tbuckley/cabot-search huggingface dataset:
Abstract LB-288: CDC7 kinase inhibition by SRA141 induces a potentially novel caspase-dependent tumor cell apoptosis associated with altered DNA replication and cell cycle dynamics
Authors: Veena Jagannathan, Snezana Milutinovic, Ryan Hansen, Bryan Strouse, Christian Hassig, Eric Brown
Journal: Cancer Research (2019)

Abstract DNA replication is a tightly regulated process required for faithful duplication of the genome. Previous research in lower eukaryotes has demonstrated a requisite role for the CDC7 protein kinase in DNA replication origin firing through phosphorylation of the MCM2-7 helicase complex. Owing to its overexpression in various neoplasms, CDC7 has emerged as an attractive target for cancer treatment. We previously reported that SRA141, a potent and selective CDC7 inhibitor, is cytotoxic to multiple tumor cell lines in vitro and demonstrates robust anti-tumor efficacy in colorectal and leukemia xenograft models. Here, we explored the effects of SRA141 on DNA replication and cell cycle dynamics and how these effects relate to the mechanism of SRA141-induced cell death in colorectal cancer cell lines. SRA141 treatment caused a complete inhibition of MCM2 phosphorylation and reduced overall cellular DNA synthesis within 3 hours, with the greatest effects observed in late S-phase. Unexpectedly, DNA combing experiments indicated that SRA141 caused a 70-90% increase in the rate of replication fork progression. These findings suggest that SRA141 may indeed limit origin firing, but this effect is compensated for in part by increased replication fork rates. Despite delay, nucleotide analog pulse-chase experiments indicated that SRA141 treated cells ultimately finished S phase and transitioned into mitosis. In contrast to other reports, no evidence of replication fork collapse was observed, indicating that the main mechanism of SRA141 cytotoxicity is not mediated through replication fork collapse. Intriguingly, some of the most pronounced effects of SRA141 treatment were on progression through M phase, as evidenced by an accumulation of mitotic cells and increased Cyclin B levels following treatment. Moreover, inhibition of Aurora B kinase, which regulates mitotic progression, strongly synergized with SRA141 in caspase-dependent cancer cell killing. Taken together, our findings indicate that the mechanism of cytotoxicity of CDC7 inhibitors is distinct from agents that cause replication fork collapse or inhibit CDKs, and thus may define a new class of cancer therapeutic agents that synergize with drugs that target certain mitotic pathways. Citation Format: Veena Jagannathan, Snezana Milutinovic, Ryan Hansen, Bryan Strouse, Christian Hassig, Eric Brown. CDC7 kinase inhibition by SRA141 induces a potentially novel caspase-dependent tumor cell apoptosis associated with altered DNA replication and cell cycle dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-288.
Abstract 1152: Disulfiram targets both proliferating cancer cells and cancer stem-like population in ER-positive breast cancer
Authors: Seojin Jang, Eunhye Oh, Yoon-Jae Kim, Tae-Min Cho, Jung Min Park, Soeun Park, Minsu Park, Jae Hong Seo, Ji Young Kim
Journal: Cancer Research (2019)

Abstract Drug repositioning can benefit from reduced development risk in terms of safety, toxicity and dosage, as it centers upon drugs that have already been tested in clinical trials. Disulfiram (DSF), a drug for the treatment of alcoholism, has potential anti-cancer activities in a copper (Cu)-dependent manner. In the present study, we investigated the effect of DSF on cell viability, apoptosis, breast cancer stem cells (BCSC)-like properties and p53 activation in ER-positive breast cancer MCF7 and T47D cells. DSF treatment caused a significant suppression of cell viability and marked induction of cell death in a Cu-dependent manner. This response was accompanied by caspase-3/-7 and p53 activation in ER-positive breast cancer cells. The latter phenomenon was associated with G1 phase arrest, coinciding with a significant increase in accumulation of nuclear p21 and downregulation of cyclin D1 and survivin. DSF treatment elicits a significant inhibitory effect on these BCSC-like properties including ALDH1 activity and CD44+/CD24- subpopulations. To examine the effect of DSF on mammosphere-forming ability, MCF7 and T47D cells were cultured in anchorage-independent serum-free culture conditions in the presence or absence of DSF and Cu. DSF considerably suppressed mammosphere formation, as evidenced by significant reduction in the number and volume of mammospheres. Our results demonstrate that DSF induces apoptosis and effectively targets cancer stem-like population, suggesting that disulfiram may be potentially effective for the treatment of ER-positive cancer. Citation Format: Seojin Jang, Eunhye Oh, Yoon-Jae Kim, Tae-Min Cho, Jung Min Park, Soeun Park, Minsu Park, Jae Hong Seo, Ji Young Kim. Disulfiram targets both proliferating cancer cells and cancer stem-like population in ER-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1152.
Comparison of Attention for Neurological Research on Social Media vs Academia
Authors: Vineet Punia, Vikram Aggarwal, Ryan Honomichl, Appaji Rayi
Journal: JAMA Neurology (2019)

ally representative estimates.Of the baseline sample, 75.7% were retained at wave IV and 0.1% of data were missing for exposure or outcome.The P value level of significance was .05,and all P values were 2-sided.Results | The sample consisted of 14 786 young adults, with mean (SE) age 28.1 (0.1) years, 49.3% female sex, and 65.6% non-Hispanic white race/ethnicity (Table ; all means and percentages were calculated with weighted data to reflect the representative proportion in the target US population).Overall, 11% of young adults were food insecure.The prevalence of migraine was higher among food-insecure vs food-secure young adults (23.9% vs 13.6%; P < .001;Figure).Food-insecure young adults had greater odds of migraine in unadjusted (odds ratio, 2.00; 95% CI, 1.68-2.38;P < .001)and adjusted (adjusted odds ratio, 1.58; 95% CI, 1.30-1.95;P < .001)models.Discussion | We found that food insecurity was associated with migraine in young adulthood.Few studies have examined the association between food insecurity and neurologic outcomes.To our knowledge, prior research on food insecurity and migraine is limited to 1 cross-sectional study representative of the Canadian population 12 years or older, which found a positive association. 2 We confirm this finding in a nationally representative sample of young adults from the United States.Food insecurity may lead directly to missed meals and indirectly to psychological stress, depression, and poor sleep, which are common precipitants of migraine. 5Conversely, frequent, chronic migraine may contribute to food insecurity by preventing attendance at work, lower productivity, and/or lost employment 6 and may also result in a reduced ability to perform household activities such as shopping and cooking. 2 Limitations include data from 2008 and inability to discern episodic vs chronic migraine.Health care clinicians caring for persons who experience migraine should consider screening for food insecurity as a potential contributor to migraine
Abstract 4348: DNA-based fusion detection using a pan-cancer tumor profiling 532-oncogene panel
Authors: Katharine Dilger, Yongming Sun, Kevin Lai, Ushati Das Chakravarty, Nicole Sponer, Kristina Giorda, Patrick Lau, Yu Wang
Journal: Cancer Research (2019)

Abstract Large-scale cancer profiling using next generation sequencing (NGS) has become instrumental to the discovery and identification of new, targetable cancer alterations. A comprehensive set of 532 oncogene targets were combined to create the new xGen® Pan-Cancer Panel V2 for hybrid capture sequencing. This xGen panel covers 2.2 Mb of the human genome, and allows for the simultaneous detection of copy number variations (CNVs), insertions and deletions (indels), gene rearrangements, and microsatellite instability across a wide range of sample types, inputs, and quality. Using a new library prep workflow optimized for low quality samples and low input, panel performance was first evaluated with 30 ng of input DNA using libraries built from matched samples [formalin-fixed paraffin-embedded (FFPE) tumor gDNA, frozen adjacent normal tissue gDNA, and cell-free DNA (cfDNA)] from five lung cancer donors (n = 15). Sample quality ranged from a mean DIN of 4.4 ±1.1 to 8.3 ±0.9 for FFPE tumor gDNA and frozen normal gDNA, respectively. After subsampling to 200X mean target coverage, 96% of target bases had at least 40X coverage for all libraries. Comparative hierarchal clustering analysis was then used to identify lung cancer mutations shared in all tumor samples. NGS gDNA reference standards from Horizon Discovery (HD753, HD798, HD799, and HD803) with verified CNVs, single nucleotide variations (SNVs), amplifications, and fusions, and were used to evaluate detection rates at different library input masses down to 1 ng. cDNA libraries were also prepared from RNA extracted from FFPE 5-Fusion RNA Multiplex Reference Standards (HD796, HD783). We identified all possible gene fusion events in the positive control using the structural variant caller, LUMPY (https://github.com/arq5x/lumpy-sv). The xGen Pan-Cancer Panel V2 enables a cost-efficient and time-saving approach for the detection of multiple oncogene targets. Citation Format: Katharine Dilger, Yongming Sun, Kevin Lai, Ushati Das Chakravarty, Nicole Sponer, Kristina Giorda, Patrick Lau, Yu Wang. DNA-based fusion detection using a pan-cancer tumor profiling 532-oncogene panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4348.
Advances in nanotechnology-based delivery systems for EGFR tyrosine kinases inhibitors in cancer therapy
Authors: Xiaohan Zhou, Kun Shi, Ying Hao, Chengli Yang, Ruoyu Zha, Cheng Yi, Zhiyong Qian
Journal: Asian Journal of Pharmaceutical Sciences (2019)

Oral tyrosine kinase inhibitors (TKIs) against epidermal growth factor receptor (EGFR) family have been introduced into the clinic to treat human malignancies for decades. Despite superior properties of EGFR-TKIs as small molecule targeted drugs, their applications are still restricted due to their low solubility, capricious oral bioavailability, large requirement of daily dose, high binding tendency to plasma albumin and initial/acquired drug resistance. Nanotechnology is a promising tool to improve efficacy of these drugs. Through non-oral routes. Various nanotechnology-based delivery approaches have been developed for providing efficient delivery of EGFR-TKIs with a better pharmacokinetic profile and tissue-targeting ability. This review aims to indicate the advantage of nanocarriers for EGFR-TKIs delivery. (A). Various types of EGFR-TKIs loaded nanocarriers (a) liposome, (b) polymer nanoparticle, (c) micelle, (d) nanogold particles.(B) Schematic illustration of nanocarriers are intended to exploit the enhanced permeability and retention effect to exit the blood vessels through leaky vasculature and accumulate within tumor tissues.(C) Schematic of increased targeting ability of nanocarriers via surface modification and the anti-cancer mechanism of EGFR inhibition.
A multicenter retrospective study of gemcitabine plus nab-paclitaxel or FOLFIRINOX in metastatic pancreatic cancer: NAPOLEON study
Authors: J. Nakazawa, T. Otsuka, M. Shimokawa, F. Koga, Y. Ueda, S. Otsu, S. Arima, M. Fukahori, A. Makiyama, H. Taguchi, T. Honda, T. Shibuki, T. Shirakawa, K. Mitsugi, K. Nio, Y. Ide, N. Ureshino
Journal: Annals of Oncology (2019)
Ideal Glucocorticoid Regimen With Abiraterone Acetate
Authors: Umang Swami, Sumanta K. Pal, Neeraj Agarwal
Journal: JAMA Oncology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Abstract 4867: Radiosurgery consultation to treatment interval, additional brain metastases during the interim and outcomes after therapy
Authors: Federico Ampil, Gloria Caldito, Troy Richards
Journal: Cancer Research (2019)

Abstract Background: Expediting the process of diagnosis and treatment should theoretically improve outcome. Delays in beginning therapy can cause anxiety to the patients and physicians who may be concerned about tumor progression before treatment is initiated. Treatment delays can be characterized as patient-generated or logistical medical infrastructure prolongations. Objective: The goal of the present study was to determine the impact of stereotactic radiosurgery (RS) consultation to treatment interval (CTI) and the development of additional brain metastases (BRM) during the interim on outcomes after RS. Methods: Between October 2014 and April 2018, 15 individuals developed more contrast-enhancing BRMs during the CTI. These patients were treated with gamma knife RS (including the six patients who underwent gross resection of metastatic intracranial neoplasm). The median duration of CTI was 19 days (range 5-61 days). A comparison of the ≤19 days CTI (eight patients) to the &amp;gt;19 days CTI (seven patients) was performed to assess the effects of the extent of delay to RS. The total number of BRM for RS was 68. The median target volume was 0.48 cm3, and the median margin dose was 24 Gy. Results: Most (67%) of the subjects exhibited good performance status. The overall crude survival rate at two years was 27%; acute or late toxicity after RS was not observed. Comparison of the CTI groups revealed: i) A longer CTI was not associated with a poorer prognosis; ii) BRM recurrence after RS was less common in this patient subgroup; iii) Quality of life (QOL) was satisfactory even though the CTI was prolonged. Conclusion: Acceptable longevity with minimal morbidity satisfying the QOL consideration was found in this audit of cases about CTI and the occurrence of more BRMs during the interim. Decreasing CTI in patients with BRM remains an important goal of quality improvement. Citation Format: Federico Ampil, Gloria Caldito, Troy Richards. Radiosurgery consultation to treatment interval, additional brain metastases during the interim and outcomes after therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4867.
An overview of new antitubercular drugs, drug candidates, and their targets
Authors: Aparna Bahuguna, Diwan S. Rawat
Journal: Medicinal Research Reviews (2019)

The causative agent of tuberculosis (TB), Mycobacterium tuberculosis and more recently totally drug-resistant strains of M. tuberculosis, display unique mechanisms to survive in the host. A four-drug treatment regimen was introduced 40 years ago but the emergence of multidrug-resistance and more recently TDR necessitates the identification of new targets and drugs for the cure of M. tuberculosis infection. The current efforts in the drug development process are insufficient to completely eradicate the TB epidemic. For almost five decades the TB drug development process remained stagnant. The last 10 years have made sudden progress giving some new and highly promising drugs including bedaquiline, delamanid, and pretomanid. Many of the candidates are repurposed compounds, which were developed to treat other infections but later, exhibited anti-TB properties also. Each class of drug has a specific target and a definite mode of action. These targets are either involved in cell wall biosynthesis, protein synthesis, DNA/RNA synthesis, or metabolism. This review discusses recent progress in the discovery of newly developed and Food and Drug Administration approved drugs as well as repurposed drugs, their targets, mode of action, drug-target interactions, and their structure-activity relationship.
Intensive Glucose Control in Patients with Type 2 Diabetes — 15-Year Follow-up
Authors: Peter D. Reaven, Nicholas V. Emanuele, Wyndy L. Wiitala, Gideon D. Bahn, Domenic J. Reda, Madeline McCarren, William C. Duckworth, Rodney A. Hayward
Journal: New England Journal of Medicine (2019)

We previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up.We observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome.There were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P = 0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75).Participants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.).
Abstract 20108: Surgical Left Atrial Appendage Closure, Perioperative Outcomes and Long Term Mortality
Authors: Alejandra Gutierrez, Han Sun, John Barnard, Marc A Gillinov, Eugene H Blackstone, Venu Menon, Oussama Wazni, David R Van Wagoner, Donald Hammer, Mina K Chung
Journal: Circulation (2017)

Introduction: Left atrial appendage closure (LAAC) is a possible alternative to anticoagulation in patients with atrial fibrillation (AF), but clinical outcomes and long-term survival after LAAC ar...
Pregnancy Zone Protein Is Associated with Airway Infection, Neutrophil Extracellular Trap Formation, and Disease Severity in Bronchiectasis
Authors: Simon Finch, Amelia Shoemark, Alison J. Dicker, Holly R. Keir, Alexandria Smith, Samantha Ong, Brandon Tan, Jean-Yu Choi, Thomas C. Fardon, Diane Cassidy, Jeffrey T. J. Huang, James D. Chalmers
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: PZP (pregnancy zone protein) is a broad-spectrum immunosuppressive protein believed to suppress T-cell function during pregnancy to prevent fetal rejection. It has not previously been reported in the airway.Objectives: To characterize PZP in the bronchiectasis airway, including its relationship with disease severity.Methods: Label-free liquid chromatography/mass spectrometry was performed for sputum protein profiling of patients with bronchiectasis confirmed by high-resolution computed tomography. Results for patients with and without Pseudomonas aeruginosa infection were compared. Sputum and serum PZP was measured by validated ELISA. Airway infection status was established by culture and 16S ribosomal RNA sequencing. Immunofluorescence, ELISA, and electron microscopy were used to identify the cellular source of PZP in neutrophils treated with multiple stimuli.Measurements and Main Results: Elevated PZP was identified by label-free liquid chromatography/mass spectrometry as being associated with P. aeruginosa infection. In a validation study of 124 patients, sputum but not serum concentrations of PZP were significantly associated with the Bronchiectasis Severity Index, the frequency of exacerbations, and symptoms. Airway infection with Proteobacteria such as P. aeruginosa was associated with higher concentrations of PZP. PZP in sputum was directly related to airway bacterial load. Neutrophils induced to form neutrophil extracellular traps (NETs) with phorbol myristate acetate released high concentrations of PZP in vitro, and fluorescence microscopy confirmed the presence of PZP in NETs, whereas fluorescence and electron microscopy localized PZP to the cytoplasm and nuclei of neutrophils. Effective antibiotic therapy reduced sputum PZP.Conclusions: PZP is released into NETs. We report a novel link between airway infection, NET formation, and disease severity in bronchiectasis during chronic airway inflammation.