tbuckley/cabot-search huggingface dataset:
Abstract 868: A Cardiac Specific Branched Chain Aminotransferase Deletion Increases Insulin Stimulated Glucose Oxidation in the Mouse Heart
Authors: Golam M Uddin, Simran Pherwani, Cory S Wagg, Keshav Gopal, Rami A Batran, Liyan Zhang, Yikuan Wu, Naayema Hussaini, Sonia Rawat, John R Ussher, Gary D Lopaschuk
Journal: Circulation Research (2019)

Impaired branched chain amino acid (BCAA) oxidation at the level of downstream BCAA catabolic enzymes cause cardiac insulin resistance and dysfunction. However, it is not known whether it is the accumulation of BCAAs or branched chain keto acids (BCKAs) due to impaired cardiac BCAA oxidation that result in these cardiac metabolic detrimental effects. Our objective was to inhibit cardiac branched chain aminotransferase (BCATm), the first enzyme in the BCAA oxidative pathway, which functions to produce BCKAs. We anticipate deletion of upstream BCAA catabolic enzyme will result in reduced cardiac BCAA oxidation and increase BCAAs but decrease BCKAs. Ten-week-old BCATm cardiac specific knockout (BCATm -/- ) male mice and their α-MHC-Cre expressing wildtype littermates (WT-Cre +/+ ) received 6 intraperitoneal injections of tamoxifen (50 mg/kg). All mice were allowed a 6-week washout post-tamoxifen, following which 16-week-old mice were used to assess cardiac energy metabolism. Isolated working hearts were perfused with oxygenated Krebs–Henseleit solution, consisting of either 5mM [5- 3 H/U- 14 C] glucose, 0.8mM palmitate, 3%BSA, 0.5mM BCAA for glycolysis and glucose oxidation measurements, or 0.5mM glucose, 0.8mM [9,10- 3 H] palmitate, 3%BSA and 0.5mM [U- 14 C] BCAA from combination of 0.15mM leucine/isoleucine and 0.2mM valine for fatty acid oxidation and BCAA oxidation measurements respectively. There was no body weight, glucose tolerance or cardiac function differences observed in BCATm -/- mice compared to WT-Cre +/+ mice (control). As expected, cardiac BCAA oxidation was significantly reduced in BCATm -/- mice compared to control, however, adding insulin after 30 min of perfusion did not change BCAA oxidation rates. Interestingly, glucose oxidation was significantly higher in BCATm -/- mice. Adding insulin further increased glucose oxidation in BCATm -/- mice. Additionally, the contribution of glucose oxidation to ATP production was significantly higher in the BCATm -/- mice compared to control. We conclude that impaired BCAA oxidation due to the upstream catabolic enzyme deletion increases cardiac insulin sensitivity. This also indicates that accumulation of BCKAs, not BCAAs, may be primarily contributing to cardiac insulin resistance.
Implementation and uptake of an interactive virtual online tumor board across NCI-Cancer Centers.
Authors: Maitri Kalra, Kelly Elizabeth McCann, Meghan Sri Karuturi, Jean Alvarez, Amanda Marie Parkes, Robert Wesolowski, Mei Wei, Sarah Schellhorn Mougalian, Greg Andrew Durm, Angel Qin, Meghna S. Trivedi, Avan J. Armaghani, Frederick Hugh Wilson, Wade Thomas Iams, Michael Cecchini, Anita Ahmed Turk, Hatem Hussein Soliman, Debu Tripathy, Samir Housri, Nadine Housri
Journal: Journal of Clinical Oncology (2019)

272 Background: Expert knowledge is often shared among academic oncologists at tumor boards (TBs) at National Cancer Institute Designated Cancer Centers (NCI-CCs), but not documented or made accessible to community oncologists. Using an oncologist-only question and answer (Q&amp;A) website, we sought to disseminate expert insights from TBs at NCI-CCs to provide educational benefit to the oncology community. Methods: A process was designed with faculty at 11 NCI-CCs to document and share discussions from TBs focused on areas of clinical complexity and practice variation on theMednet.org, an interactive Q&amp;A website of over 8,700 US oncologists. One faculty member from each TB was selected as a site leader. She or he distilled discussions about patient management from the TB into a question that addressed the clinical situation being discussed. After the question was posted, faculty at the participating NCI-CCs were asked to answer the question on theMednet. Answers were peer reviewed, indexed, stored and disseminated via email newsletters to registered oncologists. Community engagement was measured by Q&amp;A page views, upvotes of Q&amp;A, and poll participation. Results: A total of 15 Breast, Thoracic, and Gastrointestinal programs from 11 NCI-CCs participated. Between 12/2016 and 5/2019, faculty highlighted 146 questions from their TBs. Q&amp;A were viewed 43,291 times by 3,585 oncologists including 2,264 community oncologists. One hundred and eighty-four answers are posted by 56 academic physicians and peer reviewed by 76 academic physicians. One hundred and eighty-five publications were cited. Community oncologists upvoted Q&amp;A 808 times and voted in 45 polls related to the questions 1,667 times. Viewership of NCI-CC Q&amp;A increased by 419% over time. Q&amp;A were repeatedly searched and viewed, with 90% of all TB Q&amp;A viewed every month. Conclusions: Via the online Q&amp;A theMednet platform, NCI-CC providers effectively made expert knowledge easily accessible to community oncologists across the US. Timely access to evidence based recommendations from expert faculty can inform future practice choices in the community. [Table: see text]
EMA and FDA decisions based on flawed evidence to approve new cancer drugs negatively affect Latin American patients
Authors: Carlos E Durán, Martín Cañás, Thierry Christiaens
Journal: BMJ (2019)

A recent editorial1 by Mintzes and colleagues warns about using flawed clinical trials to approve new cancer drugs in Europe2 and the US.3 The implications go further, however: during the past decade, several Latin American countries have adopted regulations that abbreviate the approval process of new drugs in the case of earlier approval by the European Medicines Agency (EMA) or …
Abstract 580: Cardiovascular Risks of Oxidative DNA Damage
Authors: Kaitlin Lowran, Ann Fuelle, Phillip Popp, Colin G Wu
Journal: Circulation Research (2019)

G-quadruplexes (or G4s) are nucleic-acid structures formed by guanine-rich sequences. G4s must be timely unfolded in cells; otherwise, they can interfere with DNA replication, RNA transcription, and other essential processes. Guanine bases are susceptible to forming 8-oxoguanine (8oxoG) as a result of oxidative damage. Although 8oxoG-modified DNA sequences can still fold into stable G4s, it is not known how 8oxoG4s are removed in human cells. We have shown previously that the FANCJ DNA helicase targets G4s using an AKKQ amino acid motif and unfolds them with its motor activity. Here, we have examined the interactions of FANCJ with various 8oxoG4s using biolayer interferometry and fluorescence spectroscopy. We show that a FANCJ AKKQ peptide alone can recognize G4s independently. Moreover, this motif binds to 8oxoG4s with greater affinities. A detailed description of the mechanisms by which 8oxoG4s are repaired is essential for understanding how human hearts respond to oxidative stress. To test the importance of FANCJ AKKQ-G4 interactions in cells, we measured the total extent of oxidative DNA damage in human cardiomyocytes by single-cell electrophoresis. Cells that overexpress FANCJ can readily overcome the chemical stress induced by hydrogen peroxide treatment and the G4-stabilizing compound telomestatin. On the contrary, cells that produce a FANCJ ADDQ mutant, which cannot interact with G4s, resulted in an accumulation of 8oxoG4s. Based on this evidence, FANCJ plays an important role to alleviate the damage caused by oxidative stress. In future experiments, we plan to further examine the cardiovascular risks of DNA damage caused by FANCJ malfunctions.
Absolute Improvements in Freedom From Distant Recurrence to Tailor Adjuvant Endocrine Therapies for Premenopausal Women: Results From TEXT and SOFT
Authors: Olivia Pagani, Prudence A. Francis, Gini F. Fleming, Barbara A. Walley, Giuseppe Viale, Marco Colleoni, István Láng, Henry L. Gómez, Carlo Tondini, Graziella Pinotti, Angelo Di Leo, Alan S. Coates, Aron Goldhirsch, Richard D. Gelber, Meredith M. Regan
Journal: Journal of Clinical Oncology (2019)

PURPOSE The Tamoxifen and Exemestane Trial (TEXT)/Suppression of Ovarian Function Trial (SOFT) showed superior outcomes for premenopausal women with hormone receptor (HR)–positive breast cancer treated with adjuvant exemestane plus ovarian function suppression (OFS) or tamoxifen plus OFS versus tamoxifen alone. We previously reported the magnitude of absolute improvements in freedom from any recurrence across a continuous, composite measure of recurrence risk to tailor decision making. With longer follow-up, we now focus on distant recurrence. METHODS The TEXT/SOFT HR-positive/human epidermal growth factor receptor 2 (HER2)–negative analysis population included 4,891 women stratified by predetermined chemotherapy use. Kaplan-Meier estimates of 8-year freedom from distant recurrence were analyzed using subpopulation treatment effect pattern plot (STEPP) methodology across subpopulations defined by the continuous composite measure of recurrence risk. For each patient, the composite risk value was obtained from a Cox model that incorporated age; nodal status; tumor size; grade; and estrogen receptor, progesterone receptor, and Ki-67 labeling index expression levels. RESULTS The overall rate of 8-year freedom from distant recurrence was 91.1% and ranged from approximately 100% to 63% across lowest to highest composite risks. TEXT patients who received chemotherapy had an average absolute improvement with exemestane plus OFS versus tamoxifen plus OFS of 5.1%, and STEPP analysis showed improvements from less than 1% to more than 15% from lowest to highest composite risks. SOFT patients who remained premenopausal after chemotherapy had an average 5.2% absolute improvement with exemestane plus OFS versus tamoxifen and reached 10% across composite risks; for tamoxifen plus OFS versus tamoxifen, the maximum improvement was approximately 3.5%. Women who did not receive chemotherapy had a more than 97% rate of 8-year freedom from distant recurrence, and improvements with exemestane plus OFS ranged from 1% to 4%. CONCLUSION Premenopausal women with HR-positive/HER2-negative breast cancer and high recurrence risk, as defined by clinicopathologic characteristics, may experience a 10% to 15% absolute improvement in 8-year freedom from distant recurrence with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone. The potential benefit of escalating endocrine therapy versus tamoxifen alone is minimal for those at low recurrence risk.
Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells
Authors: Smile Echizenya, Yukiko Ishii, Satoshi Kitazawa, Tadashi Tanaka, Shun Matsuda, Eriko Watanabe, Masao Umekawa, Shunsuke Terasaka, Kiyohiro Houkin, Tomohisa Hatta, Tohru Natsume, Yoshimasa Maeda, Shin-Ichi Watanabe, Shinji Hagiwara, Toru Kondo
Journal: Neuro-Oncology (2019)

Glioblastoma-initiating cells (GICs) comprise a tumorigenic subpopulation of cells that are resistant to radio- and chemotherapies and are responsible for cancer recurrence. The aim of this study was to identify novel compounds that specifically eradicate GICs using a high throughput drug screening approach.We performed a cell proliferation/death-based drug screening using 10 560 independent compounds. We identified dihydroorotate dehydrogenase (DHODH) as a target protein of hit compound 10580 using ligand-fishing and mass spectrometry analysis. The medical efficacy of 10580 was investigated by in vitro cell proliferation/death and differentiation and in vivo tumorigenic assays.Among the effective compounds, we identified 10580, which induced cell cycle arrest, decreased the expression of stem cell factors in GICs, and prevented tumorigenesis upon oral administration without any visible side effects. Mechanistic studies revealed that 10580 decreased pyrimidine nucleotide levels and enhanced sex determining region Y-box 2 nuclear export by antagonizing the enzyme activity of DHODH, an essential enzyme for the de novo pyrimidine synthesis.In this study, we identified 10580 as a promising new drug against GICs. Given that normal tissue cells, in particular brain cells, tend to use the alternative salvage pathway for pyrimidine synthesis, our findings suggest that 10580 can be used for glioblastoma therapy without side effects.Key Points1. Chemical screening identified 10580 as a novel GIC-eliminating drug that targets DHODH, an essential enzyme for the de novo pyrimidine synthesis pathway. 2. Compound 10580 induced cell cycle arrest, apoptosis, and differentiation in GICs.
Phase I and pharmacokinetic study of the novel VEGF-directed fusion protein, aflibercept, in combination with docetaxel in women with recurrent ovarian, fallopian tube, and primary peritoneal cancer
Authors: R. L. Coleman, A. Kamat, R. Iyer, V. Kundra, M. Garcia, R. B. Jaffe, A. K. Sood
Journal: Journal of Clinical Oncology (2009)

5549 Background: VEGF blockade has proved to be a promising therapeutic strategy in solid tumors, including ovarian. Aflibercept, a novel fusion protein consisting of the extracellular domains of VEGFR1/2 binds VEGF A, B and PlGF. Aflibercept has been studied as a single agent in heavily pretreated ovarian cancer patients. We hypothesized that the combination of aflibercept and docetaxel could be safely administered to women with recurrent ovarian cancer. Correlative biomarker and imaging studies of anti-angiogenesis targeting, pharmacokinetics (PK) and preliminary efficacy were additional objectives. Methods: Eligible patients had measurable, recurrent disease with no more than 3 prior chemotherapeutic regimens. Study design was a “lead-in” phase I trial; cycle 0, administered aflibercept IV as a single agent in 1 of 3 dose levels (2, 4, or 6 mg/kg) in a 3+3 design. Aflibercept was given in subsequent cycles with docetaxel (75 mg/m2); each cycle was 21 days. Correlative studies in cycle 0 were: PK (single agent), circulating endothelial cells and precursors (CEC, CEP), and imaging FDG-PET, DCE-MRI (baseline, day 2 and day 21). Efficacy evaluation (RECIST) was conducted q2 cycles of combination therapy. Results: Nine patients were recruited, 3 at each dose level. All are evaluable. No DLTs were observed in cycles 0 and 1; The most common hematological toxicities were myelosuppression (1 Grade 4 ANC) and anemia (Grade 2). Non-hematological toxicities (Gr 3) included headache, hypertension, fatigue and ulceration. One patient each with hypertension and ulceration lead to treatment discontinuation after 4 and 13 cycles, respectively. FDG-PET defined SUVmax in target lesions within 25% of baseline in 7 patients; 2 others had &gt;25% increase at 48 hours post treatment. CECs, CEPs, DCE-MRI and PK are being analyzed. Confirmed PR was observed in 2 (22%) with 1 additional near PR. Median number of cycles: 5 (range 3–15). All have now progressed, median time to progression: 15 weeks. Conclusions: Aflibercept can be safely administered at 6 mg/kg with docetaxel repeatedly in this population of recurrent ovarian cancer patients. Preliminary efficacy supports phase II study, which is ongoing. No significant financial relationships to disclose.
Neglecting Major Health Problems and Broadcasting Minor, Uncertain Issues in Lifestyle Science
Authors: John P. A. Ioannidis
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Comprehensive immune profiling and immune-monitoring using body fluid of patients with metastatic gastric cancer
Authors: Hyung Soon Park, Woo Sun Kwon, Sejung Park, Eunji Jo, So Jung Lim, Choong-kun Lee, Jii Bum Lee, Minkyu Jung, Hyo Song Kim, Seung-Hoon Beom, Jun Yong Park, Tae Soo Kim, Hyun Cheol Chung, Sun Young Rha
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> The aim of this study is to profile the cytokines and immune cells of body fluid from metastatic gastric cancer (mGC), and evaluate the potential role as a prognostic factor and the feasibility as a predictive biomarker or monitoring source for immune checkpoint inhibitor. <h3>Methods</h3> Body fluid including ascites and pleural fluid were obtained from 55 mGC patients and 24 matched blood. VEGF-A, IL-10, and TGF-β1 were measured and immune cells were profiled by fluorescence assisted cell sorting (FACS). <h3>Results</h3> VEGF-A and IL-10 were significantly higher in body fluid than in plasma of mGC. Proportion of T lymphocytes with CD69 or PD-1, memory T cell marked with CD45RO, and number of Foxp3+ T regulatory cells (Tregs) were significantly higher in body fluid than those in blood of mGC. Proportion of CD8 T lymphocyte with memory marker (CD45RO) and activation marker (HLA-DR), CD3 T lymphocyte with PD-1, and number of FoxP3+ Tregs were identified as independent prognostic factors. When patients were classified by molecular subgroups of primary tumor, VEGF-A was significantly higher in genomically stable (GS)-like group than that in chromosomal instability (CIN)-like group while PD-L1 positive tumor cells (%) showed opposite results. Monitoring immune dynamics using body fluid was also feasible. Early activated T cell marked with CD25 was significantly increased in chemotherapy treated group. <h3>Conclusions</h3> By analyzing cytokines and proportion of immune cells in body fluid, prognosis of patients with mGC can be predicted. Immune monitoring using body fluid may provide more effective treatment for patients with mGC.
Impact of Non-CMV Specific Intravenous Immunoglobulin on Intravenous Ganciclovir Effectiveness
Authors: Mikhail Yu. Drokov, Dmitry S. Tikhomirov, Larisa Kuzmina, Tatiana A. Tupoleva, Vera Vasilyeva, Natalia Popova, Ekaterina Mikhaltsova, Olga Koroleva, Daria Dubnyak, Anna Sidorova, Ekterina Usikova, Zoya Konova, Anna Dmitrova, Tatiana V. Gaponova, Elena Parovichnikova, Valery G. Savchenko
Journal: Blood (2018)
Preliminary Results from a Phase I, First-in-Human Study of YY-20394, a Highly Selective and Highly Potent PI3Kδ Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies
Authors: Junyuan Qi, Yuqin Song, Bo Jiang, Jianyong Li, Meifeng Tu, Lingyan Ping, Zengjun Li, Wei Xu, Huayuan Zhu, Jun Zhu, Hanying Bao, Zusheng Xu, Lugui Qiu
Journal: Blood (2018)
Three-Year Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC—Update from PACIFIC
Authors: Jhanelle E. Gray, Augusto Villegas, Davey Daniel, David Vicente, Shuji Murakami, Rina Hui, Takayasu Kurata, Alberto Chiappori, Ki Hyeong Lee, Byoung Chul Cho, David Planchard, Luis Paz-Ares, Corinne Faivre-Finn, Johan F. Vansteenkiste, David R. Spigel, Catherine Wadsworth, Maria Taboada, Phillip A. Dennis, Mustafa Özgüroğlu, Scott J. Antonia
Journal: Journal of Thoracic Oncology (2019)

IntroductionIn the phase 3 PACIFIC study of patients with unresectable stage III NSCLC without progression after chemoradiotherapy, durvalumab demonstrated significant improvements versus placebo in the primary end points of progression-free survival (hazard ratio [HR] = 0.52, 95% confidence interval [CI]: 0.42–65, p < 0.0001) and overall survival (OS) (HR = 0.68, 95% CI: 0.53–0.87, p = 0.00251), with manageable safety and no detrimental effect on patient-reported outcomes. Here, we report 3-year OS rates for all patients randomized in the PACIFIC study.MethodsPatients, stratified by age, sex, and smoking history, were randomized (2:1) to receive durvalumab, 10 mg/kg intravenously every 2 weeks, or placebo for up to 12 months. OS was analyzed by using a stratified log-rank test in the intention-to-treat population. Medians and rates at 12, 24, and 36 months were estimated by the Kaplan-Meier method.ResultsAs of January 31, 2019, 48.2% of patients had died (44.1% and 56.5% in the durvalumab and placebo groups, respectively). The median duration of follow-up was 33.3 months. The updated OS remained consistent with that previously reported (stratified HR = 0.69 [95% CI: 0.55–0.86]); the median OS was not reached with durvalumab but was 29.1 months with placebo. The 12-, 24- and 36-month OS rates with durvalumab and placebo were 83.1% versus 74.6%, 66.3% versus 55.3%, and 57.0% versus 43.5%, respectively. All secondary outcomes examined showed improvements consistent with previous analyses.ConclusionsUpdated OS data from PACIFIC, including 3-year survival rates, demonstrate the long-term clinical benefit with durvalumab after chemoradiotherapy and further establish the PACIFIC regimen as the standard of care in this population.
Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy
Authors: Nikita S. Sharma, Vineet K. Gupta, Vanessa T. Garrido, Roey Hadad, Brittany C. Durden, Kousik Kesh, Bhuwan Giri, Anthony Ferrantella, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee
Journal: Journal of Clinical Investigation (2019)

Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA4, PD1, PDL1) has not been very successful against PDAC. The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on the one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase 1 (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). In the current manuscript, we targeted this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-l-norleucine [DON]). Our results showed that DON decreased the self-renewal potential and metastatic ability of tumor cells. Further, treatment with DON decreased hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM and an increased infiltration of CD8+ T cells. Additionally, treatment with DON sensitized pancreatic tumors to anti-PD1 therapy, resulting in tumor regression and prolonged survival.