tbuckley/cabot-search huggingface dataset:
Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer
Authors: Timothy J. Humpton, Brinda Alagesan, Gina M. DeNicola, Dan Lu, Georgi N. Yordanov, Carl S. Leonhardt, Melissa A. Yao, Priya Alagesan, Maya N. Zaatari, Youngkyu Park, Jeremy N. Skepper, Kay F. Macleod, Pedro A. Perez-Mancera, Michael P. Murphy, Gerard I. Evan, Karen H. Vousden, David A. Tuveson
Journal: Cancer Discovery (2019)

Abstract Activating KRAS mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identification of vulnerabilities and the development of new treatments. We show that oncogenic KRAS induces BNIP3L/NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of Nix restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. Although conditional Nix ablation in vivo initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and pancreatic intraepithelial neoplasia (PanIN) lesions progress to PDAC. We identify the KRAS–NIX mitophagy program as a novel driver of glycolysis, redox robustness, and disease progression in PDAC. Significance: NIX-mediated mitophagy is a new oncogenic KRAS effector pathway that suppresses functional mitochondrial content to stimulate cell proliferation and augment redox homeostasis. This pathway promotes the progression of PanIN to PDAC and represents a new dependency in pancreatic cancer. This article is highlighted in the In This Issue feature, p. 1143
A phase II feasibility study of palbociclib in combination with adjuvant endocrine therapy for hormone receptor-positive invasive breast carcinoma
Authors: E.L. Mayer, A. DeMichele, H.S. Rugo, K. Miller, A.G. Waks, S.E. Come, T. Mulvey, R. Jeselsohn, B. Overmoyer, H. Guo, W.T. Barry, C. Huang Bartlett, M. Koehler, E.P. Winer, H.J. Burstein
Journal: Annals of Oncology (2019)
Coronary Computed Tomography Angiography as the Investigation of Choice for Stable Chest Pain—Reply
Authors: Sanjay Kaul
Journal: JAMA Cardiology (2019)

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Advanced in silico modeling explains pharmacokinetics and biodistribution of temoporfin nanocrystals in humans
Authors: Laura Jablonka, Mukul Ashtikar, Ge Gao, Fabian Jung, Manuela Thurn, Annegret Preuß, Dietrich Scheglmann, Volker Albrecht, Beate Röder, Matthias G. Wacker
Journal: Journal of Controlled Release (2019)
Abstract 4267: mTORC1-dependent tumors have innate vulnerability to autophagic cell death by HDAC inhibitors
Authors: Fuchun Yang, Chenran Wang, Shaogang Sun, Michael Haas, Syn Yeo, Jun-Lin Guan
Journal: Cancer Research (2019)

Abstract mTORC1 plays a significant role in the development and progression of many different types of cancers. Although mTORC1 inhibitors, such as Rapamycin, have anti-tumor effects on some specific cancers, their efficacy is still largely limited to anti-proliferative effects. Histone deacetylase (HDAC) inhibitors have been proven to be effective in cancer treatment including some solid cancers. We have previously established a vascular tumor cell line, Tsc1Δ EC, which was derived from Tsc1 deletion in mouse endothelial cells leading to constitutive activation of mTORC1. Here, we found that a pan-HDAC inhibitor, SAHA, caused Tsc1Δ EC cell death and growth arrest in vitro and in vivo. Our data showed that a selective Class I HDAC inhibitor CI994 treatment also caused Tsc1Δ EC cell death. Unlike mTORC1 inhibitors, the anti-tumor activity of SAHA was dependent on mTORC1 activation but it had little effect on mTORC1 activity in mTORC1 activated tumor cells. We found that Z-VAD-FMK, a pan-caspase inhibitor, had no inhibitory effect on SAHA treatment. Cell death pathway array analysis revealed that SAHA treatment in Tsc1ΔEC upregulated autophagy-related genes. Further experiments revealed that both autophagy gene Fip200 deletion and autophagy inhibition by spautin-1 in Tsc1Δ EC impaired tumor cell death by SAHA treatment. We further found that SAHA could play a role by increasing reactive oxygen species (ROS) via autophagy. Fip200 deletion caused Nrf2 activation through p62 accumulation, which can lead to antioxidation effect through p62-Keap1-Nrf2 pathway. We showed that inhibition of p62 expression re-sensitized Fip200 deleted Tsc1Δ EC to SAHA treatment. Taken together, HDAC inhibitors treatment provides an alternative promising therapeutic strategy for mTORC1-dependent cancers. Note: This abstract was not presented at the meeting. Citation Format: Fuchun Yang, Chenran Wang, Shaogang Sun, Michael Haas, Syn Yeo, Jun-Lin Guan. mTORC1-dependent tumors have innate vulnerability to autophagic cell death by HDAC inhibitors [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 4267.
Abstract 19688: Longterm Outcomes of Endovascular Therapy for Subclavian Artery Disease in Hemodialysis Patients
Authors: Toshiya Soejima, Yoshiaki Shintani, Yoshimitsu Soga, Tomohiro Kawasaki
Journal: Circulation (2017)

Introduction: Clinical outcomes on hemodialysis are little known. Hypothesis: To investigate the long-term outcome of the endovascular therapy (EVT) for subclavian artery disease in hemodialysis (H...
Abstract 2385: Discovery of highly specific claudin 6 monoclonal antibodies
Authors: L Joe Stafford
Journal: Cancer Research (2019)

Abstract Claudin 6 (CLDN6) is an oncofetal tight junction protein involved in the cell-to-cell adhesion of epithelial and endothelial cell sheets. Although silenced in healthy adult human tissues, CLDN6 expression has been found in ovarian, gastric, pediatric, and other cancer tissues and can lead to a poor prognosis. Monoclonal antibody (MAb) discovery against CLDN6 has been encumbered by the high homology of endogenously expressed claudin 9 (CLDN9), which varies from CLDN6 by only 3 amino acids in the extracellular domain. Our MPS Antibody Discovery platform utilizes proprietary technologies to overcome key barriers to MAb discovery, enabling the isolation of MAbs against multipass membrane proteins such as CLDN6. Using the MPS platform, we have successfully isolated and characterized panels of highly specific MAbs to CLDN6. Nine chickens were immunized with the target antigen, and titer was achieved in all but one animal. Following 2 rounds of phage panning, we screened 2,000 clones for CLDN6 specificity, identifying 788 hits and 68 unique VH CDR3 families. From these clones, 72 antibodies were selected for binding to CLDN6 and CLDN6/9. Two lead antibodies, IM-171 and IM-136, showed high specificity and high affinity to CLDN6 but not to claudins 3, 4, or 9. Using high-resolution Shotgun Mutagenesis Epitope Mapping, we confirmed that our lead candidate MAbs bind distinct residues on CLDN6 compared to previously described MAbs. Specificity analysis with our Membrane Proteome Array revealed no significant binding of either of our lead MAbs to any other membrane protein in the human proteome, including any of the other 20+ claudin proteins. Both of our lead MAbs bound endogenously expressed CLDN6 on ovarian carcinoma (PA-1) cells. Our preclinical CLDN6 antibodies are now being developed for use in various formats, including bispecifics, antibody-drug conjugates, and CAR-T applications. Citation Format: L Joe Stafford. Discovery of highly specific claudin 6 monoclonal antibodies [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 2385.
Abstract 18562: Inter-individual Variation in Duration, Frequency and Burden of Paroxysmal Atrial Fibrillation in 13,350 Individuals Undergoing Extended Cardiac Rhythm Monitoring
Authors: Evan D Muse, Paddy M Barrett, Nathan E Wineinger, Steven R Steinhubl, Eric J Topol
Journal: Circulation (2017)

Introduction: Atrial fibrillation (AF) is the most common sustained arrhythmia. The characteristics of AF relating to the duration, frequency, and burden of paroxysmal AF remains unclear. These cha...
Abstract 4535: The mTOR complex 2 promotes glioblastoma migration via the interactions with multiple actin-binding and microtubule-associated proteins
Authors: Naphat Chantaravisoot, Piriya Wongkongkathep, Narawit Pacharakullanon, Fuyuhiko Tamanoi, Joseph A. Loo, Trairak Pisitkun
Journal: Cancer Research (2019)

Abstract The mechanistic target of rapamycin complex 2 (mTORC2) is one of the two multiprotein complexes in the mTOR signaling pathway. It regulates several cellular activities such as cell survival, lipid metabolism, DNA damage control, and cell motility. The mTORC2 has been reported to be involved in the promotion of metabolic reprogramming, cancer migration, and cancer invasiveness in glioblastoma. However, underlying mechanisms and roles of this particular complex in glioblastoma migration has not been completely elucidated. Previously, we characterized the mTORC2-associated interactome by affinity purification-mass spectrometry (AP-MS) technique, identifying new RICTOR-interacting partners. In addition, we also investigated the localization of RICTOR under different culture conditions and found that it correlates with migration ability of the cancer cells. When mTORC2 activity is high resulting in increased migration, RICTOR tends to localize around the cell membrane. In this work, we further determined crucial players that interact with mTORC2 to control actin cytoskeleton and microtubule dynamics to promote migration. The results from quantitative proteomic analysis of mTORC2-associated interactome suggested that the amount of certain actin-binding proteins and microtubule-associated proteins significantly changed depending on mTORC2 activity level including Gelsolin, Myosin-9, Plectin, and MAP1B. When mTORC2 signaling was inhibited resulting in reduced migration, these proteins were found to be less interacting with mTORC2. Moreover, the results also indicated that active mTORC2 links both actin cytoskeleton and microtubules together to promote migration in glioblastoma cells. Depletion of RICTOR and inhibition of mTORC2 disrupted the connection between microtubules and cell membrane. Taken together, this work provided a plausible mechanism underlying the regulation of enhanced migration in brain cancer cells. Citation Format: Naphat Chantaravisoot, Piriya Wongkongkathep, Narawit Pacharakullanon, Fuyuhiko Tamanoi, Joseph A. Loo, Trairak Pisitkun. The mTOR complex 2 promotes glioblastoma migration via the interactions with multiple actin-binding and microtubule-associated proteins [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 4535.
Abstract 3529: Sample quality control of cell-free DNA
Authors: Eva Graf
Journal: Cancer Research (2019)

Abstract Sequencing of cell-free DNA (cfDNA) is possible due to the establishment of low input library protocols for next-generation sequencing workflows. Accurate quantification of cfDNA samples is essential to determine suitable input amounts for cfDNA library preparation prior to sequencing. The main component of cfDNA samples is the mononucleosome with a size around 170 bp, sometimes with additional species representing nucleosome multimers. Further, cfDNA samples may contain larger DNA fragments dependent on pre-analytical sample treatment or extraction method. High molecular weight material can negatively influence library preparation and subsequently result in lower sequencing depth. Therefore, reliable quantification of cfDNA requires a method that separates DNA fragments by size, such as electrophoresis. This poster shows the use of an automated electrophoresis platform performing cfDNA quantification with region analysis. Moreover, the results include a score to qualify cfDNA samples according to their contamination level with high molecular weight material. This allows defining a threshold for objective sample qualification prior to library preparation. The analysis features are described with examples of typical sample patterns. Citation Format: Eva Graf. Sample quality control of cell-free DNA [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 3529.
Abstract 1037: Axl is critical for pancreatic cancer progression and metastasis
Authors: Wenting Du, Huocong Huang, Jason Toombs, Zhaoning Wang, Abdel Hosein, Natalie Burton, Rolf A. Brekken
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC), a leading cause of cancer-related death in the US, has a high metastatic rate that is associated with persistent immune suppression. Axl, a member of the TAM (Tyro3, Axl, MerTK) receptor tyrosine kinase family, has been identified as a critical factor that drives metastasis and immune suppression in many cancer types. We have shown that pharmacological inhibition of Axl significantly reduces tumor progression and metastasis and improves response to chemotherapy in multiple preclinical PDAC models. Here we demonstrate that Axl-deficient PDAC bearing mice have longer median survival, smaller tumors, fewer metastases and higher sensitivity to chemotherapy (gemcitabine) compared to Axl wild-type (WT) PDAC mice. Furthermore, Axl-deficient PDAC displays a more differentiated histology and has a more inflammatory and active immune microenvironment. Single cell RNA sequencing of PDAC genetically engineered mouse models reveals that Axl is expressed highly in tumor cells that have a mesenchymal-like phenotype and Axl expression correlates with classic markers of mesenchymal tumor cells at the RNA and protein level. To investigate the importance of Axl on tumor cells, CRISPR-Cas9 was used to knockout Axl in PDAC cells. Human and murine Axl-deficient PDAC cells displayed a more differentiated (epithelial) phenotype in vitro including reduced migratory capacity compared to Axl WT parental cells. Orthotopic injection of Axl-deficient murine PDAC cells into Axl WT mice resulted in longer median survival and fewer metastases compared to WT mice injected with WT PDAC cells. However, Axl-deficient mice injected with WT PDAC cell injection showed similar median survival and metastases as WT mice injected with WT PDAC cells. These in vivo results indicate that Axl expression on tumor cells is critical for PDAC progression and metastasis. In vitro experiments using WT and Axl-deficient human PDAC cells show that Axl is required for TGFβ-mediated epithelial to mesenchymal transition, probably through regulating the expression of Smad2 and Smad4. Interesting, Axl depletion has no effect on the mRNA level of Smad2 and Smad4, but does decrease the protein level, indicating that Axl might be involved in post-translational regulation (e.g., protein stability) of canonical TGFβ signaling intermediates. In summary, our study demonstrates that Axl expressed by pancreatic cancer cells is critical to tumor cell plasticity, tumor progression and metastasis. Citation Format: Wenting Du, Huocong Huang, Jason Toombs, Zhaoning Wang, Abdel Hosein, Natalie Burton, Rolf A. Brekken. Axl is critical for pancreatic cancer progression and metastasis [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 1037.
Generalised mosaicism for <i>TSC2</i> mutation in isolated lymphangioleiomyomatosis
Authors: Barbara Ogórek, Lana Hamieh, Kathryn Lasseter, Shefali Bagwe, Tania Machado, Carmen Herranz-Ors, Aaron R. Thorner, Anwesha Nag, Peter Gulleman, Krinio Giannikou, Lisa R. Young, Miquel Àngel Pujana, Thomas N. Darling, Souheil El-Chemaly, Joel Moss, Elizabeth P. Henske, David J. Kwiatkowski
Journal: European Respiratory Journal (2019)

<b>Analysis of plasma cell-free DNA from 61 sporadic lymphangioleiomyomatosis (LAM) patients identified generalised mosaicism for a <i>TSC2</i> mutation in one, suggesting that some sporadic LAM patients are occult generalised mosaics for <i>TSC2</i> mutations</b>http://bit.ly/2yLr0Ls
Survey on the Unmet Needs of Patients Living with mCRC – Learnings from an International Study
Authors: Z. Maravic, I. Rawicka, L. Lemmens, J. Bokros, C. González de Pedro, J. Stanisic Trenevski, M. Méndez Otero, O. Rial, T. Ferro
Journal: Annals of Oncology (2019)
Reduced-Intensity Conditioning Is Successful in Matched Sibling Bone Marrow Transplantation As a Cure for Sickle Cell Disease
Authors: Shreya Agarwal, Krupesh Patel, Alfred Gillio, Melanie Hankewycz, Nancy Durning, Jeanette Haugh, Barbara Adler-Brecher, Jennifer Krajewski
Journal: Blood (2017)
Response to: ‘Is it currently reasonable to offer short 14-day antibiotic therapies after a surgical synovectomy in native joint septic arthritis?’ by Coiffier <i>et al</i>
Authors: Ilker Uçkay, Amanda Gonzalez, Ergys Gjika
Journal: Annals of the Rheumatic Diseases (2019)

We read with great interest the (mostly justified) scientific remarks of our colleagues Coiffier et al 1 to our article,2 randomising to either 2 or 4 weeks of systemic targeted antibiotic therapy after surgical drainage of native joint bacterial arthritis in adults. This was a classical non-inferiority trial detecting a similar outcome, similar mechanical sequels and a similar proportion of antibiotic-related adverse events in the short-antibiotic treatment group when compared with the classical long antibiotic administration of 4 weeks.2

However, native joint septic arthritis is a very heterogeneous group of clinical entities with different epidemiological, microbiological and therapeutic aspects in humans. The spectrum varies between adult and paediatric patients, with and without concomitant adjacent osteomyelitis or immune suppression, pathogens ( Staphylococcus aureus, Pseudomonas aeruginosa , gonococci, viruses), anatomical localisations (extremities, hand, diabetic foot, spine, mandibular, shoulder, sacroiliac), settings (orthopaedic departments vs rheumatological services), origins (spontaneous, intravenous drug abuse, surgical site infections, post-traumatic, bites) and management (surgeons, rheumatologists, internists, emergency vs elective drainage).3

Of note, our trial accepted all surgically drained arthritis cases but was sufficiently powered for the overall population plus the subgroup of hand and wrist arthritis cases, which in turn were …
Dietary fats and mortality among patients with type 2 diabetes: analysis in two population based cohort studies
Authors: Jingjing Jiao, Gang Liu, Hyun Joon Shin, Frank B Hu, Eric B Rimm, Kathryn M Rexrode, JoAnn E Manson, Geng Zong, Qi Sun
Journal: BMJ (2019)

Abstract Objective To assess the association of dietary fatty acids with cardiovascular disease mortality and total mortality among patients with type 2 diabetes. Design Prospective, longitudinal cohort study. Setting Health professionals in the United States. Participants 11 264 participants with type 2 diabetes in the Nurses’ Health Study (1980-2014) and Health Professionals Follow-Up Study (1986-2014). Exposures Dietary fat intake assessed using validated food frequency questionnaires and updated every two to four years. Main outcome measure Total and cardiovascular disease mortality during follow-up. Results During follow-up, 2502 deaths including 646 deaths due to cardiovascular disease were documented. After multivariate adjustment, intake of polyunsaturated fatty acids (PUFAs) was associated with a lower cardiovascular disease mortality, compared with total carbohydrates: hazard ratios comparing the highest with the lowest quarter were 0.76 (95% confidence interval 0.58 to 0.99; P for trend=0.03) for total PUFAs, 0.69 (0.52 to 0.90; P=0.007) for marine n-3 PUFAs, 1.13 (0.85 to 1.51) for α-linolenic acid, and 0.75 (0.56 to 1.01) for linoleic acid. Inverse associations with total mortality were also observed for intakes of total PUFAs, n-3 PUFAs, and linoleic acid, whereas monounsaturated fatty acids of animal, but not plant, origin were associated with a higher total mortality. In models that examined the theoretical effects of substituting PUFAs for other fats, isocalorically replacing 2% of energy from saturated fatty acids with total PUFAs or linoleic acid was associated with 13% (hazard ratio 0.87, 0.77 to 0.99) or 15% (0.85, 0.73 to 0.99) lower cardiovascular disease mortality, respectively. A 2% replacement of energy from saturated fatty acids with total PUFAs was associated with 12% (hazard ratio 0.88, 0.83 to 0.94) lower total mortality. Conclusions In patients with type 2 diabetes, higher intake of PUFAs, in comparison with carbohydrates or saturated fatty acids, is associated with lower total mortality and cardiovascular disease mortality. These findings highlight the important role of quality of dietary fat in the prevention of cardiovascular disease and total mortality among adults with type 2 diabetes.