whether the diet-educated microbiota contribute to the resolution of disease. We fed mice a diet high in fat, cholesterol and fructose for 6 weeks and then in two different arms of the study, intervened with either a diet high in saturated and polyunsaturated fats and fiber or low in fats and fiber. In a second set of experiments, we performed microbiota transplants using cecal contents from mice fed one of the intervention diets to assess whether the diet-educated microbiota could impact clinical outcomes in mice fed a NAFLD-inducing diet. Pathology, steatosis, ALT/AST levels, and liver cytokine levels were measured as primary outcomes. We found that despite different microbiota compositions, both of the intervention diets reversed the progression of NAFLD and dampened inflammation. In contrast, transplantation of cecal contents from the intervention diet-fed mice to mice receiving a NAFLD-inducing diet was unable to prevent disease progression, and, in some cases, worsened disease. These data underscore the importance of dietary modifications to treat NAFLD and caution against the use of microbiota transplantation in the absence of dietary and lifestyle modifications.
New Therapeutic Horizons for Graves’ Hyperthyroidism
Authors: Laura C Lane, Tim D Cheetham, Petros Perros, Simon H S Pearce
Journal: Endocrine Reviews (2020)

Graves' hyperthyroidism is characterized by the presence of autoantibodies that stimulate the thyroid-stimulating hormone receptor (TSHR), resulting in uncontrolled secretion of excessive thyroid hormone. Conventional treatments, including antithyroid medication, radioiodine, or surgery have remained largely unchanged for the past 70 years and either lack efficacy for many patients, or result in lifelong thyroid hormone replacement therapy, in the case of the latter 2 options. The demand for new therapeutic options, combined with greater insight into basic immunobiology, has led to the emergence of novel approaches to treat Graves' hyperthyroidism. The current therapies under investigation include biologics, small molecules, and peptide immunomodulation. There is a growing focus on TSHR-specific treatment modalities, which carry the advantage of eliciting a specific, targeted approach, with the aim of avoiding disruption of the functioning immune system. These therapies present a new opportunity to supersede the inadequate treatments currently available for some Graves' patients, offering hope of successful restoration of euthyroidism without the need for ongoing therapy. Several of these therapeutic options have the potential to translate into clinical practice in the near future. This review provides a comprehensive summary of the recent advances and various stages of development of the novel therapeutic approaches to treat Graves' hyperthyroidism.
Abstract 12021: Anti-factor Xa Activity Value At Peak And Trough Times In High Risk Patients With Venous Thromboembolism On Apixaban Therapy
Authors: Ryohei Ono, Kenichi Fukushima, Tatsuro Yamazaki, Hidehisa Takahashi, Yasuhiko Hori
Journal: Circulation (2019)

Introduction: Apixaban is used for non-valvular atrial fibrillation (NVAF) or venous thromboembolism (VTE). The dosage for NVAF is 5mg twice a day (BID) or 2.5mg BID according to the dose adjustmen...
Clinical development of namitecan (ST1968), a novel camptothecin derivative with high antitumor activity: Phase I clinical data
Authors: D. Hess, S. Boehm, A. Delmonte, E. Gallerani, P. Barbieri, S. Pace, P. Carminati, S. Marsoni, N. Coceani, C. Sessa
Journal: Journal of Clinical Oncology (2009)

2570 Background: Namitecan is a new water-soluble camptothecin analogue which showed high antitumor activity in preclinical models. Aim of this trial was to determine safety, PK profile and activity in adult patients with advanced solid tumors. Methods: The dose escalation started at 2.5 mg i.v. on days 1 and 8 of a 21 day cycle (D1, D8 Q21D) and increased according to 3+3 cohort design depending on the observed toxicity. Dose limiting toxicity (DLT) definitions were: ANC &lt;0.5x10 9 /L for &gt;5 days; PLT ≥ Grade 3 (CTC V3); grade ≥2 liver/renal toxicity not recovered by D22; any non-hematologic toxicity ≥ Grade 3; D8 dose skipping due to toxicity. Maximum tolerated dose (MTD) and recommended dose (RD) were the primary end-points. Blood and urine samples were collected at cycle 1 for PK evaluation. Results: 31 pts (11 endometrial ca., 5 CRC, 5 ovarian ca., 2 NSCLC, 8 other) have been included, with 6 dose levels evaluated (2.5; 5; 10; 15; 17.5 and 20 mg). 17.5 mg was introduced later when 2/7 DLTs at 20 mg were observed (ANC G4&gt;5days, one with D8 skipping). At 17.5mg 2/4 pts experienced DLTs (ANC G4; D8 skipped). Uncomplicated neutropenia and thrombocytopenia were the most relevant G3/4 hematological toxicities. Other toxicities were mild or moderate asthenia, fatigue and alopecia. The MTD was defined at 17.5 mg and the RD was 15 mg. Stable disease ≥ 6 cycles was recorded in 6 pts (2 stable diseases ≥ 10 cycles). PK was linear and data suggest an entero-hepatic recirculation. No metabolites were found in plasma and the product resulted poorly excreted into urine. Conclusions: The MTD and RD of D1, D8 Q21D schedule have been identified. The study will continue with the evaluation of MTD and RD of a single administration per cycle (D1 Q21D), to optimize the schedule of treatment. [Table: see text]
THU0124 Autologous fibroblasts as vectors for anti_inflammatory gene therapy in murine collagen-induced arthritis
Authors: N Bessis, V Cottard, N Saidenberg-Kermanach, MC Boissier
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> No treatments effective in the long term are available for rheumatoid arthritis. <h3>Objectives</h3> Recent advances in gene therapy and cell therapy have prompted us to design for collagen-induced arthritis (CIA), a new treatment strategy involving injection of autologous fibroblasts transfected with the IL-4 gene using a nonviral method. <h3>Methods</h3> A line of immortalised fibroblasts from DBA/1 mice (DBA/1/0 cells) were transfected with a plasmid expressing IL-4 cDNA (DBA/1/IL-4 cells). Xenogeneic fibroblasts from Chinese hamster ovary (CHO) transfected with a plasmid expressing murine IL-4 cDNA were studied also. CIA was caused in DBA/1 mice by injecting bovine type II collagen (CIIB). The cells were injected into the subcutaneous tissue of the back 10 and 25 days after immunisation of the mice by 3. 106 DBA/1/0 or DBA/1/IL-4 or CHO/IL-4 cells. <h3>Results</h3> Injection of DBA/1/IL-4 cells was associated with a significant and lasting improvement in the clinical and histological evidence of joint inflammation and destruction as compared with DBA/1/0 cells and CHO/IL-4 cells. The mice injected with DBA/1/IL-4 cells showed decreases in the production of IgG2a antibody to CII and in the proliferation of CIIB-specific nodal T cells. <h3>Conclusion</h3> Taken in aggregate, these findings indicate that grafting autologous cells transfected with a gene encoding an antiinflammatory cytokine is effective in CIA and may attenuate the cytokine imbalance seen in this disease. Rheumatoid Arthritis – Clinical aspects
An AML patient derived monoclonal antibody recognizes a unique CD43 epitope expressed on all myeloid leukemias and shows strong anti-tumor reactivity in vivo
Authors: Gillissen, M. Kedde, G. de Jong, E. Yasuda, S.E. Levie, K. Wagner, A. Bakker, P. Hensbergen, J. Villaudy, P.M. van Helden, H. Spits, Hazenberg
Journal: Clinical Cancer Research (2017)
Reply to Francesco Montorsi, Andrea Salonia, and Alberto Briganti’s Letter to the Editor re: Lisa Moris, Marcus G. Cumberbatch, Thomas Van den Broeck, et al. Benefits and Risks of Primary Treatments for High-risk Localized and Locally Advanced Prostate Cancer: An International Multidisciplinary Systematic Review. Eur Urol 2020;77:614–27
Authors: Lisa Moris, Nicolas Mottet, Thomas Wiegel
Journal: European Urology (2020)
Outcomes for the elderly (≥70 years) from a three-arm phase III trial of gemcitabine in combination with carboplatin (GC) or paclitaxel (GP) versus paclitaxel plus carboplatin (PC) for advanced non-small cell lung cancer (NSCLC)
Authors: R. H. Ansari, M. J. Edelman, C. P. Belani, M. A. Socinski, C. K. Obasaju, M. J. Monberg, R. Chen, J. Treat
Journal: Journal of Clinical Oncology (2009)

8052 Background: Approximately 50% of lung cancer patients (pts) are ≥ 70 y, however, this population has been historically underrepresented in clinical trials. Even among pts ≥ 70 y, doublet chemotherapy has been shown to be superior to single-agent therapy (Lilenbaum JCO 2005, Sederholm JCO, 2005), and the efficacy and safety of platinum-based chemotherapy doublets in NSCLC pts ≥ 70 years with good PS have been reported to be similar to those in younger pts (Fossella, ASCO 2003, #2528, Kelly, ASCO 2001, A-1313). The current analysis examined whether any differences were present by age in a three arm trial of GC or GP versus a standard regimen of PC. Methods: 1135 chemonaïve pts with stage IIIB or IV NSCLC were randomized to receive: G 1000 mg/m 2 d 1,8 plus C AUC 5.5 d 1; or G 1000 mg/m 2 d 1,8 plus P 200 mg/m 2 d 1; or P 225 mg/m 2 plus C AUC 6.0 d 1. Stratification was based on stage, baseline weight loss, and brain metastases. Cycles were repeated every 21 days up to 6 cycles or disease progression. Clinical results were retrospectively analyzed in by patient age. Results: See Table . Conclusions: In this trial of commonly used regimens for advanced NSCLC, pts 70–74 years of age had significantly longer survival than pts 75–79 years of age. Pts 80+ years of age also had lower survival than the 70–74 year age group, but this difference was not statistically significant. No pts 80+ years of age had brain metastases at study entry. There was no clear pattern with respect to the effectiveness of individual treatment regimens by age group. [Table: see text] [Table: see text]
Valproic Acid Thermally Destabilizes and Inhibits SpyCas9 Activity
Authors: Xinlai Cheng
Journal: Molecular Therapy (2020)

The clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system plays an important role in prokaryotic adaptive immunity. Due to its capacity for sequence-specific gene editing, CRISPR-Cas9 has become one of the most important tools widely used for genome editing in molecular biotechnology. However, its clinical application is currently limited by unwanted mutations at off-target sites. Various strategies have been developed for precise control of Cas9 in order to reduce these off-target effects, including chemical-based approaches. From a chemical screening, I observed that valproic acid (VPA) binds to and destabilizes Streptococcus pyogenes Cas9 (SpyCas9) protein in vitro, as well as in cells, while within its therapeutical concentration range under conditions of hyperthermia as demonstrated. Conditions were generated either by an external heat bag or in combination with the photothermal therapeutic agent indocyanine green activated by a near-infrared laser. Use of other histone deacetylase inhibitors failed, suggesting a histone deacetylase inhibition-independent function of VPA. Thus, this finding provides an uncomplicated thermotherapeutical approach for timely regulation of the activity of the CRISPR-Cas9 system at desired locations. The clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system plays an important role in prokaryotic adaptive immunity. Due to its capacity for sequence-specific gene editing, CRISPR-Cas9 has become one of the most important tools widely used for genome editing in molecular biotechnology. However, its clinical application is currently limited by unwanted mutations at off-target sites. Various strategies have been developed for precise control of Cas9 in order to reduce these off-target effects, including chemical-based approaches. From a chemical screening, I observed that valproic acid (VPA) binds to and destabilizes Streptococcus pyogenes Cas9 (SpyCas9) protein in vitro, as well as in cells, while within its therapeutical concentration range under conditions of hyperthermia as demonstrated. Conditions were generated either by an external heat bag or in combination with the photothermal therapeutic agent indocyanine green activated by a near-infrared laser. Use of other histone deacetylase inhibitors failed, suggesting a histone deacetylase inhibition-independent function of VPA. Thus, this finding provides an uncomplicated thermotherapeutical approach for timely regulation of the activity of the CRISPR-Cas9 system at desired locations.
Microbiota Supplementation with Bifidobacterium and Lactobacillus Modifies the Preterm Infant Gut Microbiota and Metabolome: An Observational Study
Authors: Cristina Alcon-Giner, Matthew J. Dalby, Shabhonam Caim, Jennifer Ketskemety, Alex Shaw, Kathleen Sim, Melissa A.E. Lawson, Raymond Kiu, Charlotte Leclaire, Lisa Chalklen, Magdalena Kujawska, Suparna Mitra, Fahmina Fardus-Reid, Gustav Belteki, Katherine McColl, Jonathan R. Swann, J. Simon Kroll, Paul Clarke, Lindsay J. Hall
Journal: Cell Reports Medicine (2020)

Supplementation with members of the early-life microbiota as "probiotics" is increasingly used in attempts to beneficially manipulate the preterm infant gut microbiota. We performed a large observational longitudinal study comprising two preterm groups: 101 infants orally supplemented with Bifidobacterium and Lactobacillus (Bif/Lacto) and 133 infants non-supplemented (control) matched by age, sex, and delivery method. 16S rRNA gene profiling on fecal samples (n = 592) showed a predominance of Bifidobacterium and a lower abundance of pathobionts in the Bif/Lacto group. Metabolomic analysis showed higher fecal acetate and lactate and a lower fecal pH in the Bif/Lacto group compared to the control group. Fecal acetate positively correlated with relative abundance of Bifidobacterium, consistent with the ability of the supplemented Bifidobacterium strain to metabolize human milk oligosaccharides into acetate. This study demonstrates that microbiota supplementation is associated with a Bifidobacterium-dominated preterm microbiota and gastrointestinal environment more closely resembling that of full-term infants.
Outcome after Midam Regimen and Impact of Post-Remission Strategy in Patients with Relapsing or Refractory Acute Myeloid Leukemia
Authors: Salem Bahashwan, Cécile Moluçon-Chabrot, Eric Hermet, Aurélie Ravinet, Aurore Douge, Lauren Veronese, Andrei Tchirkov, Richard Lemal, Marc G. Berger, Olivier Tournilhac, Jacques-Olivier Bay, Romain Guieze
Journal: Blood (2017)
Accuracy of Quantitative Ultrasound for Identifying Patients with Osteoporosis
Authors: Smita Nayak, Ingram Olkin, Hau Liu, M Grabe, Michael K. Gould, IE Allen, Douglas K. Owens, Douglas Owens, Dena M. Bravata, Dena Bravata
Journal: Annals of Internal Medicine (2006)