tbuckley/cabot-search huggingface dataset:
Novel Approaches for Assessment of Bone Turnover in CKD: Is New Always Better?
Authors: Elvira O. Gosmanova, Aidar R. Gosmanov
Journal: Journal of the American Society of Nephrology (2018)

We read with great interest the report “Diagnostic accuracy of biomarkers and imaging for bone turnover in renal osteodystrophy” by Salam et al.1 published in the Journal of the American Society of Nephrology. The work expands our knowledge regarding the assessment of bone turnover in patients with advanced CKD by using noninvasive approaches, which in turn, can improve fracture risk prediction and selection of appropriate antifracture therapies in these patients. The authors divided patients not yet on dialysis and patients on dialysis on the basis of the results of bone biopsy into three groups: low-, intermediate-, and high-bone turnover states. Then, they measured serum bone turnover markers (BTMs) in all patients in attempt to find the marker(s) highly predictive of the bone turnover status. The authors found that blood intact parathyroid hormone and circulating BTMs bone alkaline phosphatase, intact procollagen type 1 N-terminal propeptide, and tartrate-resistant acid phosphatase 5b had similar diagnostic accuracy in predicting high bone turnover. However, the studied BTMs (but not intact parathyroid hormone) could relatively accurately predict low-bone turnover state. The total serum alkaline phosphatase (tAP) was also measured in all study patients. Tables 3 and 4 in ref. 1 show that tAP had comparable predictive value in identifying low- and high-bone turnover states compared with sensitivity and specificity of the studied circulating BTMs. The assay for tAP is widely available and inexpensive, and it is part of routine biochemical assessment of patients with CKD in the clinic. Elevated tAP was shown to be associated with higher rates of fractures and all-cause mortality in CKD.2,3 On the basis of the authors’ findings, a single tAP measurement could allow one to initiate a global bone turnover assessment before addressing the levels of less readily available BTMs, such as bone alkaline phosphatase, intact procollagen type 1 N-terminal propeptide, and tartrate-resistant acid phosphatase 5b. Although it is clearly important to continue advancing noninvasive diagnostic methods for clinical evaluation of bone turnover in CKD, it is also important to continue acknowledging that “older” approaches evaluating the bone turnover can provide information that at least has similar clinical meaning at a lesser cost. The authors did not discuss potential benefits of tAP in characterization of bone turnover status in patients with CKD. It would be interesting to learn the authors’ perspectives on pros and cons of measuring tAP to evaluate bone turnover state in light of the reported novel findings. Disclosures None.
Abstract 582: Accelerating drug development with a CLIA approved functional test using patient derived organoids
Authors: Franz X. Schaub, Michael J. Churchill, Hallie A. Swan, Rachele Rosati, Roland M. Watt, Reid C. Shaw, Stephanie A. Murphy, Robert L. Diaz, Shalini C. Pereira, Carla Grandori
Journal: Cancer Research (2018)

Abstract The pool of targeted therapies is expanding steadily providing novel treatment opportunities. However, the process of expanding indications and including additional cancer types after initial approval is slow. Here we present an in vitro clinical trial platform using the data from the first CLIA-approved Precision Medicine Platform using high-throughput screening (P.A.R.I.S. Assay, SEngine Precision Medicine, Seattle, WA). Briefly, patient-derived tumor cells from biopsies are expanded as living organoids, and functionally evaluated using a high-throughput drug screen. The drug library currently includes FDA approved and experimental drugs. Results are integrated with known genomic information and reported to the clinician to highlight treatment options of an individual patient. Combining this data from multiple patients enables the discovery of novel indications and biomarkers. To date we have acquired data from a wide range of tumor types including hard-to-treat cancers, rare tumor types and tumors from heavily pretreated patients. In addition, we also have collected data from more than 100 patient derived cell lines. Using the data analysis platform developed in R, the drug responses across all patient screens of a given drug can be analyzed to find common indicators of sensitivities. For instance, a BRD4 inhibitor (CPI-203), which was tested on 8 different primary tumor samples, was selectively active in a subset of the patients. Interestingly, most of the responding tumor types are ovarian and breast cancer cases with mutations in BRCA1 or EZH2. However, there are currently no clinical trials investigating the more developed BRD4 inhibitor CPI-0610 for breast or ovarian cancer. Non-responders, on the other hand, are spread between multiple cancer types. The number of patients receiving the P.A.R.I.S. test is steadily increasing and these patient cases contribute to our knowledge base. As this test is used to inform clinicians about potential treatment opportunities, we are also accumulating information on how these patients respond to treatment. Overall, this platform will provide real world data for optimal drug combinations and novel biomarkers to quickly expand indications of existing drugs. Citation Format: Franz X. Schaub, Michael J. Churchill, Hallie A. Swan, Rachele Rosati, Roland M. Watt, Reid C. Shaw, Stephanie A. Murphy, Robert L. Diaz, Shalini C. Pereira, Carla Grandori. Accelerating drug development with a CLIA approved functional test using patient derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 582.
Local Phototherapy Synergizes with Immunoadjuvant for Treatment of Pancreatic Cancer through Induced Immunogenic Tumor Vaccine
Authors: Feifan Zhou, Jingxuan Yang, Yuqing Zhang, Mingyang Liu, Mark L. Lang, Min Li, Wei R. Chen
Journal: Clinical Cancer Research (2018)

Abstract Purpose: To develop a synergistic combination therapy for advanced pancreatic cancer, using local phototherapy and immunotherapy, and to determine the efficacy and mechanism of the novel combination therapy using a highly metastatic pancreatic tumor model in mice. Experimental Design: Mice bearing Panc02-H7 pancreatic tumors (both subcutaneous and orthotopic) were treated with noninvasive or interventional photothermal therapy, followed by local application of an immunoadjuvant. Tumor growth and animal survival were assessed. Immune cell populations within spleen and tumors were evaluated by FACS and IHC, and cytokine levels were determined by ELISA. Results: Up to 75% of mice bearing subcutaneous tumors treated with combination therapy had complete tumor regression. Local photothermal therapy exposed/released damage-associated molecular patterns, which initiated an immunogenic tumor cell death, resulting in infiltration of antigen-presenting cells and Th1 immunity. Concomitant application of immunoadjuvant amplified Th1 immunity, especially the tumor-specific cytotoxic T lymphocyte response, with increased quantity and quality of T cells. Combination therapy also induced tumor-specific immune memory, as demonstrated by resistance to tumor rechallenge and production of memory T cells. For the treatment of orthotopic tumor, the combination therapy significantly reduced the primary tumors and metastases, and prolonged the animal survival time. Conclusions: This study indicated that combination of local phototherapy and immunotherapy induced a systemic immunity against established tumors and metastases in an aggressive, preclinical pancreatic tumor model, leading to a potential clinical method for patients with advanced pancreatic cancer. Clin Cancer Res; 24(21); 5335–46. ©2018 AACR.
E-cigarettes: relax rules to help more smokers quit, say MPs
Authors: Jacqui Wise
Journal: BMJ (2018)

MPs have called for a relaxation of regulations relating to electronic cigarettes—including those covering advertising, licensing, and product formulation—to encourage more people to stop smoking.1

A report from the Science and Technology Committee, which is likely to spark controversy, reiterates Public Health England’s claim that e-cigarettes are 95% less harmful than conventional cigarettes.2 This claim has been disputed by some experts because it relies on a single study, some of whose authors had potential conflicts of interest.345

The select committee’s report says that the risk among smokers of continuing to use conventional cigarettes is greater than the uncertainty over long term use of e-cigarettes. It finds no evidence that e-cigarettes are a significant gateway to conventional smoking, including …
CTCF maintains regulatory homeostasis of cancer pathways
Authors: Sarah J. Aitken, Ximena Ibarra-Soria, Elissavet Kentepozidou, Paul Flicek, Christine Feig, John C. Marioni, Duncan T. Odom
Journal: Genome biology (2018)

CTCF binding to DNA helps partition the mammalian genome into discrete structural and regulatory domains. Complete removal of CTCF from mammalian cells causes catastrophic genome dysregulation, likely due to widespread collapse of 3D chromatin looping and alterations to inter- and intra-TAD interactions within the nucleus. In contrast, Ctcf hemizygous mice with lifelong reduction of CTCF expression are viable, albeit with increased cancer incidence. Here, we exploit chronic Ctcf hemizygosity to reveal its homeostatic roles in maintaining genome function and integrity. We find that Ctcf hemizygous cells show modest but robust changes in almost a thousand sites of genomic CTCF occupancy; these are enriched for lower affinity binding events with weaker evolutionary conservation across the mouse lineage. Furthermore, we observe dysregulation of the expression of several hundred genes, which are concentrated in cancer-related pathways, and are caused by changes in transcriptional regulation. Chromatin structure is preserved but some loop interactions are destabilized; these are often found around differentially expressed genes and their enhancers. Importantly, the transcriptional alterations identified in vitro are recapitulated in mouse tumors and also in human cancers. This multi-dimensional genomic and epigenomic profiling of a Ctcf hemizygous mouse model system shows that chronic depletion of CTCF dysregulates steady-state gene expression by subtly altering transcriptional regulation, changes which can also be observed in primary tumors.
Evaluation of Exercise Capacity Using Submaximal Exercise at a Constant Work Rate in Patients With Cardiovascular Disease
Authors: AkiraKoike, TakashiYajima, HiromasaAdachi, NoritakaShimizu, HiroshiKano, KeiichiSugimoto, AkihiroNiwa, FumiakiMarumo, MichiakiHiroe
Journal: Circulation (1995)

Background Symptom-limited incremental exercise tests are used to estimate the severity of cardiovascular disease and the patient’s daily activity. However, there is a need for objective parameters for submaximal exercise. To test the hypothesis that a decrease in maximal exercise capacity can be estimated by oxygen uptake (Vo2) kinetics, we measured the time constant of Vo2 both during the onset of constant work rate exercise at 50 W and during recovery from this exercise and compared it with data obtained during maximal exercise in patients with cardiovascular disease and in normal subjects. Methods and Results A total of 34 patients with cardiovascular disease and 14 normal subjects performed 6 minutes of 50-W constant work rate exercise and an incremental exercise test to the symptom-limited maximum on a cycle ergometer. Vo2 was calculated from respiratory gas analysis on a breath-by-breath basis. The time constant of Vo2 during the onset of 50-W exercise was 61.4±15.2 seconds in patients with car...
Abstract 1152: Therapeutic response to PD1/PDL1 axis in a disseminated C1498 syngeneic tumor model
Authors: Vivek Mahajan, Thi Bui, Ian Belle, Edgar Wood, Lindsay Usher, Elizabeth Rainbolt, Shasta Kidder, Aidan Synnott, David Harris
Journal: Cancer Research (2018)

Abstract The majority of the leukemia cases are diagnosed in adults, of which, acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) are the most common subtypes. Treatment options include chemotherapy, stem cell transplantation and more recently the use of checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 to enhance antitumor responses. In this study we developed a disseminated AML disease model using PD-L1+, C1498 tumor cells to evaluate the therapeutic response to immune checkpoint inhibitors, PD-1, PD-L1 and CTLA-4 and to examine the effect of treatment on infiltration of immune cell populations in selected tissues. C1498 cells were transduced with a lentivirus vector construct containing luciferase and GFP reporter genes. Upon establishment of a clonal population with stable reporter expression, C1498-GFP-Luc expressing cells were implanted intravenously into syngeneic albino C57BL/6 mice and growth of the leukemic tumor cells was monitored via in vivo bioluminescence imaging (BLI) using IVIS Spectrum CT®. In vehicle-treated animals tumor growth was progressive and most animals reached endpoint within 30 days. Luciferase expression was widespread with metastatic development in peripheral organs and tissues. An efficacious response to therapy directed against the PD-1/PD-L1 axis was observed, with anti-PD-L1 showing greater overall efficacy than anti-PD-1. Combination of either PD-1/PD-L1 with anti-CTLA-4 further improved the therapeutic efficacy as measured by prolonged survival and reduced tumor growth. To gain mechanistic insights into how these immunotherapies function in suppressing tumor growth we performed additional studies utilizing flow cytometry and immunohistochemistry to assess the composition and phenotype of immune cell infiltrates in hematological and non-hematological tissues. In summary, comprehensive immunological characterization of the C1498 model revealed the importance of PD1 / PD-L1 pathway in immune evasion and provides a rationale for therapeutic intervention with checkpoint blockade. Citation Format: Vivek Mahajan, Thi Bui, Ian Belle, Edgar Wood, Lindsay Usher, Elizabeth Rainbolt, Shasta Kidder, Aidan Synnott, David Harris. Therapeutic response to PD1/PDL1 axis in a disseminated C1498 syngeneic tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1152.
Circulating cell‐free DNA and ineffective erythropoiesis in nontransfusion‐dependent β‐thalassemia
Authors: Dario Tavazzi, Irene Motta, Giovanna Graziadei, Maurizio Sampietro, Lorena Duca, Maria Domenica Cappellini
Journal: American Journal of Hematology (2018)

Circulating cell-free DNA and ineffective erythropoiesis in nontransfusion-dependent β-thalassemiaTo the
Autonomic Tone Variations Before the Onset of Paroxysmal Atrial Fibrillation
Authors: MarcoBettoni, MarcZimmermann
Journal: Circulation (2002)

Background— Mechanisms favoring the occurrence of paroxysmal atrial fibrillation (PAF) are complex and poorly defined. This study was designed to analyze dynamic changes in autonomic tone preceding the onset of PAF in a large group of patients. Methods and Results— Holter tapes from 77 unselected consecutive patients (63 men and 14 women aged 58±12 years) with PAF were analyzed. A total of 147 episodes of sustained AF (>30 minutes) were recorded and submitted to time-domain and frequency-domain heart rate variability analyses; 6 periods were studied using repeated measures ANOVA: the 24-hour period, the hour preceding PAF, and the 20 minutes before PAF divided into four 5-minute periods. In the time-domain analyses, a linear decrease in mean RR interval from 925±16 to 906±16 ms (P<0.0002) was observed before the onset of PAF, together with a significant increase in the standard deviation of NN intervals from 65±4 to 70±4 ms (P<0.02). In the frequency-domain analyses, a significant increase in high-frequen...
Abstract 386: Heme function in promoting tumorigenic potential of lung cancer cells
Authors: Chantal Vidal, Sagar Sohoni, Li Zhang
Journal: Cancer Research (2018)

Abstract Heme, also known as iron protoporphyrin IX, is an essential molecule for living organisms. Heme serves as a prosthetic group in enzymes, and acts as a signaling molecule in diverse cellular processes. Mammalian cells can synthesize heme endogenously, or they can import heme from circulation via heme transporters. The synthesis of heme is carried out by eight enzymes, the first of which is the rate-limiting enzyme 5-aminolevulinate (ALA) synthase. Heme can also be transported intracellularly by transporters, such as HCP1 (heme carrier protein 1) and HRG1 (heme responsive gene 1). Finally, levels of heme are also maintained by the degrading enzyme, heme oxygenase-1 (HO-1). HO-1 is localized to the endoplasmic reticulum and is the rate-limiting enzyme in the catabolism of heme. HO-1 cleaves heme to biliverdin and carbon monoxide. Biliverdin is converted to bilirubin, which is an antioxidant and scavenger of ROS. Heme also serves as a catalytic site for various proteins that are involved in aerobic metabolism, such as respiratory chain cytochromes. For example, complex II, III, and IV of the mitochondria require heme for proper function. Importantly, epidemiologic studies have shown the association of dietary heme intake, mainly from red meat, with different cancers, including lung cancer. Therefore, we have analyzed the levels of heme synthesis, uptake, degradation, oxygen consumption and mitochondrial proteins in an immortalized, nontumorigenic human bronchial epithelial cell line (NL20) compared to the tumorigenic counterpart (NL20-TA). These studies showed that the tumorigenic cell line expressed significantly higher levels of heme flux compared to the nontumorigenic cell line. This led us to alter heme availability by overexpressing the rate-limiting enzyme of heme synthesis as well as the rate-limiting enzyme of heme degradation. Experiments are under way to characterize their effects on tumor growth and metastasis. Citation Format: Chantal Vidal, Sagar Sohoni, Li Zhang. Heme function in promoting tumorigenic potential of lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 386.
Functional Blockade of Platelet-Derived Growth Factor Receptor-β but Not of Receptor-α Prevents Vascular Smooth Muscle Cell Accumulation in Fibrous Cap Lesions in Apolipoprotein E–Deficient Mice
Authors: HidetoSano, TetsuoSudo, MasayukiYokode, ToshinoriMurayama, HiroshiKataoka, NobuyukiTakakura, SatomiNishikawa, Shin-IchiNishikawa, ToruKita
Journal: Circulation (2001)

Background—The vascular smooth muscle cell (VSMC) is the central cell component involved in the fibroproliferative response in atherogenesis. As the lesion advances, VSMCs migrate from the media into the subendothelial space, thereby forming fibrous plaque lesions. Platelet-derived growth factor (PDGF) has been known to be a potent chemoattractant and mitogen for SMCs, but the pathophysiological role of the 2 PDGF receptors, receptor-α (PDGFR-α) and receptor-β (PDGFR-β) in atherogenesis is poorly understood. To clarify this problem, we prepared antagonistic rat monoclonal antibodies, APA5 and APB5, against murine PDGFR-α and PDGFR-β, respectively. Methods and Results—Apolipoprotein E–deficient mice were fed a high-fat diet containing 0.3% cholesterol from 6 weeks of age and subjected to injection with 1 mg/d IP of either antibody from 12 to 18 weeks every other day. In the mice injected with APB5, the aortic atherosclerotic lesion size and the number of intimal VSMCs were reduced by 67% and 80%, respectiv...
Abstract 1942: Synthetic lethal interaction between SETD2 loss and inhibition of PI3Kβ in clear cell renal cell carcinoma (ccRCC)
Authors: Esteban Terzo, Yun C. Chiang, Anna Chytil, Valerie M. Jansen, Kimryn Rathmell
Journal: Cancer Research (2018)

Abstract Renal cell carcinoma (RCC) is a high-risk and high-mortality cancer for which several new targeted therapies exist. However, responses of primary clear cell RCC (ccRCC) tumors and metastases to these targeted agents are variable, and complete responses are relatively uncommon underscoring the need to identify reliable biomarkers to predict tumor behavior. Bi-allelic inactivation of the tumor suppressor gene SETD2, encoding a lysine methyltransferase, occur in approximately 20% of ccRCC tumors while the SETD2 protein deficiency rate has been reported to be as high as 34%. The phosphatidylinositide 3-kinases (PI3Ks) have emerged as important therapeutic targets for the treatment of solid and hematological malignancies, including ccRCC. Here, we show that genetic and pharmacologic inhibition of the PI3Kβ isoform results in inhibition of SETD2 deficient (-/-) ccRCC-derived 786-O and A498 cells, which exhibit increased sensitivity to PI3Kβ-specific inhibitors TGX221 (IC50 = 2.3 - 4.5 µM, respectively) and AZD8186 (IC50 = 1.79 - 0.24 µM, respectively) as compared to SETD2 proficient (+/+) 786-O cells (IC50 = &amp;gt;10 µM). Inhibition of the p110δ isoform alone had a modest effect on ccRCC cell growth and migration. Importantly, genetic (with siRNA) and pharmacologic (with BYL719) inhibition of p110α had no effect on the ccRCC cell lines. Inhibition of AKT with the small molecule inhibitor MK2206 recapitulated the effects seen with AZD8186 in ccRCC cell lines with SETD2 loss, suggesting PI3Kβ mediates the synthetic lethality via AKT signaling in the context of SETD2 loss in ccRCC. Our work strongly suggests a synthetic lethal-type of interaction between PI3Kβ inhibition and SETD2 loss and offers a rationale for further translational and clinical investigation of small molecule inhibitors of PI3Kβ in RCC. Xenograft studies are ongoing to investigate the in vivo efficacy of AZD8186. Citation Format: Esteban Terzo, Yun C. Chiang, Anna Chytil, Valerie M. Jansen, Kimryn Rathmell. Synthetic lethal interaction between SETD2 loss and inhibition of PI3Kβ in clear cell renal cell carcinoma (ccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1942.
Effects of Carbon Dioxide on Cerebral Hemo-dynamics in Normal Subjects and in Cerebrovascular Disease Studied by Carotid Injection of Radioalbumin
Authors: CesareFieschi, AlessandroAgnoli, EldaGalbo
Journal: Circulation Research (1963)

A study has been made in 11 normal elderly subjects and 26 patients suffering from the sequelae of cerebral apoplexy on the effects of the inhalation of a hypercapnic mixture on pulse rate, arterial pressure, arterial O2 and CO2 and the radioencephalo-graphic curves recorded during injection of radioalbumin into the carotid artery. The hemodynamic response of the cerebral circulation to hypercapnia was very rapid and intense in normal subjects and in a number of patients with history of apoplexy. In a number of patients with vascular disease, on the other hand, the response was considerably delayed in time, more so than reduced in intensity. Taking into account the early time course of the response, this hypercapnia test may provide a dynamic basis for evaluating severe degrees of reduced hemodynamic adaptability of the cerebral circulation.