tbuckley/cabot-search huggingface dataset:
Abstract 792: A novel covalent reversible BTK inhibitor for B cell malignancies with enhanced selectivity and in vivo efficacy
Authors: Xi Chen, Shaoqiang Huang, Fred Hu, Jun Xian, Jian Yang, Jing Qiang, Meijie Le, Yuchuan Wu
Journal: Cancer Research (2018)

Abstract Bruton's tyrosine kinase (BTK), a member of Tec family kinase, plays a pivotal role in the regulation of BCR signaling, which is important for B cell development and function. Ibrutinib, which has been approved by FDA, is an effective treatment option for multiple types of B cell neoplasms. However, the treatment associated adverse events (AEs) are one of the major concerns due to its poor kinase selectivity . Here, we present a novel covalent, but reversible BTK inhibitor, XNW-1011, which demonstrated enhanced potency, better selectivity, improved drug-like properties and superior in vivo efficacy with a favorable safety profile. XNW-1011 was developed structurally and biochemically differently from current BTK inhibitors, being more potent and highly selective. In the in vitro assay, unlike Ibrutinib, it did not inhibit EGFR, ITK, JAK3, LYN and SRC. It completely suppressed the cell proliferation of a panel of lymphoma cell lines such as TMD-8 and Rec-1. Besides, XNW-1011 inhibited cellular phosphorylation of BTK and calcium efflux, confirming the inhibition of activation of BTK in vitro. We have shown that XNW-1011 formed covalent bond with cysteine in a cysteine reactivity assay. In addition, a washout assay by Western Blot confirmed the reversibility of inhibition of XNW-1011 to BTK. XNW-1011 has a good prolife of ADME, which translated into improved in vivo PK properties over Ibrutinib (low clearance and prolonged half-life). XNW-1011 was further evaluated in several animal models such as REC-1 and TMD-8 tumor xenografts. XNW-1011 inhibited tumor growth with as low as 3.125 mpk by BID and resulted in tumor regression with 12.5 mpk by BID. Interestingly, XNW-1011 completely inhibited the tumor growth of a patient derived xenograft (PDX) with Myd88 mutation. The dose proportionality was confirmed through determination of the plasma concentration and in vivo BTK occupancy in the last day of treatment. In summary, XNW-1011 is a potent, selective, covalent reversible BTK inhibitor with improved ADME prolife and in vivo efficacy, which makes it suitable for further evaluation in clinical setting. Citation Format: Xi Chen, Shaoqiang Huang, Fred Hu, Jun Xian, Jian Yang, Jing Qiang, Meijie Le, Yuchuan Wu. A novel covalent reversible BTK inhibitor for B cell malignancies with enhanced selectivity and in vivo efficacy [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 792.
Cell Volume, Plasma Volume and Cell Percentage in Splanchnic Circulation of Splenectomized Dogs
Authors: Shuchien
Journal: Circulation Research (1963)

The circulating splanchnic cell and  volumes were measured with the regional dilution technique in splenectomized dogs under sodium pentobarbital. For a 10-kg dog, the average circulating splanchnic cell volume is 56 (SEm = 5.0) ml and the average circulating splanchnic  volume is 98 (SEm = 7.2) ml. These values represent 20% of the total  volume respectively. The splanchnic cell percentage, averaging 36.3% (SEm = 1.32%), is significantly lower than the large vessel cell percentage (average 42.4%) and is almost equal to the overall cell percentage. The splanehnic Fcells value averages 0.86 and is almost the same as the overall Fcells value. Therefore, the splanchnic circulation contains a portion of the total extra plasma in proportion to the blood volume in this region. The splanchnic mean circulation time of the  (average 42 seconds) is significantly longer than that of the cells (average 33 seconds).
Comparative efficacy and tolerability of pharmacological agents for management of mild to moderate ulcerative colitis: a systematic review and network meta-analyses
Authors: Nghia H Nguyen, Mathurin Fumery, Parambir S Dulai, Larry J Prokop, William J Sandborn, Mohammad Hassan Murad, Siddharth Singh
Journal: The Lancet. Gastroenterology & hepatology (2018)
Phosphoinositide 3-Kinase Isoforms Selectively Couple Receptors to Vascular L-Type Ca2+ Channels
Authors: NathalieMacrez, ChantalMironneau, ValérieCarricaburu, Jean-FrançoisQuignard, AlekseiBabich, CorneliaCzupalla, BerndNürnberg, JeanMironneau
Journal: Circulation Research (2001)

Heterodimeric class I phosphoinositide 3-kinase (PI3K) has been shown to be involved in the stimulation of voltage-gated Ca2+ channels by various mediators. In this study, we bring evidences that vascular L-type Ca2+ channels can be modulated by both tyrosine kinase–regulated class Ia and G protein–regulated class Ib PI3Ks. Purified recombinant PI3Ks increased the peak Ca2+ channel current density when applied intracellularly. Furthermore, PI3Kα-, β-, and δ-mediated stimulations of Ca2+ channel currents were increased by preactivation by a phosphotyrosyl peptide, whereas PI3Kγ- and β-mediated effects were increased by Gβγ. In freshly isolated and cultured vascular myocytes, angiotensin II and Gβγ stimulated L-type Ca2+ channel current. In contrast, platelet-derived growth factor (PDGF)-BB and the phosphotyrosyl peptide did not stimulate Ca2+ channel current in freshly isolated cells despite the presence of endogenous PDGF receptors and PI3Kα and PI3Kγ. Interestingly, when endogenous PI3Kβ expression arose...
Response assessment of meningioma: 1D, 2D, and volumetric criteria for treatment response and tumor progression
Authors: Raymond Y Huang, Prashin Unadkat, Wenya Linda Bi, Elizabeth George, Matthias Preusser, Jay D McCracken, Joseph R Keen, William L Read, Jeffrey J Olson, Katharina Seystahl, Emilie Le Rhun, Ulrich Roelcke, Susanne Koeppen, Julia Furtner, Michael Weller, Jeffrey J Raizer, David Schiff, Patrick Y Wen
Journal: Neuro-Oncology (2018)

Meningiomas are the most common primary brain tumors in adults. Due to their variable growth rates and irregular tumor shapes, response assessment in clinical trials remains challenging and no standard criteria have been defined. We evaluated 1D, 2D, and volume imaging criteria to assess whether a volumetric approach might be a superior surrogate for overall survival (OS).In this retrospective multicenter study, we evaluated the clinical and imaging data of 93 patients with recurrent meningiomas treated with pharmacotherapy. One-dimensional (1D), 2D, and volumetric measurements of enhancing tumor on pre- and post-treatment MRI were compared at 6 and 12 months after treatment initiation. Cox proportional hazards models were used to examine the relationship between each imaging criterion and OS.The median age of the patient cohort is 51 years (range 12-88), with 14 World Health Organization (WHO) grade I, 53 WHO grade II, and 26 WHO grade III meningiomas. Volumetric increase of 40% and unidimensional increase by 10 mm at 6 months and 12 months provided the strongest association with overall survival (HR = 2.58 and 3.24 respectively, p<0.01). Setting a volume change threshold above 40% did not correlate with survival. The interobserver agreement of 1D, 2D, and volume criteria is only moderate (kappa = 0.49, 0.46, 0.52, respectively). None of the criteria based on tumor size reduction were associated with OS (P > 0.09).Compared with 1D (Response Evaluation Criteria In Solid Tumors 1.1) and 2D (Response Assessment in Neuro-Oncology) approaches, volumetric criteria for tumor progression has a stronger association with OS, although the differences were only modest. The interobserver variability is moderate for all 3 methods. Further validation of these findings in an independent patient cohort is needed.
Indications and Contraindications for the Use of Molar Sodium Lactate
Authors: Samuelbellet, Fredwasserman
Journal: Circulation (1957)

The experience with molar sodium lactate has been extended to include 101 patients. Certain indications and relative contraindications to its use have crystallized. Administration of this agent is shown to be a physiologic and effective method for treating patients with severe hyperpotassemia, multiple Stokes-Adams, attacks, and cardiac arrest, particularly that occurring in the operating room complicating cardiac surgery. For many patients in these categories, sodium lactate was life saving even though it was generally given after other more commonly used drugs and methods of therapy had proved ineffective in restoring cardiac rhythm. In the total group of patients untoward effects were few.
Abstract 2806: Inhibition of melanoma development by Isatin analogs
Authors: Dhimant H. Desai, Raghvendra Gowda, Krishne Gowda, Saketh S. Dinavahi, Gavin P. Robertson, Shantu G. Amin
Journal: Cancer Research (2018)

Abstract Despite major breakthroughs in melanoma drug development, there remains a need for new drugs and novel approaches. Of the three forms of skin cancer, malignant melanoma has the most significant impact on human health carrying the highest risk of mortality from metastasis. An estimated 87,110 new cases of invasive melanoma will be diagnosed and 9,730 people will die of melanoma in the USA in 2017. Melanoma accounts for less than one percent of skin cancer cases, but the vast majority of skin cancer deaths. The vast majority of melanomas are caused by the sun. In fact, one UK study found that about 86 percent of melanomas can be attributed to exposure to ultraviolet (UV) radiation from the sun. The estimated 5-year survival rate for patients whose melanoma is detected early is about 98 percent in the USA, whereas, the survival rate falls to 62 percent when the disease reaches the lymph nodes, and 18 percent when the disease metastasizes to distant organs. Thus, novel effective therapies are urgently needed to treat this disease. The Isatin (1H-indole-2,3-dione) is found as an endogenous molecule in humans and other mammals and its analogs display diverse types of biological activities including anti-cancer activities. Earlier our group synthesized a novel series of 5,7-dibromoisatin analogs. Various melanoma cells were treated with several Isatin derivatives having functional groups like selenocyanate, thiocyanates, thiourea, and selenourea for 72 hours and the cell survival was estimated by MTS assay. Agents were treated with melanoma cell lines UACC 903, 1205 Lu or normal fibroblast cell line FF2441. Treatment with KS99, a thiocyanate analog and KS101, a selenourea analog of 5,7-dibromoisatin effectively killed melanoma cells after 72 h treatment. Overall, IC50 values of Isatin derivatives on melanoma cell lines were 3.0-5.7μM and 2.1-5.7μM, respectively. IC50 value on normal fibroblast cells with these Isatin derivatives was 5.4-20.7μM. KS101 was toxic to the xenograft mice at 1mg/kg body weight, animals developed vein inflammatic symptoms after 20 days of treatment. However, liposomal formulation of KS101 was safe up to 30mg/kg body weight in 1205 xenografted nude mice when treated alternate days by tail vein injection. The melanoma tumor burden was reduced by 47%. We will discuss structural activity relationship (SAR) of Isatin derivatives, and its in vitro and in vivo inhibitory effects against melanoma. Citation Format: Dhimant H. Desai, Raghvendra Gowda, Krishne Gowda, Saketh S. Dinavahi, Gavin P. Robertson, Shantu G. Amin. Inhibition of melanoma development by Isatin analogs [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 2806.
Abstract 4575: Efficient and accurate NGS approach for liquid biopsy detection and monitoring
Authors: Ke Tang, Christopher Kasbek, Yang Song, Qingxuan Song, Si Chen, Nouran Almalki, Xu Zhang, Jun T. Huang
Journal: Cancer Research (2018)

Abstract Liquid biopsy detection using ctDNA has great potential in cancer diagnosis, monitoring, and predicting survival. However, detection sensitivity and specificity remains a major challenge at the current stage. Here we utilized targeted next-generation sequencing (NGS) approach to develop a noninvasive test to identify SNVs, indels, and fusions present at low frequencies in lung cancer patients. Target regions of interest were sequenced using tagging of individual molecules, followed by amplicon library generation and massive parallel sequencing using Illumina platform. The variants were called and annotated using our in-house AGIS (Actionable Genomic Interpretation System) bioinformatics pipeline. This CLIA-approved NGS panel (LiquidGx™ Lung) detects 112 variants in 10 genes (AKT1, ALK, BRAF, EGFR, ERBB2, KRAS, MET, PIK3CA, RET, and ROS1) with detection limit of 0.1%. Mutations are detected with 94% sensitivity and 99.8% specificity in a short turnaround time of 4-6 days. To assess the performance in a clinical setting, accurate sequencing was performed on 210 lung cancer patients; the frequency of mutations identified of each gene closely mirrored the published lung cancer tissue biopsy data. In summary, we have developed a potent liquid biopsy platform for highly sensitive genomic biomarker test. Our technology is also available as an assay development service and can be easily adaptable to the diagnosis and monitoring of other cancer types. Citation Format: Ke Tang, Christopher Kasbek, Yang Song, Qingxuan Song, Si Chen, Nouran Almalki, Xu Zhang, Jun T. Huang. Efficient and accurate NGS approach for liquid biopsy detection and monitoring [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 4575.
Depression of Endothelial Nitric Oxide Synthase but Increased Expression of Endothelin-1 Immunoreactivity in Rat Thoracic Aortic Endothelium Associated With Long-term, but Not Short-term, Sympathectomy
Authors: GjumrakchAliev, VeraRalevic, GeoffreyBurnstock
Journal: Circulation Research (1996)

Recent pharmacological studies have shown that perivascular nerves can influence the development and function of vascular endothelial cells (ECs). However, morphological studies have not yet been carried out to investigate whether these functional changes are associated with changes in vasoactive substances in ECs. We used postembedding electron microscopy (EM) triple gold–labeling immunocytochemistry to study the effects of short-term sympathectomy (3 days after 6-hydroxydopamine [6-OHDA] treatment) and long-term sympathectomy (guanethidine and 8 days after 6-OHDA) on the distribution of vasoactive substances in ECs of the rat thoracic aorta. The postembedding immunocytochemistry, which can detect levels of label in individual cells, showed that there was a significant decrease in endothelial NO synthase (NOS3)–labeled, serotonin (5-HT)–labeled, and substance P (SP)–labeled, but a significant increase in endothelin-1 (ET-1)–labeled, gold particles in ECs after long-term, but not after short-term (3-day),...
Abstract 12195: Carbohydrate and Protein but not Fat or Fiber Affects Glycemic Index and Glycemic Load Value Determinations
Authors: Huicui Meng, Nirupa R Matthan, Lynne M Ausman, Alice H Lichtenstein
Journal: Circulation (2016)

Introduction: Dietary glycemic index (GI) and glycemic load (GL) values have been calculated using data derived from instruments designed to estimate daily food intake. Since the absolute amount of carbohydrate (CHO) and combination of CHO with other macronutrients and fiber is highly variable among dietary patterns, the accuracy of these values is uncertain. This issue is of concern when dietary GI and GL values are used to identify diet/health outcome associations. Hypothesis: Increasing amounts of macronutrients (CHO, protein and fat) and fiber added to a test CHO challenge (50g available CHO) from white bread (WB) will alter GI and GL values. Methods: The trial included 4 studies, during which subjects (n=20-22, 50% female, 50-80y, BMI 25-30kg/m 2 , free from chronic disease and having fasting glucose levels ≤125mg/dL) received food challenges containing different amounts of the variable nutrient in a random order. In all studies, a glucose drink (50g available CHO/500mL) was used as the reference food. Studies 1-3 consisted of 4 food challenges, containing WB (50g available CHO+500mL water) alone or with additional CHO (12.5g, 25g, 50g), protein (12.5g, 25g, 50g) and fat (5.6g, 11.1g, 22.2g) from Rice Chex breakfast cereal (General Mills), tuna, and unsalted butter, respectively. Study 4 consisted of 3 food challenges, containing WB alone or with additional fiber (4.8g, 9.6g) from Cheerios (General Mills). Arterialized venous blood was sampled at 0, 15, 30, 45, 60, 90 and 120 minutes, and GI and GL values were calculated using the recommended incremental area under the curve (AUC) method. Results: Addition of 12.5g, 25g and 50g additional CHO to WB incrementally increased glucose AUC (p&lt;0.0001), GI (p&lt;0.0001) and GL (p&lt;0.0001) values; while addition of protein (50g) to WB decreased glucose AUC (p=0.0026), GI (p=0.0139) and GL (p=0.0140) values. Addition of fat or fiber to WB had no significant effect on any measure. Conclusions: These data indicate that variability in postprandial GI and GL values is introduced when CHO containing foods are consumed in different amounts or in combination with protein. These conclusions raise the issue of whether GI and GL values from individual foods should be used to calculate dietary GI and GL values from dietary intake data.
Renal Biopsy and Its Clinical Correlation in Toxemia of Pregnancy
Authors: Albertaltchek
Journal: Circulation (1964)

Through the combination of a renal biopsy technique modified for pregnant women, electron microscopy, and knowledge of fine (ultramicroscopic) glomerular anatomy, the pathology of the renal glomerular lesion of toxemia of pregnancy (preeclampsia-eclampsia) has been defined. The lesion is pathognomonic and consists of swelling of the cytoplasm of the endothelial cell, deposits underneath the basement membrane and within the swollen endothelial cytoplasm, and an increase of intercapillary cells. The lesion reduces the glomerular capillary lumen. It is the most sensitive pathological lesion of toxemia in the body, and is present in all cases of toxemia. Once formed, the lesion persists until evacuation of the uterus, in spite of apparent clinical improvement with therapy. The lesion accounts for the characteristically decreased glomerular filtration rate in toxemia, and this may be a factor in the formation of edema. Demonstration of the lesion is the only laboratory method that can reliably differentiate to...
Abstract 302: Selective Mcl-1 inhibition by AZD5991 induces on-target cell death and achieves antitumor activity in multiple myeloma and acute myeloid leukemia
Authors: Adriana E. Tron, Matthew A. Belmonte, Steven Criscione, Edwin A. Clark, Eric Gangl, Francis D. Gibbons, Jeffrey W. Tyner, Stephen E. Kurtz, Qing Ye, Alexander W. Hird, Alwin Schuller, J. Paul Secrist
Journal: Cancer Research (2018)

Abstract Mcl-1 is a member of the Bcl/Mcl family of proteins that promotes cell survival by preventing induction of apoptosis in a broad range of cancers. High expression of Mcl-1 has been linked to tumor development and resistance to anticancer therapies, underscoring the potential of Mcl-1 inhibitors as anticancer drugs. We have previously shown that AZD5991, a rationally designed macrocycle with sub-nanomolar affinity for Mcl-1 and high selectivity, induces rapid and irreversible commitment to apoptosis in Mcl-1-dependent cancer cells in a manner dependent on proapoptotic BAK. Here, we demonstrate that AZD5991 exhibits cytotoxic activity (GI50&amp;lt;100nM) in various MM and AML cell lines in vitro with an activity profile distinct from the selective Bcl2 inhibitor venetoclax. In vivo, AZD5991 shows potent antitumor activity with complete (100%) tumor regression in several mouse MM and AML xenograft models after a single tolerated dose. AZD5991 shows enhanced efficacy in vivo when combined with standard-of-care agents. Pharmacodynamic studies confirmed that AZD5991 kills cancer cells by activation of the mitochondrial apoptotic pathway. Ex vivo analysis indicates that AZD5991 has single agent activity in primary AML patient samples with LC50 values in the low nanomolar range. Consistent with our findings in AML cell lines, the activity profile for AZD5991 in AML primary samples was distinct from venetoclax, highlighting the unique therapeutic opportunity for AZD5991. Based on these data a phase I clinical trial has been launched for evaluation of AZD5991 in patients with MM and other hematologic malignancies (NCT03218683). Citation Format: Adriana E. Tron, Matthew A. Belmonte, Steven Criscione, Edwin A. Clark, Eric Gangl, Francis D. Gibbons, Jeffrey W. Tyner, Stephen E. Kurtz, Qing Ye, Alexander W. Hird, Alwin Schuller, J. Paul Secrist. Selective Mcl-1 inhibition by AZD5991 induces on-target cell death and achieves antitumor activity in multiple myeloma and acute myeloid leukemia [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 302.
Abstract 5035: Identification of novel therapeutics of bladder cancer cells through upregulation of SPARC expression in using 2D cell cultures and 3D bladder organoids
Authors: Chirayu M. Patel, Cristina Ivan, Anthony Atala, Neveen Said
Journal: Cancer Research (2018)

Abstract We have recently reported the tumor suppressor effect of SPARC in urinary bladder cancer. We have shown that the loss of SPARC in bladder cancer resulted accelerated bladder carcinogenesis and metastasis multiple pathways involving cell cycle deregulation, inflammation and angiogenesis. We have also reported that SPARC protein expression significantly decreased in the cancerous compartment in advanced human bladder cancer as well as in carcinogen-induced murine urothelial cancer. However, the mechanism of the downregulation of SPARC expression in cancer in general and in bladder cancer in particular is still unraveled. The purpose of our study is to identify therapeutic candidates as regulators of SPARC expression in bladder cancer. We developed an in vitro 3-D bladder model system “bladder organoids” that comprises the normal and cancerous urothelial cell, bladder smooth muscle cells, fibroblasts and endothelial cells. We differentially expressed fluorescent SPARC promoter reports in the cancerous and non-cancerous cells to screen for the differential expression of SPARC in each cell type using FDA-approved and natural product drug libraries and to determine the cytotoxicity on cancerous vs non-cancerous cells. Real time monitoring of changes in SPARC expression was done by measuring fluorescence intensity using IncuCyte® ZOOM and InCell Analyzer 1000 Live Imaging Analysis Systems. We identified drugs that consistently exhibited dose-dependent augmentation or down-regulation of SPARC expression in cancer cells. Our screens using the identified novel up-regulators of SPARC expression that differentially reduce the viability of cancer cells and spare non-cancer cells in the organoids. Our efforts produced a platform that mimics bladder cancer microenvironment that can be adapted for throughput screening for targeted personalized therapies. Citation Format: Chirayu M. Patel, Cristina Ivan, Anthony Atala, Neveen Said. Identification of novel therapeutics of bladder cancer cells through upregulation of SPARC expression in using 2D cell cultures and 3D bladder 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 5035.