tbuckley/cabot-search huggingface dataset:
PB1835 A PHASE 1/1B DOSE‐ESCALATION TRIAL EVALUATING CPI‐818, AN ORAL INTERLEUKIN‐2‐INDUCIBLE T‐CELL KINASE INHIBITOR, IN PATIENTS WITH RELAPSED/REFRACTORY T‐CELL LYMPHOMA
Authors: M. Mobasher, R.A. Miller, J. Janc, L. Kwei, C. Barker, A. Mohammady, G. Luciano, M. Khodadoust, D. Radeski, S.M. Horwitz, Y.H. Kim
Journal: HemaSphere (2019)

Background: Interleukin‐2‐Inducible T‐Cell Kinase (ITK) is a Tec‐family, non‐receptor tyrosine kinase expressed in T cells that plays a key role in T‐cell receptor (TCR) signaling, which is required for development of T‐cells. In T‐cell lymphoproliferative disorders, expression of the TCR and its downstream signaling components are maintained, which suggests that malignant cells may exploit this growth and survival pathway to their advantage. Professional antigen‐presenting cells abundant in the lymphoma microenvironment may provide antigen to drive TCR signaling through ITK, which is expressed in a variety of T‐cell lymphomas including PTCL, CTCL, ALCL, and in a subgroup of T‐lymphoblastic leukemia/lymphoma. CPI‐818 is a first‐in‐class, irreversible, covalent‐binding ITK inhibitor with a high degree of selectivity for ITK. By inhibiting ITK, CPI‐818 blocks signaling pathways that are essential to inflammatory responses and has shown to inhibit tumor growth in animal models. Aims: To test the effect of CPI‐818 clinically, a phase 1/1b dose‐escalation trial of CPI‐818 is initiated in subjects with relapsed/refractory T‐cell lymphoma. Methods: The trial will include patients with various types of T‐cell lymphoma (PTCL and CTCL) who have progressed on, refractory to, relapsed, or intolerant to at least 2 standard therapies; age ≥ 18 yo; have ECOG status 0‐1; adequate organ function; and without any other condition that would contraindicate the use of the investigational product. Dose Escalation with 3 + 3 (+ optional 3) design will consist of up to 6 ascending dose levels (100,200, 400, 600, 900, and 1200 mg BID) of CPI‐818. In the Dose Expansion phase, there will be 4 disease‐specific expansion cohorts (AITL, PTCL‐NOS, CTCL and other T‐cell lymphoma), and each cohort may enroll up to a maximum of 28 subjects/cohort based on a 2‐stage expansion design‐ Figure. The objectives of the study are to evaluate the safety and tolerability of CPI‐818; establish the maximum tolerated dose or the maximum administered dose of CPI‐818; evaluate pharmacokinetics and pharmacodynamics of CPI‐818 in humans; assess the anti‐tumor activity of CPI‐818 and identify potential biomarker signals. Study schema in the figure. Approximately 151 subjects will be enrolled at approximately 35 sites in the US, South Korea, and Australia. Results: None. Trial in progress Summary/Conclusion: None. Trial in progress image
Hepatocyte growth factor-regulated tyrosine kinase substrate is essential for endothelial cell polarity and cerebrovascular stability
Authors: Zhenyang Yu, Jian Zeng, Jun Wang, Yaxiong Cui, Xiaopeng Song, Yizhe Zhang, Xuan Cheng, Ning Hou, Yan Teng, Yu Lan, Yeguang Chen, Xiao Yang
Journal: Cardiovascular Research (2020)

Hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs), a key component of the endosomal sorting complex required for transport (ESCRT), has been implicated in many essential biological processes. However, the physiological role of endogenous Hgs in the vascular system has not previously been explored. Here, we have generated brain endothelial cell (EC) specific Hgs knockout mice to uncover the function of Hgs in EC polarity and cerebrovascular stability.
Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions
Authors: Alvaro A. Ordonez, Hechuan Wang, Gesham Magombedze, Camilo A. Ruiz-Bedoya, Shashikant Srivastava, Allen Chen, Elizabeth W. Tucker, Michael E. Urbanowski, Lisa Pieterse, E. Fabian Cardozo, Martin A. Lodge, Maunank R. Shah, Daniel P. Holt, William B. Mathews, Robert F. Dannals, Jogarao V. S. Gobburu, Charles A. Peloquin, Steven P. Rowe, Tawanda Gumbo, Vijay D. Ivaturi, Sanjay K. Jain
Journal: Nature Medicine (2020)
Use of the 21-Gene Recurrence Score to Predict Clinical Outcomes in Early Breast Cancer—Reply
Authors: Joseph A. Sparano
Journal: JAMA Oncology (2020)

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
PS983 NOVEL MOLECULAR PATHOGENESIS AND THERAPEUTIC TARGET IN ACUTE ERYTHROID LEUKEMIA
Authors: J. Takeda, L.-Y. Shih, K. Yoshida, H. Makishima, T. Yoshizato, Y. Shiozawa, Y. Ochi, A. Kon, A. Yoda, M. Nakagawa, Y. Nannya, K. Kataoka, M. Sanada, K. Chiba, Y. Shiraishi, S. Miyano, N. Hiramoto, S. Chiba, Y. Miyazaki, A. Takaori-Kondo, T. Ishikawa, C. Kerr, J. Maciejewski, A. Ganser, M. Heuser, F. Thol, S. Ogawa
Journal: HemaSphere (2019)

Background: Signal transducer and activator of transcription 3 (STAT3) plays a central role in proliferation, differentiation and oncogenic transformation. It is expressed in two alternatively spliced isoforms, STAT3α and truncated STAT3β, which lacks the C-terminal transactivation domain and instead carries seven unique amino acids. Interestingly, STAT3β recently gained attention as a powerful anti-tumorigenic molecule and protective prognostic marker. This has been shown in patients with esophageal squamous cell carcinoma as well as in mouse models for breast, skin and colon cancer. Deregulated STAT3 signaling is frequently observed in leukemogenesis and generally associated with a poor clinical outcome in patients with acute myeloid leukemia (AML). In addition, it has been shown that the expression ratios of STAT3α and STAT3β change upon myeloid differentiation. However, the exact role of STAT3β in AML patients and during disease progression remains unknown. Aims: The goal of our study is to analyze the contribution of the two STAT3 isoforms to leukemogenesis with a particular focus on STAT3β in AML development. Methods: We analyzed more than 50 AML patient samples for STAT3β/STAT3α mRNA expression levels and its correlation with clinical prognosis and overall survival. Furthermore, we generated an inducible Stat3β transgenic mouse model and crossed it with Pten-deficient mice, a previously described model for AML. In addition, we used fetal liver-derived stem cells from Stat3β transgenic mice, transduced with a retrovirus encoding for the MLL-AF9 translocation, in a transplant model for AML. Results: We observed a correlation between clinical prognosis and STAT3β/STAT3α expression ratio. A higher STAT3β/STAT3α ratio was further associated with a favorable clinical prognosis and a significantly increased overall survival. In both in vivo mouse models we could demonstrate that the expression of STAT3β impairs leukemogenesis and leukemic cell infiltration into hematopoietic organs. The STAT3β-dependent delay in disease progression and leukemic infiltration resulted in a significant increase of overall survival. Summary/Conclusion: In summary, the results of our study demonstrate STAT3β as an anti-tumorigenic molecule in AML mouse models and the STAT3β/STAT3α ratio in AML patient derived blasts positively correlates with survival.
Post-Systolic Shortening by Speckle Tracking Echocardiography Predicts Cardiac Events in Type 2 Diabetes
Authors: Philip Brainin, Magnus T. Jensen, Tor Biering-Sørensen, Rasmus Møgelvang, Thomas Fritz-Hansen, Tina Vilsbøll, Peter Rossing, Peter Godsk Jørgensen
Journal: JACC. Cardiovascular imaging (2020)
Recent strategies and advances in the fabrication of nano lipid carriers and their application towards brain targeting
Authors: Mukta Agrawal, Swarnlata Saraf, Shailendra Saraf, Sunil Kumar Dubey, Anu Puri, Ravish J. Patel, None Ajazuddin, V. Ravichandiran, Upadhyayula Suryanarayana Murty, Amit Alexander
Journal: Journal of Controlled Release (2020)
18F-FDG PET/CT and 68Ga-DOTATOC PET/CT in Diffuse Pancreatic Neuroendocrine Tumor
Authors: Xia Ji, Aisheng Dong, Qi He, Hui Dong, Changjing Zuo
Journal: Clinical Nuclear Medicine (2020)

Abstract We present 2 cases of pancreatic neuroendocrine tumor with diffuse involvement of the entire pancreas. One case with G2 pancreatic neuroendocrine tumor showed nearly normal pancreatic shape and signal intensity on MRI, normal pancreatic 18 FDG uptake, and diffuse pancreatic 68 Ga-DOTATOC uptake. The other case with G3 pancreatic neuroendocrine tumor showed diffusely enlarged pancreas with abnormal MR signal intensity and increased 18 FDG uptake. These 2 cases indicate that neuroendocrine tumor should be included in the differential diagnosis of diffuse pancreatic diseases. Somatostatin receptor imaging may be helpful for the diagnosis of diffuse pancreatic neuroendocrine tumor in equivocal cases.
Availability of Naloxone at Rural Georgia Pharmacies, 2019
Authors: Jennifer L. Nguyen, Lauren R. Gilbert, Lauren Beasley, John J. Brooks, Jennifer Elliott, K. Bryant Smalley, Jacob C. Warren
Journal: JAMA Network Open (2020)

This cross-sectional study evaluates the availability of naloxone, pharmacists' awareness of the standing order regarding dispensing naloxone without a prescription, and the cost of the drug from chain and independent pharmacies in rural counties in Georgia.
Truncated ASPP2 Drives Initiation and Progression of Invasive Lobular Carcinoma via Distinct Mechanisms
Authors: Koen Schipper, Anne Paulien Drenth, Eline van der Burg, Samuel Cornelissen, Sjoerd Klarenbeek, Micha Nethe, Jos Jonkers
Journal: Cancer Research (2020)

Invasive lobular carcinoma (ILC) accounts for 8%-14% of all breast cancer cases. The main hallmark of ILCs is the functional loss of the cell-cell adhesion protein E-cadherin. Nonetheless, loss of E-cadherin alone does not predispose mice to mammary tumor development, indicating that additional perturbations are required for ILC formation. Previously, we identified an N-terminal truncation variant of ASPP2 (t-ASPP2) as a driver of ILC in mice with mammary-specific loss of E-cadherin. Here we showed that expression of t-ASPP2 induced actomyosin relaxation, enabling adhesion and survival of E-cadherin-deficient murine mammary epithelial cells on stiff matrices like fibrillar collagen. The induction of actomyosin relaxation by t-ASPP2 was dependent on its interaction with protein phosphatase 1, but not on t-ASPP2-induced YAP activation. Truncated ASPP2 collaborated with both E-cadherin loss and PI3K pathway activation via PTEN loss in ILC development. t-ASPP2-induced actomyosin relaxation was required for ILC initiation, but not progression. Conversely, YAP activation induced by t-ASPP2 contributed to tumor growth and progression while being dispensable for tumor initiation. Together, these findings highlight two distinct mechanisms through which t-ASPP2 promotes ILC initiation and progression. SIGNIFICANCE: Truncated ASPP2 cooperates with E-cadherin and PTEN loss to drive breast cancer initiation and progression via two distinct mechanisms. ASPP2-induced actomyosin relaxation drives tumor initiation, while ASPP2-mediated YAP activation enhances tumor progression.
Genetic Variation in Type 1 Diabetes Reconfigures the 3D Chromatin Organization of T Cells and Alters Gene Expression
Authors: Maria Fasolino, Naomi Goldman, Wenliang Wang, Benjamin Cattau, Yeqiao Zhou, Jelena Petrovic, Verena M. Link, Allison Cote, Aditi Chandra, Michael Silverman, Eric F. Joyce, Shawn C. Little, Klaus H. Kaestner, Ali Naji, Arjun Raj, Jorge Henao-Mejia, Robert B. Faryabi, Golnaz Vahedi
Journal: Immunity (2020)
Deletion of Protein Kinase D3 Promotes Liver Fibrosis in Mice
Authors: Shuya Zhang, Huan Liu, Meimei Yin, Xiuying Pei, Angelika Hausser, Eri Ishikawa, Sho Yamasaki, Zheng Gen Jin
Journal: Hepatology (2020)

Background and Aims Liver fibrosis (LF) is a central pathological process that occurs in most types of chronic liver diseases. Advanced LF causes cirrhosis, hepatocellular carcinoma, and liver failure. However, the exact molecular mechanisms underlying the initiation and progression of LF remain largely unknown. Approach and Results This study was designed to investigate the role of protein kinase D3 (PKD3; gene name Prkd3 ) in the regulation of liver homeostasis. We generated global Prkd3 knockout ( Prkd3−/− ) mice and myeloid‐cell–specific Prkd3 knockout ( Prkd3 ∆LysM ) mice, and we found that both Prkd3−/− mice and Prkd3∆LysM mice displayed spontaneous LF. PKD3 deficiency also aggravated CCl 4 ‐induced LF. PKD3 is highly expressed in hepatic macrophages (HMs), and PKD3 deficiency skewed macrophage polarization toward a profibrotic phenotype. Activated profibrotic macrophages produced transforming growth factor beta that, in turn, activates hepatic stellate cells to become matrix‐producing myofibroblasts. Moreover, PKD3 deficiency decreased the phosphatase activity of SH2‐containing protein tyrosine phosphatase‐1 (a bona‐fide PKD3 substrate), resulting in sustained signal transducer and activator of transcription 6 activation in macrophages. In addition, we observed that PKD3 expression in HMs was down‐regulated in cirrhotic human liver tissues. Conclusions PKD3 deletion in mice drives LF through the profibrotic macrophage activation.
Endoscopic ultrasound-guided injection of coils for the treatment of refractory post-ERCP bleeding
Authors: Edson Guzmán-Calderón, Francisco Ruiz, Juan Antonio Casellas, Juan Martinez-Sempere, Lucía Medina-Prado, Jose R. Aparicio
Journal: Endoscopy (2020)

An 82-year-old woman was referred for endoscopic retrograde cholangiopancreatography (ERCP) for choledocholithiasis. After cannulation of the pancreatic duct, transpancreatic sphincterotomy and placement of a 5-fr stent in the pancreas were performed.
FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia
Authors: Jun Long, Ming-Yuan Jia, Wei-Yue Fang, Xin-Jie Chen, Li-Li Mu, Zhong-Yu Wang, Yan Shen, Ru-Fang Xiang, Li-Ning Wang, Ling Wang, Chuan-He Jiang, Jie-Ling Jiang, Wen-Jun Zhang, Yi-Dan Sun, Li Chang, Wen-Hui Gao, Ying Wang, Jun-Min Li, Deng-Li Hong, Ai-Bin Liang, Jiong Hu
Journal: Blood (2020)
Characteristics of postinflammatory hyper- and hypopigmentation in patients with psoriasis: A survey study
Authors: Séverine Amico, Thomas Barnetche, Laure Dequidt, Antoine Fauconneau, Emilie Gérard, Lucile Boursault, Katia Boniface, Anne-Sophie Darrigade, Julien Seneschal
Journal: Journal of the American Academy of Dermatology (2020)
Spotlighting the hypoxia‐centrosome amplification axis
Authors: Karuna Mittal, Ritu Aneja
Journal: Medicinal Research Reviews (2020)

The abysmal success rate of anticancer drugs in clinical trials, is in part, attributable to discordance between cultured cancer cells and patient tumors. While tumors in vivo, display a lower mitotic index, patient tumors portray much higher centrosomal aberrations, relative to in vitro cultured cells. The microenvironment too differs considerably between the in vitro and in vivo scenarios. Notably, another hallmark of cancer, hypoxia, is not recapitulated in cell lines cultured under normoxic conditions. These observations raise the possibility that hypoxia may be the missing link that explains the discordance between cell biological phenomena in vitro versus physiological conditions. Further, the interplay between hypoxia and centrosome amplification (CA) is relatively understudied. Recent research from our laboratory, geared toward examining the biological link between the two, has uncovered that hypoxia induces the expression of proteins (Plk4, Aurora A, Cyclin D) implicated in CA, in a hypoxia-inducible factor 1α (HIF-1α)-dependent context. Our studies evidence that hypoxia fuels CA that underlie intratumoral heterogeneity and metastatic potential of cancer cells. Given the advent of HIF-1α inhibitors, this research has ramifications in aiding patient risk stratification and designing new cancer drug therapies to facilitate clinical decision-making.
Abstract P3-11-18: Partial RALBP1 loss depletes DNA repair pathway genes
Authors: Sanjay Awasthi, Chhanda Bose, Catherine Jones, Rakhshanda Rahman, Sharad S. Singhal, Sharda P. Singh
Journal: Cancer Research (2020)

Abstract TP53 (p53) functions as a stress-responsive, genome protective, tumor suppressor whose functions are lost or altered a majority of breast cancers. TP53 homozygous null mice uniformly die of spontaneous malignancy. The human RALBP1 gene (18p11.22) encodes is a stress-protective, anti-apoptotic mercapturic acid pathway transporter protein (RLIP76 or Rlip) regulated by the Ral/Rac/Rho pathways. In stark contrast to TP53 null mice, RALBP1-null mice are highly cancer resistant, even to the most potent known chemical carcinogens benzo[a]pyrene or dimethylbenzanthracene. We recently reported that pharmacologically or chemically induced haploinsufficiency of Rlip switches off spontaneous carcinogenesis in p53-null mice (Proc. Natl. Acad Sci USA, 2018; 115:3918), indicating an existential role of Rlip in p53-deficient cancer cells and suggesting the possibility that DNA-repair deficient cells could be particularly susceptible to Rlip depletion. Results of present studies demonstrated that RALBP1 depletion by antisense inhibited the growth of the MDA-MB231 cell line in-vitro and in xenografts. Remarkably, Rlip depletion with antisense or upon treatment with an orange-derived flavanone (2-hydroxyflavanone) depleted the expression of PALB2 as well as BRCA1 and BRCA2 in triple negative breast cancer cell lines, and synergistically increased the efficacy of PARP inhibition. These findings suggest that drugs that inhibit or deplete Rlip could be useful in sensitizing DNA-repair sufficient triple negative breast cancer to PARP inhibitors. Citation Format: Sanjay Awasthi, Chhanda Bose, Catherine Jones, Rakhshanda Rahman, Sharad S. Singhal, Sharda P. Singh. Partial RALBP1 loss depletes DNA repair pathway genes [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-18.
ESR/ERS statement paper on lung cancer screening
Authors: Hans-Ulrich Kauczor, Anne-Marie Baird, Torsten Gerriet Blum, Lorenzo Bonomo, Clementine Bostantzoglou, Otto Burghuber, Blanka Čepická, Alina Comanescu, Sébastien Couraud, Anand Devaraj, Vagn Jespersen, Sergey Morozov, Inbar Nardi Agmon, Nir Peled, Pippa Powell, Helmut Prosch, Sofia Ravara, Janette Rawlinson, Marie-Pierre Revel, Mario Silva, Annemiek Snoeckx, Bram van Ginneken, Jan P. van Meerbeeck, Constantine Vardavas, Oyunbileg von Stackelberg, Mina Gaga
Journal: European Respiratory Journal (2020)

In Europe, lung cancer ranks third among the most common cancers, remaining the biggest killer. Since the publication of the first European Society of Radiology and European Respiratory Society joint white paper on lung cancer screening (LCS) in 2015, many new findings have been published and discussions have increased considerably. Thus, this updated expert opinion represents a narrative, non-systematic review of the evidence from LCS trials and description of the current practice of LCS as well as aspects that have not received adequate attention until now. Reaching out to the potential participants (persons at high risk), optimal communication and shared decision-making will be key starting points. Furthermore, standards for infrastructure, pathways and quality assurance are pivotal, including promoting tobacco cessation, benefits and harms, overdiagnosis, quality, minimum radiation exposure, definition of management of positive screen results and incidental findings linked to respective actions as well as cost-effectiveness. This requires a multidisciplinary team with experts from pulmonology and radiology as well as thoracic oncologists, thoracic surgeons, pathologists, family doctors, patient representatives and others. The ESR and ERS agree that Europe's health systems need to adapt to allow citizens to benefit from organised pathways, rather than unsupervised initiatives, to allow early diagnosis of lung cancer and reduce the mortality rate. Now is the time to set up and conduct demonstration programmes focusing, among other points, on methodology, standardisation, tobacco cessation, education on healthy lifestyle, cost-effectiveness and a central registry.
Correlated Evolution of Large DNA Fragments in the 3D Genome of Arabidopsis thaliana
Authors: Yubin Yan, Zhaohong Li, Ye Li, Zefeng Wu, Ruolin Yang
Journal: Molecular Biology and Evolution (2020)

In eukaryotes, the three-dimensional (3D) conformation of the genome is far from random, and this nonrandom chromatin organization is strongly correlated with gene expression and protein function, which are two critical determinants of the selective constraints and evolutionary rates of genes. However, whether genes and other elements that are located close to each other in the 3D genome evolve in a coordinated way has not been investigated in any organism. To address this question, we constructed chromatin interaction networks (CINs) in Arabidopsis thaliana based on high-throughput chromosome conformation capture data and demonstrated that adjacent large DNA fragments in the CIN indeed exhibit more similar levels of polymorphism and evolutionary rates than random fragment pairs. Using simulations that account for the linear distance between fragments, we proved that the 3D chromosomal organization plays a role in the observed correlated evolution. Spatially interacting fragments also exhibit more similar mutation rates and functional constraints in both coding and noncoding regions than the random expectations, indicating that the correlated evolution between 3D neighbors is a result of combined evolutionary forces. A collection of 39 genomic and epigenomic features can explain much of the variance in genetic diversity and evolutionary rates across the genome. Moreover, features that have a greater effect on the evolution of regional sequences tend to show higher similarity between neighboring fragments in the CIN, suggesting a pivotal role of epigenetic modifications and chromatin organization in determining the correlated evolution of large DNA fragments in the 3D genome.