tbuckley/cabot-search huggingface dataset:
Differential gene expression profiles as markers of radioresistance in esophageal cancer
Authors: Stephen Maher, Niamh Lynam-Lennon, John Reynolds
Journal: Cancer Research (2008)

1456  Purpose:  Esophageal cancer is an aggressive disease with increasing annual incidence and an extremely poor prognosis. Current treatment regimes incorporate a multimodal approach, whereby patients receive neoadjuvant radiochemotherapy prior to surgery. Molecular predictors of response to therapy are essential to improve patient selection and ultimately therapeutic efficacy for this disease. The purpose of this study was to identify genes and gene sets indicative of resistance to radiation in esophageal cancer cell lines.  Methods:  KYSE-410 human esophageal squamous cell carcinoma cells were treated with fractionated doses of 2 Gy X-ray radiation (250 keV, 15 mA, 38 s) every 2 weeks until radioresistant cell lines were established. The parent line was maintained in a similar manner to the radioresistant cells except it received no radiation. Resistance to radiation was determined as a measure of sensitivity to radiation-induced apoptosis, which was measured by Annexin-V/PI staining and flow cytometry. The KYSE-410 parent and radioresistant clone were treated with or without 2 Gy radiation. After 24 h cells were harvested, RNA isolated, and cDNA generated. cDNA from each treatment was applied to pathway-focused qRT-PCR arrays and differentially-induced gene expression analysed. Radioresistance-associated genes identified from the arrays were validated by semi-quantitative RT-PCR.  Results:  It was found that treatment of KYSE-410 cells with continuously fractionated doses of radiation resulted in the generation of radioresistant clones. Exposure of KYSE-410 parent to a bolus 10 Gy (250 keV, 15 mA, 3 min 5 s) resulted in 25.4±1.5% versus 5.3±1.5% apoptosis in unstimulated controls. Exposure of KYSE-410 radioresistant clones to 10 Gy radiation resulted in 7.7±1.3 compared to 3.9±0.9% apoptosis in unstimulated controls. Gene array analysis revealed that 9 genes (from a total of 84) were differentially regulated in response to radiation between parent and radioresistant cells. These genes were involved in cell cycle control (p16), apoptosis (Granzyme A, TNFα, TNFRSF25), invasion and metastasis (MMP1, S100A4 (also involved in cell cycle control)), angiogenesis (IFNβ1, TGFβ1), and gene transcription (c-Myc). In response to radiation in radioresistant cells p16, IFNβ1, MMP1, S100A4, and TNFRSF25 were upregulated, while granzyme A, c-Myc, TGFβ1, and TNFα were downregulated relative to parent controls. The effect of X-ray irradiation on the expression of these genes was subsequently validated by RT-PCR.  Conclusions:  These data indicate that genes involved in cell cycle control and apoptosis are differentially regulated in response to radiation in radioresistant versus radiosensitive esophageal tumour cells. Future work will assess the involvement of the identified genes in resistance to radiation-induced apoptosis, and the expression of a number of these markers in patient pre-treatment biopsy material.
Comparison of pattern of disease progression and prevalence of acquired T790M mutation in Malaysia patients with EGFR mutant lung adenocarcinoma upon failure of first-line afatinib, gefitinib and erlotinib
Authors: C.S. Chai, O. Po Lin, C.K. Liam, Y.K. Pang, G.F. Ho, A. Alip, C.K. Wong, M.E. Poh, J.L. Tan
Journal: Annals of Oncology (2019)
Activated Endothelial TGFβ1 Signaling Promotes Venous Thrombus Nonresolution in Mice Via Endothelin-1
Authors: Magdalena L. Bochenek, Christiane Leidinger, Nico S. Rosinus, Rajinikanth Gogiraju, Stefan Guth, Lukas Hobohm, Kerstin Jurk, Eckhard Mayer, Thomas Münzel, Mareike Lankeit, Markus Bosmann, Stavros Konstantinides, Katrin Schäfer
Journal: Circulation Research (2019)

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by defective thrombus resolution, pulmonary artery obstruction, and vasculopathy. TGFβ (transforming growth factor-β) signaling mutations have been implicated in pulmonary arterial hypertension, whereas the role of TGFβ in the pathophysiology of CTEPH is unknown.To determine whether defective TGFβ signaling in endothelial cells contributes to thrombus nonresolution and fibrosis.Venous thrombosis was induced by inferior vena cava ligation in mice with genetic deletion of TGFβ1 in platelets (Plt.TGFβ-KO) or TGFβ type II receptors in endothelial cells (End.TGFβRII-KO). Pulmonary endarterectomy specimens from CTEPH patients were analyzed using immunohistochemistry. Primary human and mouse endothelial cells were studied using confocal microscopy, quantitative polymerase chain reaction, and Western blot. Absence of TGFβ1 in platelets did not alter platelet number or function but was associated with faster venous thrombus resolution, whereas endothelial TGFβRII deletion resulted in larger, more fibrotic and higher vascularized venous thrombi. Increased circulating active TGFβ1 levels, endothelial TGFβRI/ALK1 (activin receptor-like kinase), and TGFβRI/ALK5 expression were detected in End.TGFβRII-KO mice, and activated TGFβ signaling was present in vessel-rich areas of CTEPH specimens. CTEPH-endothelial cells and murine endothelial cells lacking TGFβRII simultaneously expressed endothelial and mesenchymal markers and transcription factors regulating endothelial-to-mesenchymal transition, similar to TGFβ1-stimulated endothelial cells. Mechanistically, increased endothelin-1 levels were detected in TGFβRII-KO endothelial cells, murine venous thrombi, or endarterectomy specimens and plasma of CTEPH patients, and endothelin-1 overexpression was prevented by inhibition of ALK5, and to a lesser extent of ALK1. ALK5 inhibition and endothelin receptor antagonization inhibited mesenchymal lineage conversion in TGFβ1-exposed human and murine endothelial cells and improved venous thrombus resolution and pulmonary vaso-occlusions in End.TGFβRII-KO mice.Endothelial TGFβ1 signaling via type I receptors and endothelin-1 contribute to mesenchymal lineage transition and thrombofibrosis, which were prevented by blocking endothelin receptors. Our findings may have relevant implications for the prevention and management of CTEPH.
Adoption of molecular testing in breast cancer in a tertiary care center in a developing country
Authors: P.K. Dash, V.P.B. Koyyala, M. Suryavanshi, A. Jajodia, S. Pasricha, V. Goel, S.J. Bothra, S. Goyal, U. Batra, D.C. Doval
Journal: Annals of Oncology (2019)
Emetic risk of carboplatin plus pemetrexed is higher than that of carboplatin plus paclitaxel in patients with lung cancer: A propensity score-matched analysis
Authors: K. Matsuo, M. Shimokawa, T. Hayashi, H. Iihara, T. Nakano, O. Imakyure, T. Egawa
Journal: Annals of Oncology (2019)
Setting the Stage for Islet Autoimmunity in Type 2 Diabetes: Obesity-Associated Chronic Systemic Inflammation and Endoplasmic Reticulum (ER) Stress
Authors: Barbara M. Brooks-Worrell, Jerry P. Palmer
Journal: Diabetes Care (2019)

Islet autoimmunity has been identified as a component of both type 1 (T1D) and type 2 (T2D) diabetes, but the pathway through which islet autoimmunity develops in T1D and T2D may be different. Acknowledging the presence of islet autoimmunity in the pathophysiology of T2D, a historically nonautoimmune metabolic disease, would pave the way for important changes in classifications of and therapeutic options for T2D. In order to fully appreciate the importance of islet autoimmunity in T2D, the underlying mechanisms for immune system activation need to be explored. In this review, we focus on the potential origin of immune system activation (innate and adaptive) leading to the development of islet autoimmunity in T2D.
Differential skewing of donor-unrestricted and γδ T cell repertoires in tuberculosis-infected human lungs
Authors: Paul Ogongo, Adrie J.C. Steyn, Farina Karim, Kaylesh J. Dullabh, Ismael Awala, Rajhmun Madansein, Alasdair Leslie, Samuel M. Behar
Journal: Journal of Clinical Investigation (2019)

Unconventional T cells that recognize mycobacterial antigens are of great interest as potential vaccine targets against tuberculosis (TB). This includes donor-unrestricted T cells (DURTs), such as mucosa-associated invariant T cells (MAITs), CD1-restricted T cells, and γδ T cells. We exploited the distinctive nature of DURTs and γδ T cell receptors (TCRs) to investigate the involvement of these T cells during TB in the human lung by global TCR sequencing. Making use of surgical lung resections, we investigated the distribution, frequency, and characteristics of TCRs in lung tissue and matched blood from individuals infected with TB. Despite depletion of MAITs and certain CD1-restricted T cells from the blood, we found that the DURT repertoire was well preserved in the lungs, irrespective of disease status or HIV coinfection. The TCRδ repertoire, in contrast, was highly skewed in the lungs, where it was dominated by Vδ1 and distinguished by highly localized clonal expansions, consistent with the nonrecirculating lung-resident γδ T cell population. These data show that repertoire sequencing is a powerful tool for tracking T cell subsets during disease.
Abstract 18613: RNA-seq Identifies Shared and Divergent Expression Signatures of Heart Failure in Human Heart Tissue
Authors: Mary E Sweet, Andrea Cocciolo, Dobromir Slavov, Sharon L Graw, Kenneth L Jones, T. B Reece, Amrut V Ambardekar, Michael R Bristow, Luisa Mestroni, Matthew R Taylor
Journal: Circulation (2017)

Heart failure (HF) occurs when disease or injury weakens the heart muscle and its ability to pump blood effectively. Current HF treatment paradigms are based on symptom and LV dysfunction severity,...
Population-level analysis reveals the widespread occurrence and phenotypic consequence of DNA methylation variation not tagged by genetic variation in maize
Authors: Jing Xu, Guo Chen, Peter J. Hermanson, Qiang Xu, Changshuo Sun, Wenqing Chen, Qiuxin Kan, Minqi Li, Peter A. Crisp, Jianbing Yan, Lin Li, Nathan M. Springer, Qing Li
Journal: Genome biology (2019)

DNA methylation can provide a source of heritable information that is sometimes entirely uncoupled from genetic variation. However, the extent of this uncoupling and the roles of DNA methylation in shaping diversity of both gene expression and phenotypes are hotly debated. Here, we investigate the genetic basis and biological functions of DNA methylation at a population scale in maize.We perform targeted DNA methylation profiling for a diverse panel of 263 maize inbred genotypes. All genotypes show similar levels of DNA methylation globally, highlighting the importance of DNA methylation in maize development. Nevertheless, we identify more than 16,000 differentially methylated regions (DMRs) that are distributed across the 10 maize chromosomes. Genome-wide association analysis with high-density genetic markers reveals that over 60% of the DMRs are not tagged by SNPs, suggesting the presence of unique information in DMRs. Strong associations between DMRs and the expression of many genes are identified in both the leaf and kernel tissues, pointing to the biological significance of methylation variation. Association analysis with 986 metabolic traits suggests that DNA methylation is associated with phenotypic variation of 156 traits. There are some traits that only show significant associations with DMRs and not with SNPs.These results suggest that DNA methylation can provide unique information to explain phenotypic variation in maize.
Additional Questions Regarding Wide QRS Tachycardia and Atrial Fibrillation—Reply
Authors: Eric A. Bucklew, Steven E. Reis, Krishna Kancharla
Journal: JAMA Internal Medicine (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 Internal Medicine 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 Internal Medicine journal
Survival and treatment patterns in patients (pts) with locally advanced or metastatic NSCLC treated with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIS): Analysis of US insurance claims databases
Authors: R. Soo, T. Seto, J.E. Gray, P. Karimi, A. Taylor, W. Sawyer, E. Thiel, E. Marchlewicz, M. Brouillette
Journal: Annals of Oncology (2019)
Longitudinal, strain-specific Staphylococcus aureus introduction and transmission events in households of children with community-associated meticillin-resistant S aureus skin and soft tissue infection: a prospective cohort study
Authors: Ryan L Mork, Patrick G Hogan, Carol E Muenks, Mary G Boyle, Ryley M Thompson, Melanie L Sullivan, John J Morelli, Jennifer Seigel, Rachel C Orscheln, Juliane Bubeck Wardenburg, Sarah J Gehlert, Carey-Ann D Burnham, Andrey Rzhetsky, Stephanie A Fritz
Journal: The Lancet Infectious Diseases (2019)
A placebo controlled, randomized, double-blinded trial of olanzapine for the treatment of chronic nausea and/or vomiting, unrelated to chemotherapy/radiation.
Authors: Rudolph M. Navari
Journal: Journal of Clinical Oncology (2019)

118 Background: Patients with advanced cancer experience substantial nausea/vomiting. Methods: Eligible patients had advanced cancer without receiving chemotherapy/radiation for the prior 14 days and chronic nausea (&gt;3, 0-10, VAS) that had been present for &gt;1 week and/or vomiting &gt;5 times during the prior week. Patients were randomized, in a double blind manner, to receive olanzapine (5 mg) or a placebo, orally, days 1-7. Prior to starting treatment (Day 1) and daily for 7 days (Days 2-8), patients recorded the intensity of their appetite, nausea, fatigue, sedation, and pain using a numerical VAS, and the number of emetic episodes/24 hours. The primary study endpoint was the change in VAS nausea scores from baseline to the last treatment day. Nausea change scores were compared between arms using a Wilcoxon rank sum test. Results: Thirty patients were enrolled in the study. No patient reported any apparent adverse event or excess sedation. Data are shown in the table. Conclusions: Olanzapine 5 mg/day significantly decreased nausea and emesis in this patient population. [Table: see text]
Corticosteroids Do Not Influence the Efficacy and Kinetics of CAR-T Cells for B-Cell Acute Lymphoblastic Leukemia
Authors: Shuangyou Liu, Biping Deng, Jing PAN, Zhichao Yin, Yuehui Lin, Zhuojun Ling, Tong Wu, Zhiyong Gao, Yanzhi Song, Yongqiang Zhao, Chunrong Tong
Journal: Blood (2019)
Intranasal delivery of paeoniflorin nanocrystals for brain targeting
Authors: Chaoyin Wu, Benyue Li, Yi Zhang, Tingting Chen, Chuangrong Chen, Wei Jiang, Qi Wang, Tongkai Chen
Journal: Asian Journal of Pharmaceutical Sciences (2019)

Paeoniflorin (PA) is an anti-Parkinson Chinese medicine with inferior bioavailability and difficulty in delivery to the brain. This research is to develop an efficacious PA nanocrystal formulation (PA-NCs) that is suitable for intranasal administration to treat Parkinson's disease (PD). PA-NCs were fabricated through an antisolvent precipitation method using TPGS as the stabilizer. The rod-shaped PA-NCs had particle size of 139.6 ± 1.3 nm and zeta potential of -23.2 ± 0.529 mV. A molecular dynamics simulation indicated that van der Waals forces are the primary drivers of interactions between PA and TPGS. In the ex vivo nasal mucosa permeation assay, the cumulative drug release at 24 h was 87.14% ± 5.34%, which was significantly higher than that of free PA. PA-NCs exhibited substantially improved cellular uptake as well as permeability on Calu-3 cells as compared to PA alone. FRET imaging analysis demonstrated that intact NCs could be internalized into Calu-3 cells. Moreover, PA-NCs conferred desirable protective effect against MPP+-induced SH-SY5Y cellular damage. Pharmacokinetic studies revealed a higher PA concentration in the brain following intranasal delivery of PA-NCs. In summary, the intranasal administration of PA-NCs is a promising treatment strategy for PD.
Maintenance of Efficacy and Safety of Ustekinumab Through One Year in a Phase <scp>II</scp> Multicenter, Prospective, Randomized, Double‐Blind, Placebo‐Controlled Crossover Trial of Patients With Active Systemic Lupus Erythematosus
Authors: Ronald F. van Vollenhoven, Bevra H. Hahn, George C. Tsokos, Peter Lipsky, Kaiyin Fei, Robert M. Gordon, Irene Gregan, Kim Hung Lo, Marc Chevrier, Shawn Rose
Journal: Arthritis & Rheumatology (2019)

To evaluate the efficacy and safety of ustekinumab through 1 year in a phase II trial in patients with systemic lupus erythematosus (SLE).Eligible patients were diagnosed as having clinically active SLE (based on Systemic Lupus International Collaborating Clinics criteria), despite standard background therapy. Active disease was defined by an SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 as well as having ≥1 British Isles Lupus Assessment Group (BILAG) A organ domain score and/or ≥2 BILAG B organ domain scores present at screening. Patients (n = 102) were randomized (3:2) to receive either ustekinumab (~6 mg/kg of single intravenous infusion at week 0, then 90-mg subcutaneous injections every 8 weeks beginning at week 8) or a matching placebo added to standard therapy. At week 24, the placebo group crossed over to receive a subcutaneous 90-mg dose of ustekinumab every 8 weeks, and the original ustekinumab group continued to receive therapy through week 40. Maintenance of efficacy was assessed using the SLEDAI-2K, the SLE Responder Index 4 (SRI-4), physician global assessment, and mucocutaneous and joint disease measures in a modified intent-to-treat population.SRI-4 response rates were significantly greater in the ustekinumab group (62%) versus the placebo group (33%) in the week 24 primary end point analysis (P = 0.006) and were maintained at week 48 (63.3%) in the ustekinumab group. In the ustekinumab group, response rates across other disease measures were also maintained through week 48. Among patients in the placebo group who crossed over to ustekinumab treatment (n = 33), increased response rates across efficacy measures were noted. Among all ustekinumab-treated patients, 81.7% had ≥1 adverse event (AE), and 15.1% had ≥1 serious AE through week 56. No deaths, malignancies, opportunistic infections, or tuberculosis cases were observed.Ustekinumab provided sustained clinical benefit in patients with SLE through 1 year, with a safety profile consistent with other indications.
Whole-Slide Image Analysis Reveals Quantitative Landscape of Tumor–Immune Microenvironment in Colorectal Cancers
Authors: Seung-Yeon Yoo, Hye Eun Park, Jung Ho Kim, Xianyu Wen, Seorin Jeong, Nam-Yun Cho, Hwang Gwan Gwon, Kwangsoo Kim, Hye Seung Lee, Seung-Yong Jeong, Kyu Joo Park, Sae-Won Han, Tae-You Kim, Jeong Mo Bae, Gyeong Hoon Kang
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Despite the well-known prognostic value of the tumor–immune microenvironment (TIME) in colorectal cancers, objective and readily applicable methods for quantifying tumor-infiltrating lymphocytes (TIL) and the tumor–stroma ratio (TSR) are not yet available. Experimental Design: We established an open-source software-based analytic pipeline for quantifying TILs and the TSR from whole-slide images obtained after CD3 and CD8 IHC staining. Using a random forest classifier, the method separately quantified intraepithelial TILs (iTIL) and stromal TILs (sTIL). We applied this method to discovery and validation cohorts of 578 and 283 stage III or high-risk stage II colorectal cancers patients, respectively, who were subjected to curative surgical resection and oxlaliplatin-based adjuvant chemotherapy. Results: Automatic quantification of iTILs and sTILs showed a moderate concordance with that obtained after visual inspection by a pathologist. The K-means–based consensus clustering of 197 TIME parameters that showed robustness against interobserver variations caused colorectal cancers to be grouped into five distinctive subgroups, reminiscent of those for consensus molecular subtypes (CMS1-4 and mixed/intermediate group). In accordance with the original CMS report, the CMS4-like subgroup (cluster 4) was significantly associated with a worse 5-year relapse-free survival and proved to be an independent prognostic factor. The clinicopathologic and prognostic features of the TIME subgroups have been validated in an independent validation cohort. Conclusions: Machine-learning–based image analysis can be useful for extracting quantitative information about the TIME, using whole-slide histopathologic images. This information can classify colorectal cancers into clinicopathologically relevant subgroups without performing a molecular analysis of the tumors.
Pharmacogenomic analysis of patient-derived tumor cells in gynecologic cancers
Authors: Jason K. Sa, Jae Ryoung Hwang, Young-Jae Cho, Ji-Yoon Ryu, Jung-Joo Choi, Soo Young Jeong, Jihye Kim, Myeong Seon Kim, E. Sun Paik, Yoo-Young Lee, Chel Hun Choi, Tae-Joong Kim, Byoung-Gie Kim, Duk-Soo Bae, Yeri Lee, Nam-Gu Her, Yong Jae Shin, Hee Jin Cho, Ja Yeon Kim, Yun Jee Seo, Harim Koo, Jeong-Woo Oh, Taebum Lee, Hyun-Soo Kim, Sang Yong Song, Joon Seol Bae, Woong-Yang Park, Hee Dong Han, Hyung Jun Ahn, Anil K. Sood, Raul Rabadan, Jin-Ku Lee, Do-Hyun Nam, Jeong-Won Lee
Journal: Genome biology (2019)

Abstract Background Gynecologic malignancy is one of the leading causes of mortality in female adults worldwide. Comprehensive genomic analysis has revealed a list of molecular aberrations that are essential to tumorigenesis, progression, and metastasis of gynecologic tumors. However, targeting such alterations has frequently led to treatment failures due to underlying genomic complexity and simultaneous activation of various tumor cell survival pathway molecules. A compilation of molecular characterization of tumors with pharmacological drug response is the next step toward clinical application of patient-tailored treatment regimens. Results Toward this goal, we establish a library of 139 gynecologic tumors including epithelial ovarian cancers (EOCs), cervical, endometrial tumors, and uterine sarcomas that are genomically and/or pharmacologically annotated and explore dynamic pharmacogenomic associations against 37 molecularly targeted drugs. We discover lineage-specific drug sensitivities based on subcategorization of gynecologic tumors and identify TP53 mutation as a molecular determinant that elicits therapeutic response to poly (ADP-Ribose) polymerase (PARP) inhibitor. We further identify transcriptome expression of inhibitor of DNA biding 2 (ID2) as a potential predictive biomarker for treatment response to olaparib. Conclusions Together, our results demonstrate the potential utility of rapid drug screening combined with genomic profiling for precision treatment of gynecologic cancers.