tbuckley/cabot-search huggingface dataset:
The role of p38 activation in suppressing ovarian cancer metastatic colonization
Authors: Jennifer Taylor, Tamara Lotan, Jonathan Hickson, Kay Macleod, Russell Bainer, Yoav Gilad, Mark Lingen, S. Yamada, Carrie Rinker-Schaeffer
Journal: Cancer Research (2008)

1617  Introduction: Our lab has identified JNKK1/MKK4, hereafter referred to as MKK4, as a metastasis suppressor of ovarian cancer metastasis. Ectopic expression of MKK4 in human ovarian carcinoma SKOv3ip.1 cells reduces the number of intraperitoneal (i.p.) metastases at 30 days post injection (dpi) by 87% [Can Res (2006) 66(4):2264-70] and prolongs animal survival by 70% [Can Res (2002) 62:6717-23]. Subsequent studies support a model in which p38 signaling is associated with decreased proliferation and upregulation of p21 in disseminated cells in vivo. In this study we proposed (1) to investigate the activation of and requirement for p38 signaling in metastasis suppression, and (2) to determine the molecular mechanisms by which MKK4 induces a growth arrest of disseminated cells.  Methods: In control and HA-MKK4-expressing SKOv3ip.1 cells, p38 activity was inhibited using the specific chemical inhibitor SB 203580, dominant negative p38 isoforms, and stable siRNA expression. Experimental metastasis assays were conducted in female nude mice by injecting SKOV3ip.1 cells i.p., sacrificing at 30 dpi, and counting metastases. Laser Capture Microdissection (LCM) was used to isolate RNA and analyze changes in gene expression in MKK4-expressing cells isolated from omental metastases harvested from 30 animals at 3 dpi, 14 dpi, and from overt metastases. RNA from 5000 cells was collected from each specimen by LCM, amplified, and hybridized onto Affymetrix U133A/B microarrays.  Results and Discussion: Inhibition of p38 activity decreased the ability of MKK4 to suppress metastasis nearly 2 fold, consistent with a role for p38 in regulating metastatic colonization. Activation of p38 was detected after detachment of cells from a solid surface. LCM of specimen from 14 dpi animals indicates collecting 5000 cells is technically feasible, and analysis of RNA quality demonstrates that intact RNA can be obtained following the sectioning, staining, and preservation protocol used in this study. Microarray analysis of RNA obtained by this method will further investigate how transcriptional regulation by MKK4-p38 signaling modulates the growth arrest observed during metastatic colonization. Because MKK4 is upstream of AP-1 transcription factors, we hypothesize that many target genes associated with AP-1-transcription and involved in cell cycle progression, such as Cyclin D1, p21, p27, and Cyclin B, will be differentially regulated by HA-MKK4. The role of these genes in metastasis suppression will subsequently be investigated in our robust functional in vivo assay. The molecular mechanisms of how p38 signaling regulates a delay in proliferation will be an important contribution to the understanding of stress signaling and may provide insight into therapeutically targetable signaling events.
Screening for Unhealthy Alcohol Use
Authors: Angela Bazzi, Richard Saitz
Journal: JAMA (2018)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Percutaneous versus surgical femoro-femoral veno-arterial ECMO: a propensity score matched study
Authors: Pichoy Danial, David Hajage, Lee S. Nguyen, Ciro Mastroianni, Pierre Demondion, Matthieu Schmidt, Adrien Bouglé, Julien Amour, Pascal Leprince, Alain Combes, Guillaume Lebreton
Journal: Intensive Care Medicine (2018)
Improvement in Neuropathy Outcomes With Normalizing HbA1c in Patients With Type 2 Diabetes
Authors: Fukashi Ishibashi, Miki Taniguchi, Aiko Kosaka, Harumi Uetake, Mitra Tavakoli
Journal: Diabetes Care (2018)

To investigate the impact of normalizing HbA1c by extensive HbA1c control (EHC) on neuropathy outcome measures (NOMs), nephropathy, and retinopathy in type 2 diabetes.Detailed clinical and neurological examinations were performed in two cohorts of 38 patients with uncontrolled type 2 diabetes (HbA1c 9.6% [81.4 mmol/mol]) at baseline and after glycemic control (GC) with or without EHC by diet restriction and hypoglycemic agents over 4 years along with 48 control subjects with normal glucose tolerance (NGT) and 34 subjects with impaired glucose tolerance (IGT) only at baseline. EHC patients, control subjects, and subjects with IGT underwent oral glucose tolerance tests. Glycemic variability (GV) was evaluated by SD and coefficient of variation of monthly measured HbA1c levels and casual plasma glucose.In the EHC cohort, HbA1c levels over 4.3 years and the last 2 years improved to 6.1% (43.2 mmol/mol) and 5.8% (39.9 mmol/mol) with 7.3 kg body wt reduction, and 50% and 28.9% of patients returned to IGT and NGT, respectively, at end point. Baseline neurophysiological and corneal nerve fiber (CNF) measures were impaired in patients. Normalized HbA1c with EHC improved neurophysiological and CNF measures to be similar for those for IGT, while GC without EHC (mean HbA1c level 7.0% [53.5 mmol/mol]) improved only vibration perception. The mean normalized HbA1c levels by EHC determined NOM improvements. The high GV and baseline HbA1c levels compromised NOMs. Albumin excretion rate significantly decreased, while retinopathy severity and frequency insignificantly worsened on EHC.Normalizing HbA1c in type 2 diabetes of short duration improves microvascular complications including neuropathy and nephropathy more effectively than standard GC but not retinopathy.
Preclinical Evaluation of ADVM-022, a Novel Gene Therapy Approach to Treating Wet Age-Related Macular Degeneration
Authors: Ruslan Grishanin, Brian Vuillemenot, Pallavi Sharma, Annahita Keravala, Judith Greengard, Claire Gelfman, Mark Blumenkrantz, Matthew Lawrence, Wenzheng Hu, Szilárd Kiss, Mehdi Gasmi
Journal: Molecular Therapy (2018)

Inhibition of vascular endothelial growth factor, a key contributor to the choroidal neovascularization associated with wet age-related macular degeneration, is the mode of action of several approved therapies, including aflibercept, which requires frequent intravitreal injections to provide clinical benefit. Lack of compliance with the dosing schedule may result in recurrence of active wet macular degeneration, leading to irreversible vision impairment. Gene therapy providing sustained anti-vascular endothelial growth factor levels in the retina following a single injection could drastically reduce the treatment burden and improve visual outcomes. ADVM-022, an adeno-associated virus vector encoding aflibercept, is optimized for intravitreal delivery and strong protein expression. Here, we report the long-term expression and efficacy of ADVM-022-derived aflibercept in a laser-induced choroidal neovascularization model in non-human primates. Intravitreal administration of ADVM-022 was well tolerated and resulted in sustained aflibercept levels. In addition, ADVM-022 administration 13 months before lasering prevented the occurrence of clinically relevant choroidal neovascularization lesions, similar to animals that received a bolus of intravitreal aflibercept (standard of care) at the time of lesioning. These results demonstrate that a single intravitreal administration of ADVM-022 may provide a safe and effective long-term treatment option for wet macular degeneration and may ultimately improve patients' visual outcomes.
Sixty seconds on . . . reverse mentoring
Authors: Ann Robinson
Journal: BMJ (2018)

Hold your horses. The act of flipping traditional roles so that the more junior person acts as mentor to the senior person is gaining traction. It’s been described as a “social exchange tool for keeping Boomers engaged and Millennials committed.”1

General Electric chief executive Jack Welch is said to have returned to the US after an overseas trip in 1999 and ordered his senior staff to find junior mentors who could teach them computer …
Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells
Authors: Courtney L. Jones, Brett M. Stevens, Angelo D'Alessandro, Julie A. Reisz, Rachel Culp-Hill, Travis Nemkov, Shanshan Pei, Nabilah Khan, Biniam Adane, Haobin Ye, Anna Krug, Dominik Reinhold, Clayton Smith, James DeGregori, Daniel A. Pollyea, Craig T. Jordan
Journal: Cancer Cell (2018)
Abstract #4347: Pim kinases are potential molecular targets in K-Ras mediated transformation of pancreatic cancer
Authors: Michael Cobb, Stephen Allsop, Annika Barnett, Kashif Hall, Desinia Johnson, Tiffany Parms, Arnicia Sanders, Dapeng Xu, Xiaoxin Chen, Brian Bednarski, Hong Kim, Albert Baldwin, Antonio Baines
Journal: Cancer Research (2009)

Pancreatic cancer is the 4th most common cause of cancer deaths in the United States. A better understanding of the molecular mechanisms leading to the development of pancreatic cancer remains a major goal for defining appropriate treatment strategies. The presence of oncogenically mutated K-Ras in 90% of human pancreatic ductal adenocarcinomas (PDAC) strongly suggests a critical role for this genetic mutation in the development of this disease. However, despite many years of research, there are no anti-Ras therapies that have successfully reached the clinic. Microarray studies have revealed hundreds of genes that are differentially expressed in pancreatic cancer tissues/cells compared with the normal pancreas. One of the genes that have been found to be overexpressed after oncogenic K-ras activation in immortalized human pancreatic ductal epithelial cells is the Pim-1 kinase. Most recently, another member of the Pim kinase family, Pim-3, was shown to be aberrantly expressed and to block apoptosis in PDAC cell lines and patient tumors. With these and other observations implicating Pim kinases as oncogenes and inhibitors of apoptosis, the overall goal of our research is to determine the functional significance of the Pim kinase family in K-Ras mediated transformation of PDAC. We hypothesize that inhibition of Pim function will be an effective approach for antagonizing the aberrant growth of pancreatic carcinoma. From our studies, we were able to observe that not only Pim-3, but Pim-1 and Pim-2 kinases are expressed in human pancreatic cancer cell lines. In addition, immunohistochemical analysis demonstrated the aberrant expression of all the Pims in human pancreatic cancer tissues. Furthermore, we attempted to demonstrate if K-Ras activation could regulate Pim-1 expression. To determine this contribution, we used a Ras-transformed human pancreatic ductal epithelial cell in which transformation is dependent on oncogenic K-Ras activation. Overexpression of oncogenic K-ras showed an increase in Pim-1 protein expression. Also, we observed that suppression of K-Ras by short hairpin RNAs in a pancreatic cancer cell led to a decrease in Pim-1 expression. The culmination of these results suggests that K-Ras is able to regulate Pim-1 expression in pancreatic cancer. Future work will help to define the role of K-Ras activation in Pim upregulation and determine the consequences of Pim inhibition on PDAC growth. Furthermore, these findings will allow us to critically validate these kinases as novel biomarkers and therapeutic targets for PDAC treatment.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4347.
A prospective phase III randomized study to evaluate the efficacy of olanzapine for prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy (HEC)
Authors: J.K. Pehalajani, K. Govind Babu, D. Lokanatha, L.A. Jacob, M.C. Suresh Babu, K.N. Lokesh, A.H. Rudresha, L.K. Rajeev, S.C. Smitha, G.V. Giri
Journal: Annals of Oncology (2018)
Mesh scandal: lessons from Wall Street ignored
Authors: Mark Wilson
Journal: BMJ (2018)

The mesh scandal is all too familiar.1 It joins a growing list of scandals where commercial conflicts of interest (COIs) and effective marketing of a defective product have led to serious injury and loss of life. Against the backdrop of Avandia, Vioxx, Praxil, the opioid crisis, and now the mesh scandal, one wonders what kind of tipping point is needed to prevent a …
Lupeol, a novel diet-based triterpene modulates insulin growth factor receptor 1 and β-catenin signaling in human prostate cancer cells
Authors: Mohammad Saleem, Yewseok Suh, Bilal Hafeez, Jeremy Johnson, Imtiyaz Murtaza, Hasan Mukhtar
Journal: Cancer Research (2008)

1245  Recently we showed that Lupeol, a dietary triterpene, activates apoptotic machinery, decreases serum- PSA levels and inhibits the tumorigenicity of androgen-sensitive prostate cancer (PCa) cells. Current study was conducted to understand the mechanistic basis of the effect of Lupeol in androgen-sensitive (LNCaP) PCa cells. Lupeol (30-50μM) treatment (for 21 days) was observed to inhibit the proliferative and clonogenic potential of LNCaP cells. Lupeol treated cells exhibited reduced expression level of PCNA protein, a marker of proliferation. To understand the mechanism of action of Lupeol, we first determined the effect of Lupeol in a focused microarray of 288-well characterized PCa-associated genes. We found that Lupeol (20 μM) significantly modulates the expression level of genes which are known to be associated with proliferation and survival. Lupeol treatment decreased the mRNA expression level of insulin growth factor receptor-1, myc, cyclin D1, ERBB2 and Jun, and caused an increase in the mRNA expression level of IGFBP6, STEAP1, TIMP3 and KLK10. Immunoblot analysis indicated that Lupeol-induced modulations in the mRNA expression levels of these genes corroborated well with the expression level of their products (proteins). Interestingly, genes which are modulated by Lupeol are also known to be associated directly or indirectly with β-catenin signaling which is highly aberrant in PCa patients. We therefore investigated the effect of Lupeol on the upstream regulators of β-catenin signaling including GSK3β/Axin complex. Treatment of cells with Lupeol (5-30 μM) significantly reduced levels of β-catenin in the cytoplasm as well as in nuclear fractions with an increase in the expression levels of GSK3β/Axin complex, thus rendering β-catenin prone to degradation. Next, we employed luciferase reporter assay to measure the transcriptional activity of TCF responsive element, a marker for β-catenin signaling, and observed that Lupeol caused a significant reduction in the transcriptional activation of TCF responsive element in pTK-TCF-Luc-transfected LNCaP cells. We further observed that Lupeol treatment significantly decreased the expression level of matrix metalloproteinase (MMP)-2 and MMP-7 proteins which are known as downstream targets of β-catenin signaling. Treatment of cells with Lupeol significantly reduced the enzymatic activity of MMP-2. Finally, we evaluated the effect of Lupeol treatment on the transcriptional activity of MMP-2. We observed that Lupeol treatment significantly reduced the transcriptional activity of MMP-2 gene in pGL2-MMP-2-Luc-transfected LNCaP cells. We conclude that Lupeol being a multi-target agent effectively targets IGFR1/β-catenin axis thus leading to the inhibition in the proliferation of PCa cells. We suggest that Lupeol could be developed as an agent for chemoprevention as well as chemotherapy of human PCa..
Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis
Authors: Ming Chen, Jiangwen Zhang, Alice H. Berger, Moussa S. Diolombi, Christopher Ng, Jacqueline Fung, Roderick T. Bronson, Mireia Castillo-Martin, Tin Htwe Thin, Carlos Cordon-Cardo, Robin Plevin, Pier Paolo Pandolfi
Journal: Journal of Clinical Investigation (2018)

Recurrent broad-scale heterozygous deletions are frequently observed in human cancer. Here we tested the hypothesis that compound haploinsufficiency of neighboring genes at chromosome 8p promotes tumorigenesis. By targeting the mouse orthologs of human DOK2 and DUSP4 genes, which were co-deleted in approximately half of human lung adenocarcinomas, we found that compound-heterozygous deletion of Dok2 and Dusp4 in mice resulted in lung tumorigenesis with short latency and high incidence, and that their co-deletion synergistically activated MAPK signaling and promoted cell proliferation. Conversely, restoration of DOK2 and DUSP4 in lung cancer cells suppressed MAPK activation and cell proliferation. Importantly, in contrast to downregulation of DOK2 or DUSP4 alone, concomitant downregulation of DOK2 and DUSP4 was associated with poor survival in human lung adenocarcinoma. Therefore, our findings lend in vivo experimental support to the notion that compound haploinsufficiency, due to broad-scale chromosome deletions, constitutes a driving force in tumorigenesis.
Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer
Authors: Khyati N. Shah, Roma Bhatt, Julia Rotow, Julia Rohrberg, Victor Olivas, Victoria E. Wang, Golzar Hemmati, Maria M. Martins, Ashley Maynard, Jonathan Kuhn, Jacqueline Galeas, Hayley J. Donnella, Swati Kaushik, Angel Ku, Sophie Dumont, Gregor Krings, Henry J. Haringsma, Liliane Robillard, Andrew D. Simmons, Thomas C. Harding, Frank McCormick, Andrei Goga, Collin M. Blakely, Trever G. Bivona, Sourav Bandyopadhyay
Journal: Nature Medicine (2018)
Intraoperative carbon nanoparticles mapping in secondary total thyroidectomy for recurrent thyroid nodules: Results of a 8-criterion case-match study (case control study)
Authors: Xi Cheng, Haoran Feng, Lingxie Chen, Zhijian Jin, Tanglei Shao, Yue Wang, Juyong Liang, Hanxin Sun, Weiping Yang, Ren Zhao, Baiyong Shen, Jie Kuang, Jiqi Yan, Weihua Qiu
Journal: International Journal of Surgery (2018)
Abstract 12934: Prognostic Impact of Impaired Pulmonary Function in Acute Decompensated Heart Failure With Preserved Ejection Fraction
Authors: Rika Kawakami, Yasuki Nakada, Tomoya Ueda, Hiroyuki Okura, Yoshihiko Saito
Journal: Circulation (2016)

Background: An association between heart failure (HF) and impaired pulmonary function is clinically important. Therefore, we aimed to investigate the prognostic importance of impaired pulmonary function in acute decompensated heart failure (ADHF) patients. Method: This study was prospective prognostic study performed as part of NARA-HF3 study between April 2011 and December 2014. ADHF patients were tested for pulmonary function using spirometry before discharge. The following pulmonary function test (PFT) was measured; forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV 1 ). Patients were classified into 2 groups based on predicted FVC and FEV 1 /FVC percent predicted ratio: normal PFT groups (FVC≥80%, FEV 1 /FVC≥70%) and abnormal PFT groups (obstructive, restrictive and mixed pattern). Result: Among a total of 313 patients, 64.2% had abnormal spirometry ( 11.8%, 38.3% and 14.1% for obstructive , restrictive and mixed, respectively ). Abnormal PFT groups were significantly older, had a higher prevalence of atrial fibrillation and a significantly higher mean LVEF compared to normal PFT groups. There was no significant difference in smoking history, sex, eGFR and BNP levels at discharge both groups. Abnormal PFT was found to be associated with higher rate of all-cause mortality or HF hospitalizations (Figure A, B). The abnormal PFT groups had worse prognosis than normal PFT groups in HF with preserved ejection fraction (HFpEF) (LVEF≥50%) but not in HF with reduced EF (HFrEF) (LVEF&lt;50%) (Figure C, D). Cox proportional hazards regression analysis revealed that impaired pulmonary function was an independent prognostic predictor for ADHF, especially for HFpEF (HR 2.58, 95% CI 1.29 to 5.77, p=0.006). Conclusion: Impaired pulmonary function was associated with poor prognosis in patients with HFpEF, but not in those with HFrEF.
Targeting Purinergic Receptor P2Y2 Prevents the Growth of Pancreatic Ductal Adenocarcinoma by Inhibiting Cancer Cell Glycolysis
Authors: Li-Peng Hu, Xiao-Xin Zhang, Shu-Heng Jiang, Ling-Ye Tao, Qing Li, Li-Li Zhu, Ming-Wei Yang, Yan-Miao Huo, Yong-Sheng Jiang, Guang-Ang Tian, Xiao-Yan Cao, Yan-Li Zhang, Qin Yang, Xiao-Mei Yang, Ya-Hui Wang, Jun Li, Gary Guishan Xiao, Yong-Wei Sun, Zhi-Gang Zhang
Journal: Clinical Cancer Research (2018)

Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP-P2RY2 axis could be a potential therapeutic approach for PDAC treatment.Expression of P2RY2 was determined in 264 human PDAC samples and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity, and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression.P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT-mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevated expression of c-Myc and HIF1α, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacologic inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. In addition, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice.These findings reveal the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.