tbuckley/cabot-search huggingface dataset:
Cancer’s got nerve: Schwann cells drive perineural invasion
Authors: Salma H. Azam, Chad V. Pecot
Journal: Journal of Clinical Investigation (2016)

The invasion of cancer cells around and into nerves is associated with increased cancer aggression and poor patient outcome. As this perineural invasion increases disease severity, a better understanding of how the process is regulated may help in the development of therapeutics to target neuronal involvement in cancer. In this issue of the JCI, Deborde and colleagues show that direct contact between Schwann cells and cancer cells promotes cancer cell dissociation, migration, and invasion. Moreover, their data specifically suggest NCAM1 as an important molecular mediator of this Schwann cell-directed regulation of cancer cells in perineural invasion. The results of this study provide new insight into the cellular and molecular mechanisms of perineural invasion.
Abstract PR04: Targeting super-enhancer driven oncogene transcription through cyclin-dependent kinase inhibitors
Authors: Malgorzata Krajewska, Nathan F. Moore, Edmond Chipumuro, Tinghu Zhang, Eugenio Marco, Clark Hatheway, Bandana Sharma, Nicholas Kwiatkowski, Guo-Cheng Yuan, Richard A. Young, Nathanael S. Gray, Rani E. George
Journal: Cancer Research (2016)

Abstract Cyclin-dependent kinases (CDKs) with primary roles in transcription regulation are emerging as tractable therapeutic targets in cancers driven by the aberrant expression of oncogenic transcription factors. Our goal is to disrupt the myriad and pleomorphic features of oncogenic MYC through inhibiting CDKs involved in its transcriptional amplifier role. CDK7 participates in transcription initiation by phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase (Pol) II and also functions as a CDK-activating kinase, while CDK12 functions in transcription elongation and RNA processing. Using a novel covalent CDK7 inhibitor, THZ1, we demonstrated striking activity and selectivity in neuroblastoma (NB) cells driven by high MYCN expression. This response translated to significant tumor regression in a mouse model of high-risk NB, without introducing discernible toxicity. We determined that this effect was associated with global inhibition of MYCN-dependent transcriptional amplification. THZ1 led to preferential downregulation of Pol II occupancy at super-enhancer-associated genes, including MYCN and other master transcription factors critical to neuronal development such as PHOX2B, GATA2, and DBH. Similarly, inhibition of CDK12 activity using a novel, first-in-class small molecule inhibitor, THZ-5-31-1, resulted in potent antitumor activity in MYCN-overexpressing NB cells. THZ-5-31-1 doses sufficient to induce PARP cleavage did not lead to significant inhibition of global transcription elongation. Rather, cytotoxicity was associated with preferential downregulation of RNA processing factors and a higher percentage of immature mRNA transcripts. Together, these results suggest that transcriptional CDK inhibitors, by affecting different aspects of the transcription machinery, may inhibit the growth of cancers driven by oncogenic transcription factors such as MYC. Citation Format: Malgorzata Krajewska, Nathan F. Moore, Edmond Chipumuro, Tinghu Zhang, Eugenio Marco, Clark Hatheway, Bandana Sharma, Nicholas Kwiatkowski, Guo-Cheng Yuan, Richard A. Young, Nathanael S. Gray, Rani E. George. Targeting super-enhancer driven oncogene transcription through cyclin-dependent kinase inhibitors. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr PR04.
Childhood obsessive-compulsive disorder
Authors: J L Rapoport, S E Swedo, H L Leonard
Journal: American Journal of Psychiatry (1981)

Childhood obsessive compulsive disorder has recently been recognized as being more common than previously believed, supporting epidemiologic studies in adults that found rates far higher than clinical studies have suggested. Clinically, presentation is generally similar to that for adult patients, but compulsions may occur in the absence of obsessions although both obsessions and compulsions are common. Symptoms typically change over time, but almost all subjects at some time experienced excess washing as one of their symptoms. There is an increased rate of obsessive compulsive disorder and of motor tics in the relatives of children with obsessive compulsive disorder. As with Tourette's disorder, partial voluntary control of symptoms is usual. Prospective follow-up studies show continued disability from obsessive compulsive disorder and continued comorbidity with affective disorders. Obsessive compulsive symptoms are selectively associated with several childhood onset neurologic disorders such as Tourette's disorder and Sydenham's chorea, both presumed to be basal ganglia disorders. The implication of this association is that there may be hard-wired complex behaviors subsumed by basal ganglia frontal cortical pathways that are inappropriately released in obsessive compulsive disorder.
Immune and Stromal Classification of Colorectal Cancer Is Associated with Molecular Subtypes and Relevant for Precision Immunotherapy
Authors: Etienne Becht, Aurélien de Reyniès, Nicolas A. Giraldo, Camilla Pilati, Bénédicte Buttard, Laetitia Lacroix, Janick Selves, Catherine Sautès-Fridman, Pierre Laurent-Puig, Wolf Herman Fridman
Journal: Clinical Cancer Research (2016)

The tumor microenvironment is formed by many distinct and interacting cell populations, and its composition may predict patients' prognosis and response to therapies. Colorectal cancer is a heterogeneous disease in which immune classifications and four consensus molecular subgroups (CMS) have been described. Our aim was to integrate the composition of the tumor microenvironment with the consensus molecular classification of colorectal cancer.We retrospectively analyzed the composition and the functional orientation of the immune, fibroblastic, and angiogenic microenvironment of 1,388 colorectal cancer tumors from three independent cohorts using transcriptomics. We validated our findings using immunohistochemistry.We report that colorectal cancer molecular subgroups and microenvironmental signatures are highly correlated. Out of the four molecular subgroups, two highly express immune-specific genes. The good-prognosis microsatellite instable-enriched subgroup (CMS1) is characterized by overexpression of genes specific to cytotoxic lymphocytes. In contrast, the poor-prognosis mesenchymal subgroup (CMS4) expresses markers of lymphocytes and of cells of monocytic origin. The mesenchymal subgroup also displays an angiogenic, inflammatory, and immunosuppressive signature, a coordinated pattern that we also found in breast (n = 254), ovarian (n = 97), lung (n = 80), and kidney (n = 143) cancers. Pathologic examination revealed that the mesenchymal subtype is characterized by a high density of fibroblasts that likely produce the chemokines and cytokines that favor tumor-associated inflammation and support angiogenesis, resulting in a poor prognosis. In contrast, the canonical (CMS2) and metabolic (CMS3) subtypes with intermediate prognosis exhibit low immune and inflammatory signatures.The distinct immune orientations of the colorectal cancer molecular subtypes pave the way for tailored immunotherapies. Clin Cancer Res; 22(16); 4057-66. ©2016 AACR.
pH‐Sensing Hydrogel Fibers: Flexible pH‐Sensing Hydrogel Fibers for Epidermal Applications (Adv. Healthcare Mater. 6/2016)
Authors: Ali Tamayol, Mohsen Akbari, Yael Zilberman, Mattia Comotto, Emal Lesha, Ludovic Serex, Sara Bagherifard, Yu Chen, Guoqing Fu, Shideh Kabiri Ameri, Weitong Ruan, Eric L. Miller, Mehmet R. Dokmeci, Sameer Sonkusale, Ali Khademhosseini
Journal: Advanced Healthcare Materials (2016)

On page 711 S. Sonkusale, A. Khademhosseini, and co-workers present pH-responsive hydrogel fibers that can be used for long-term monitoring of epidermal wound conditions. pH-responsive dyes are loaded into mesoporous microparticles, which are then embedded into hydrogel fibers developed through microfluidic spinning. The fabricated pH-responsive microfibers are flexible and can create conformal contact with skin. Images of the pH-sensing fibers during real-time pH measurement can be captured with a smart phone camera for convenient readout on-site.
Binge eating associated with oral contraceptives
Authors: R A Moskovitz, A Lingao
Journal: American Journal of Psychiatry (1979)

A case report provides evidence to support a neurophysiologic mechanism for the binge-eating syndrome associated with oral contraceptives.  A 25-year-old single woman referred for compulsive eating of 3 years duration had experienced since age 21 abrupt episodic eating binges characterized by a driven ego-alien feeling.  The episodes lasted from 15 minutes to several hours and occurred in clusters over 2-5 days and the patient could recall no binge-free interval longer than 1 month since the onset of the episodes.  There were no other major psychiatric or neurologic symptoms and the only remarkable aspect of her medical history was the use of oral contraceptives continually since age 19.  She had taken 1 combination pill for 2 years and changed to another which contained 1 mg of norethindrone and .05 mg of mestranol when she was 21.  An initial EEG was remarkable for bifrontal rhythmic slow and sharp activity.  Ater discontinuation of the oral contraceptives the patient reported a gradual improvement in symptoms.  A follow-up EEG 5 months later showed marked reduction of epileptiform activity and was only marginally abnormal.  It is postulated that the marked improvement in the patients symptoms and the associated improvement in her EEG resulted directly from her discontinuing the use of oral contraceptives.  These assumptions are limited by omission of blind technique and failure to rechallenge the patient with her medication.  Nevertheless the subacute time course of her improvement suggests that this was not a placebo effect.
BMET-37PHASE I STUDY OF AZD3759, AN EGFR INHIBITOR WITH BLOOD BRAIN BARRIER (BBB) PENETRATION, FOR THE TREATMENT OF EGFRm+ NON-SMALL CELL LUNG CANCER (NSCLC) WITH BRAIN METASTASIS AND LEPTOMENGINGEAL METASTASIS
Authors: Myung-Ju Ahn, Dong-Wan Kim, Paul Martin, Chris Davison, Zhenfan Yang, Haiyi Jiang, James Chih-Hsin Yang
Journal: Neuro-Oncology (2015)

BACKGROUND: EGFRm+ NSCLC with central nervous system (CNS) metastases, including BM (brain metastasis) and LM (leptomeningeal metastasis), has high unmet medical need due to lack of effective treatment. We discovered AZD3759, an oral EGFR inhibitor with better BBB penetration than other available EGFR TKIs, which demonstrates profound anti-tumor effect in preclinical BM and LM models. Here we present preliminary data of AZD3759 in an ongoing phase I study. METHODS: This is an open label, multi-center study to assess safety and tolerability of AZD3759 in patients with EGFRm+ NSCLC who progressed with EGFR TKI and chemotherapy. This First Time in Human study aims to determine the maximal tolerated dose (MTD) and/or recommended phase II dose (RP2D) and preliminary efficacy. RESULTS: To date, 17 patients with advanced stage EGFRm+ NSCLC were enrolled into the study (5 in 50mg bid, 7 in 100mg bid and 5 in 200mg bid cohorts, respectively). 11 and 2 out of 17 patients have measurable BM and LM, respectively. Dose-dependent plasma and CSF (cerebral spinal fluid) exposure of AZD3759 was observed. At the dose of 200mg, all patients had CSF Ctrough concentration above pEGFR IC50 in EGFRm+ cells. Adverse events were consistent with inhibition of wild type EGFR (5 patients experienced skin rash and/or diarrhea, mainly grade 1). No dose limiting toxicities were observed to date. In 16 the evaluable patients with measurable BM, 4 showed tumor shrinkage in the brain. In 2 evaluable patients with LM, 1 patient showed a 94% reduction of pEGFR in tumor cells in CSF, determined by H score using immunohistochemistry assay. CONCLUSION: AZD3759 is an EGFR TKI with good BBB penetration with potential to treat EGFRm+ NSCLC patients with BM and LM. The phase 1 study is ongoing and updated clinical results will be presented in the meeting.
Components of the eIF4F complex are potential therapeutic targets for malignant peripheral nerve sheath tumors and vestibular schwannomas
Authors: Janet L. Oblinger, Sarah S. Burns, Elena M. Akhmametyeva, Jie Huang, Li Pan, Yulin Ren, Rulong Shen, Beth Miles-Markley, Aaron C. Moberly, A. Douglas Kinghorn, D. Bradley Welling, Long-Sheng Chang
Journal: Neuro-Oncology (2016)

The eukaryotic initiation factor 4F (eIF4F) complex plays a pivotal role in protein translation initiation; however, its importance in malignant and benign Schwann cell tumors has not been explored, and whether blocking eIF4F function is effective for treating these tumors is not known. Immunostaining was performed on human malignant peripheral nerve sheath tumors (MPNSTs) and vestibular schwannomas (VSs) for eIF4F components. The role of eIF4A and eIF4E in cell growth was assessed by RNA interference. Various natural compounds were screened for their growth-inhibitory activity. Flow cytometry and Western blotting were performed to characterize the action of silvestrol, and its antitumor activity was verified in orthotopic mouse models. MPNSTs and VSs frequently overexpressed eIF4A, eIF4E, and/or eIF4G. Depletion of eIF4A1, eIF4A2, and eIF4E substantially reduced MPNST cell growth. From screening a panel of plant-derived compounds, the eIF4A inhibitor silvestrol was identified as a leading agent with nanomolar IC50 values in MPNST and VS cells. Silvestrol induced G2/M arrest in both NF1-deficient and NF1-expressing MPNST cells and primary VS cells. Silvestrol consistently decreased the levels of multiple cyclins, Aurora A, and mitogenic kinases AKT and ERKs. Silvestrol treatment dramatically suppressed tumor growth in mouse models for NF1−/− MPNST and Nf2−/− schwannoma. This decreased tumor growth was accompanied by elevated phospho-histone H3 and TUNEL labeling, consistent with G2/M arrest and apoptosis in silvestrol-treated tumor cells. The eIF4F complex is a potential therapeutic target in MPNSTs and VS, and silvestrol may be a promising agent for treating these tumors.
JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma
Authors: Tiffany Sin Yu Chan, Cynthia Hawkins, Jonathan R. Krieger, C. Jane McGlade, Annie Huang
Journal: Cancer Research (2016)

Abstract Substantial evidence links Myc–PI3K/AKT signaling to the most aggressive subtype of medulloblastoma and this axis in medulloblastoma therapy. In this study, we advance understanding of how Myc–PI3K/AKT signaling contributes to this malignancy, specifically, in identifying the Myc-interacting protein JPO2 and its partner binding protein LEDGF/p75 as critical modulators of PI3K/AKT signaling and metastasis in medulloblastoma. JPO2 overexpression induced metastatic medulloblastoma in vivo through two synergistic feed-forward regulatory circuits involving LEDGF/p75 and AKT that promote metastatic phenotypes in this setting. Overall, our findings highlight two novel prometastatic loci in medulloblastoma and point to the JPO2:LEDGF/p75 protein complex as a potentially new targetable component of PI3K/AKT signaling in medulloblastoma. Cancer Res; 76(9); 2802–12. ©2016 AACR.
Methylnaltrexone treatment of opioid-induced constipation in cancer patients
Authors: S. B. Karver, N. E. Slatkin, J. Thomas, R. J. Israel
Journal: Journal of Clinical Oncology (2007)

9081 Background: Constipation is a common and distressing side effect of opioid treatment particularly in patients with cancer. Two phase 3 trials (Studies 301 and 302) reported that subcutaneous (SC) methylnaltrexone was well tolerated and effective in inducing laxation in patients with advanced illness with opioid-induced constipation (OIC) while maintaining central analgesia. Aims: To evaluate improvement in constipation in cancer patients treated with methylnaltrexone in the above studies. Methods: In Study 301, 124 cancer patients received a single dose of methylnaltrexone (SC 0.15mg/kg, 0.30mg/kg) or placebo. In Study 302, 78 cancer patients received either 0.15mg/kg SC QOD methylnaltrexone for 2 weeks (total of 7 doses) or placebo. Patients had a life expectancy of 1–6 months, no laxation within 48 hours, and were maintained on stable opioids and baseline laxatives. The primary efficacy endpoints were laxation within 4 hours after a single or first dose of study drug and laxation within 4 hours for at least 2 of the first 4 doses (Study 302). The secondary endpoints were laxation within 24 hours, pain scores, and opioid withdrawal symptoms. Results: A majority of the methylnaltrexone-treated cancer patients had a laxation within the first 4 hours of study drug administration ( Table ). There were no clinically significant changes in pain scores or opioid withdrawal symptoms. Conclusions: Our results demonstrate that in cancer patients with advanced illness and OIC, methylnaltrexone significantly improved constipation, without loss of pain control or opioid withdrawal. [Table: see text] No significant financial relationships to disclose.
Outcomes Of Haematopoietic Stem Cell Transplantation (HSCT) for Severe Congenital Neutropenia (SCN): Preliminary Results
Authors: Francesca Fioredda, Liesbeth C de Wreede, Michaela Calvillo, Bobby Gaspar, Mahmoud Aljurf, Anja van Biezen, Giuseppe Morreale, Christina Peters, Erica M Knoedler, Amal Al-Seraihy, M. Akif Yesilipek, Alain Fisher, Marc Bierings, Jean Donadieu, Gulyuz Ozturk, Francoise Bourge, Victoria Bordon, Owen Smith, Andrea Bacigalupo, Jakob Passweg, Gerard Socie, Hubert Shretzenmeier, Judith Marsh, Carlo Dufour
Journal: Blood (2013)
The MKK6/p38 Stress Kinase Cascade Is Critical for Tumor Necrosis Factor-–Induced Expression of Monocyte-Chemoattractant Protein-1 in Endothelial Cells
Authors: Matthias Goebeler, Karin Kilian, Reinhard Gillitzer, Manfred Kunz, Teizo Yoshimura, Eva-B. Bröcker, Ulf R. Rapp, Stephan Ludwig
Journal: Blood (1999)
Abstract 76: Meox1 is a Cell-cycle Oscillator Required for Mitotic Transition and Proliferation in Cardiac Fibroblasts
Authors: Shuichiro Higo, Yoshihiro Asano, Yuki Masumura, Yasushi Sakata, Masafumi Kitakaze, Seiji Takashima
Journal: Circulation Research (2014)

Background: Tissue fibrosis plays important roles in the pathogenesis of chronic diseases, including heart failure. The mechanism underlying interstitial fibroblast proliferation is a promising analytical target for therapeutic applications. Here we developed quantitative epigenome profiling to identify a critical regulator in interstitial cell populations that emerges during the progression of heart failure. Methods and Results: We subjected pressure-overloaded hearts of mice to trimethylated histone H3 lysine 4 (H3K4me3) ChIP-sequence and RNA-sequence. Expression analysis followed by quantitative H3K4me3 profiling identified 45 fibrosis-related genes with significant H3K4me3 enrichment in failing hearts, including Meox1 transcription factor. Meox1 emerged in the interstitial fibrotic region in failing heart, and intriguingly Meox1 was expressed in the limited population of cardiac fibroblasts both in vivo and in vitro. Meox1-positive fibroblasts were increased in response to a paracrine signal from cardiomyocytes, and knockdown of Meox1 completely inhibited the reactive proliferation of cardiac fibroblasts stimulated by conditioned medium from cardiomyocytes. Gene expression profiling combined with siRNAs clarified that Meox1 depletion resulted in down regulation in the mitosis-related genes including Aurora B kinase. Indeed, Meox1 depletion decreased the cells under mitosis, but conversely increased the proportion of DNA synthesizing cells, thereby inhibited mitotic transition. The cell-cycle synchronization analysis and promoter analysis using live-cell imaging clarified that Meox1 oscillated throughout the cell-cycle and specifically emerged in G2/M phase. Finally, we revealed that Meox1 heterogenously expressed in the interstitial fibrotic are of human ventricular heart tissues from patients with end-stage heart failure. Notably, Meox1 expression was significantly correlated with the fibrosis-related genes in diseased ventricular heart tissues (n=15), suggesting the pathological relevance in clinical settings. Conclusion: Our findings identify a novel cell-cycle regulator and propose that Meox1 is a potential target for therapies aimed at preventing tissue fibrosis.
&lt;italic&gt;N&lt;/italic&gt;-Nitroso-&lt;italic&gt;N&lt;/italic&gt;-Methylurea-Induced Mammary Tumors in the Rat: Role of Prolactin and a Prolactin-Lowering Drug&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: P Gandilhon, R Mélançon, J Djiane, P A Kelly
Journal: JNCI Journal of the National Cancer Institute (1983)

Female outbred Sprague-Dawley rats bearing N-nitroso-N-methylurea (NMU)-induced mammary tumors received various endocrine therapies 3 months after the first NMU injection. Rats were divided into 5 groups (15-20 rats/group) and received a 4-week treatment as follows: group 1, controls; group 2, ovariectomized; group 3, 0.5 mg 2-bromoergocryptine (CB-154) injected so twice daily; group 4a, pituitary implant under the kidney capsule; and group 4b, CB-154 injected during the last 2 weeks of the experiment in rats bearing a pituitary implant. Castration of rats with established NMU-induced tumors resulted in a decrease in both tumor number and size, but these parameters again started to increase 3 weeks post castration. CB-154 failed to reduce the tumor number but did arrest the increase in tumor size. In the animals with a pituitary implant, both tumor number and tumor size increased progressively at a greater rate than in control animals, whereas the addition of CB-154 (group 4b) stabilized the tumor growth. Ovariectomy (OVX) resulted in a significant decline of steroid receptor levels. Prolactin (PRL) receptor levels were significantly stimulated by the pituitary implant, and CB-154 prevented this increase. The present studies confirmed that NMU-induced mammary tumors are less hormone-dependent (response to OVX) than 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumors. The role of PRL also appears to be less important, at least for established tumors, for NMU-induced mammary tumors than for DMBA-induced mammary tumors.
Injection Practices Among Nurses--Valcea, Romania, 1998
Journal: JAMA (2001)

The surveillance data collected by the Romanian Ministry of Health during 1997-98 indicated that acute hepatitis B virus (HBV) infection was associated with receiving injections among children aged <5 years.  It is noted that in Romania injection frequently is used by nurses to administer medication.  In view of this interviews were conducted among clinic and hospital nurses in Romania in order to identify the practices that might have resulted in injection-associated HBV transmission.  A total of 180 nurses on the payroll agreed to be interviewed.  Overall results showed that although nurses used new disposable syringes and needles other inadequate infection control practices and situations might explain injection-associated HBV transmission. These include preparing injections in areas potentially contaminated with blood multidose vial handling and inadequate supplies.  Results of the survey were used by the Romanian Coalition to Prevent Nosocomial Infection to prepare standards for infection safety to protect patients and health care workers from HBV infection.