tbuckley/cabot-search huggingface dataset:
Myeloid Growth Factor Therapy for Prophylaxis of Febrile Neutropenia in Non-Myeloid Malignancies: Appropriate Doses and Schedules
Authors: Betsy L. Althaus
Journal: Journal of the National Comprehensive Cancer Network (2007)

Myeloid growth factors (MGFs) are used for the prophylaxis of febrile neutropenia and maintenance of scheduled dose delivery in the treatment of patients undergoing cancer chemotherapy. To spare cost and for patient convenience, in adults MGFs are used at schedules, doses, and durations that differ from the approved prescribing information of the U.S. Food and Drug Administration. These variations include rounding doses to convenient sizes, fewer days of treatment, a shorter interval between cycles, and same-day administration with chemotherapy. Some of these variations are supported by clinical trial results and practice guidelines.
Abstract 150: Long non-coding RNA are differentially expressed in breast cancer clinical subtypes
Authors: Surendra Kumar, Michael Seiler, Sunniva Bjørklund, Anne-Lise Børresen-Dale, Vessela Kristensen, Gyan Bhanot, Shridar Ganesan
Journal: Cancer Research (2015)

Abstract A primary benefit of RNA-Seq over traditional DNA microarrays is the ability to interrogate expression in unannotated areas of the transcriptome. Methods for identifying novel genes in genomic DNA sequence can use features such as an open reading frame and conserved functional protein elements. Non-coding RNA structures are more difficult to detect, and most of our knowledge of them comes from expressed sequence tags (ESTs), which are large, sequenced contigs from transcriptome cDNA libraries. Carninci et al. showed that over half of these sequences appear to originate from non-coding sources, though very few are annotated. Moreover, many of these non-coding sources are poorly conserved over multiple species indicating that these transcripts may not be functional, but instead, may be the result of “random” transcription. As more studies focus on these “non-coding” regions of the genome evidence of conservation and functionality is emerging. To identifying possibly functional transcripts, we took the approach of identifying only non-coding transcripts which were differentially expressed between breast cancer tumor subtypes, and tumor versus non-tumor samples by RNAseq analysis. We reason that such ncRNA transcription is more likely to be functional because of its association with a specific disease phenotype and the possibility that they affect some regulatory pathway. We have identified known long-non coding tumor suppressors, such as H19 and MEG3, as expressed exclusively in non-tumor samples. In addition we have identified 59 intergenic regions representing a total of 132 300 bp which were differentially expressed between ER+/HER2- and ER-/HER2- breast tumor subtypes. This resulted in 4 potential non-coding regions associated with ER-/HER2- tumors, and 6 potential non-coding regions associated with ER+/HER2- tumors. These transcripts are of great interest, and should be studied in more detail to elucidate the function of these non-coding RNA molecules. Citation Format: Surendra Kumar, Michael Seiler, Sunniva Bjørklund, Anne-Lise Børresen-Dale, Vessela Kristensen, Gyan Bhanot, Shridar Ganesan. Long non-coding RNA are differentially expressed in breast cancer clinical subtypes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 150. doi:10.1158/1538-7445.AM2015-150
Spermicides and birth defects [editorial]
Authors: Oakley Gp
Journal: JAMA (1982)

Jick and collagues reported last year a cohort study of 4665 patients from the Group Health Cooperative (CHC) in Seattle suggesting that presumed spermicide users had infants with a higher rate of malformations than presumed nonusers.  They reported a 2-fold increase in major malformations and specific increases for Downs syndrome limb reduction deformities and hypospadias.  They also noted an increase for neoplasms.  The authors regarded the data as tentative because no well-defined syndrome was found among the infants of users.  The diversity of the increased malformations was another strong reason to consider the findings tentative.  There are other reasons for considering the findings tentative or preliminary.  One must have reservations regarding the accuracy with which infants were classified as  or unexposed.  The authors argue that the vast majority of GHC members who used spermicides obtained them from the GHC pharmacy.  Their argument is not based  direct data but  a study that showed that 98% of GHC women who took hormones available only by prescription obtained them from the pharmacy.  The argument is weak since spermicides are relatively inexpensive and widely available without prescription.  It is likely that GHC members did purchase spermicides on the outside.  Insufficient information is given to know to what extent such purchases occurred and whether such purchases were biased.  Without such information it is necessary to ask whether misclassification played a role in the reported positive associations.  The reported incidence of major malformations in hospital-based studies is about 2%.  The fact that the 2-fold increase in the study is based  the apparent 50% decrease in reporting of defects in the  group rather than  an increase above the 2% level for the exposed group argues for the tentative nature of these findings.  In this issue of the JAMA Shapiro et al. report from the Collaborative Perinatal Study data that they can find no increase of overall malformations among 476 infants with a history of 1st trimester exposure to nonmercurial spermicides when compared with 49820 unexposed infants.  Polendak et al. reports  spermicide exposure of 715 women who had infants with major malformations.  On the basis of the 3 studies it seems clear that no causal association has been shown between spermicide use and birth defects.
Genetically Engineered Multivalent Proteins for Targeted Immunotherapy
Authors: James E. Talmadge
Journal: Clinical Cancer Research (2016)

mAbs initiated the unprecedented breakthroughs in cancer immunotherapy and are rapidly evolving with multiple therapeutic platforms. One next-generation strategy engineers multivalent proteins that ligate single-chain variable fragments targeting cellular effectors, tumor-associated antigens, and cytokines. These developing therapeutics target and regulate cellular effector bioactivity and significantly improve clinical outcomes. Clin Cancer Res; 22(14); 3419-21. ©2016 AACRSee related article by Vallera et al., p. 3440.
Genetic risk assessment and specific-locus mutations in the ad-3 region of Neurospora crassa.
Authors: F J de Serres
Journal: Environmental Health Perspectives (1994)

Data from experiments on the induction of specific-locus mutations in model systems are used in genetic risk assessment to estimate potential adverse effects in the human population. In such assessments with radiation or chemical mutagens, the following information is required: a) spontaneous and induced forward-mutation frequencies, b) dose-response curves for the overall induction of specific-locus mutations, c) genetic characterization of spontaneous and induced mutations, and d) dose-response curves for the different genotypic classes. Specific-locus assays in most eukaryote assay systems provide only portions of the information required for such assessments. In recognition of the need for more detailed information for risk assessment, a model system has been developed for specific-locus assays in Neurospora crassa. The adenine-3 (ad-3) specific-locus assay was modeled after the two-gene morphological specific-locus assay in the dilute-short-ear region of the mouse and detects forward-mutations at two closely linked loci: ad-3A and ad-3B. A computerized data management program has made it possible to obtain precise dose-response curves not only for the overall induction of ad-3 mutations, but also for various genotypic subclasses. In addition, computerized statistical programs have been developed to compare dose-response curves. These methods of analysis have shown that the overall dose-response curve for specific-locus mutations in the ad-3 region is a composite of many different genotypic subclasses. In addition, these subclasses may have very different induction kinetics from those of the overall dose-response curve for ad-3 mutations.
Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection
Authors: Christin Peteranderl, Luisa Morales-Nebreda, Balachandar Selvakumar, Emilia Lecuona, István Vadász, Rory E. Morty, Carole Schmoldt, Julia Bespalowa, Thorsten Wolff, Stephan Pleschka, Konstantin Mayer, Stefan Gattenloehner, Ludger Fink, Juergen Lohmeyer, Werner Seeger, Jacob I. Sznajder, Gökhan M. Mutlu, G.R. Scott Budinger, Susanne Herold
Journal: Journal of Clinical Investigation (2016)

Influenza A viruses (IAV) can cause lung injury and acute respiratory distress syndrome (ARDS), which is characterized by accumulation of excessive fluid (edema) in the alveolar airspaces and leads to hypoxemia and death if not corrected. Clearance of excess edema fluid is driven mostly by the alveolar epithelial Na,K-ATPase and is crucial for survival of patients with ARDS. We therefore investigated whether IAV infection alters Na,K-ATPase expression and function in alveolar epithelial cells (AECs) and the ability of the lung to clear edema. IAV infection reduced Na,K-ATPase in the plasma membrane of human and murine AECs and in distal lung epithelium of infected mice. Moreover, induced Na,K-ATPase improved alveolar fluid clearance (AFC) in IAV-infected mice. We identified a paracrine cell communication network between infected and noninfected AECs and alveolar macrophages that leads to decreased alveolar epithelial Na,K-ATPase function and plasma membrane abundance and inhibition of AFC. We determined that the IAV-induced reduction of Na,K-ATPase is mediated by a host signaling pathway that involves epithelial type I IFN and an IFN-dependent elevation of macrophage TNF-related apoptosis–inducing ligand (TRAIL). Our data reveal that interruption of this cellular crosstalk improves edema resolution, which is of biologic and clinical importance to patients with IAV-induced lung injury.
Decisions on restarting anticoagulation should be made earlier after rebleeding
Authors: Ian L P Beales
Journal: BMJ (2016)

Staerk and colleagues’ paper provides support for the important, perhaps underused, practice of reintroducing anticoagulation after a gastrointestinal haemorrhage.1 Some aspects of the paper need to be put into context. The data on antiplatelet agents for atrial fibrillation have little relevance to current practice because the management and epidemiology of gastrointestinal bleeding has changed over the course of the study (1996-2012). Improvements in endoscopic and medical management have …
Lead and hyperactivity. Behavioral response to chelation: a pilot study
Authors: O J David, S P Hoffman, J Sverd, J Clark, K Voeller
Journal: American Journal of Psychiatry (1976)

Lead-chelating medication was used to treat 13 hyperkinetic school children whose blood and urine lead levels were in an elevated but "nontoxic" range. Six children with histories of etiologically relevant perinatal or developmental complications showed relatively little improvement. Seven other children with unremarkable histories, and for whom a lead etiology could thus be entertained, showed marked improvement. The authors conclude that lead may play an important role in the etiology of some cases of hyperactivity; lead-chelating agents may have a major place in the treatment of hyperactivity; and the medical workup of hyperactivity should include lead level measurements and careful consideration of other possible etiological factors.
Compte rendu de la situation à Amsterdam : augmentation des maladies sexuellement transmissibles et des comportements sexuels à risque chez les hommes homosexuels, liée à la mise sur le marché de nouveaux traitements anti-VIH
Authors: G Stolte, N H T M Dukers, J B F de Wit, H Fennema, R A Coutinho
Journal: Eurosurveillance (2002)

L’inquietude provoquee par l’augmentation des maladies sexuellement transmissibles (MST) a fait l’objet de deux etudes realisees par le departement de recherche sur le Sida du municipal health service (Centre de soin municipal) d’Amsterdam. Les resultats indiquent que l’introduction de traitements antiretroviraux fortement actifs (Highly Active Antiretroviral Therapies ou HAART) ont pu avoir une influence sur l’augmentation des MST et des comportements sexuels a risque.
Depletion of the Ras Association Domain Family 1, Isoform A–Associated Novel Microtubule-Associated Protein, C19ORF5/MAP1S, Causes Mitotic Abnormalities
Authors: أشرف دلول, فريدة لطيف
Journal: Cancer Research (2007)

Ras association domain family 1, isoform A (RASSF1A) is a
novel tumor suppressor gene that is found to be inactivated in
more than 40 types of sporadic cancers. In addition, mouse
Rassf1a knockout models have an increased frequency of
spontaneous and induced tumors. The mechanisms by which
RASSF1A exerts its tumor suppression activities or the
pathways it can regulate are not yet fully understood. Using
yeast two-hybrid system, we have previously identified
C19ORF5/MAP1S as the major RASSF1A-interacting protein.
C19ORF5 has two conserved microtubule-associated regions
and may function to anchor RASSF1A to the centrosomes.
In this study, we have analyzed the cellular functions of
C19ORF5. By using small interfering RNA–mediated depletion
and time-lapse video microscopy, we show that C19ORF5
knockdown causes mitotic abnormalities that consist of
failure to form a stable metaphase plate, premature sister
chromatid separation, lagging chromosomes, and multipolar
spindles. We also show that a fraction of C19ORF5 localizes to
the spindle microtubules. Additionally, we show here that
C19ORF5 localizes to the microtubule-organizing centers
during microtubule regrowth after nocodazole washout.
Knockdown of C19ORF5 disrupts the microtubule-organizing
center and results in microtubule nucleation from several
sites. Whereas the localization of pericentrin is not affected,
A- and ;-tubulin localization and sites of nucleation are
greatly altered by C19ORF5 depletion. This may indicate
that C19ORF5 plays a role in anchoring the microtubuleorganizing
center to the centrosomes. In addition, we show
that the NH2 terminus of C19ORF5 is essential for this process.
This novel role for C19ORF5 could explain the resulting
mitotic abnormalities that occur on its depletion and can
potentially provide an underlying mechanism for the frequent
centrosome and microtubule abnormalities detected in
several cancers.
Phase 1 study of paclitaxel, cisplatin, and 5-fluorouracil (TCF) in patients with advanced gastric cancer
Authors: K. Yokoi, K. Omura, M. Hirano, T. Hara, Y. Munemoto, Y. Asada, J. Sakamoto
Journal: Journal of Clinical Oncology (2006)

14134 Background: Paclitaxel is effective against gastric cancer with serosal involvement and/or peritoneal dissemination. Combination of cisplatin and 5-fluorouracil is also active against advanced gastric cancer. Therefore, we designed a phase I trial of a combination of paclitaxel, cisplatin and 5-fluorouracil (TCF) to explore potential synergistic effect. Methods: Eligible patients had metastatic or unresectable gastric cancer with up to 1 prior chemotherapy regimen. The fixed dose of cisplatin 25 mg/m 2 and paclitaxel 80 mg/m 2 with escalation dose of 5-fluorouracil from 300 mg/m 2 to a maximum of 600 mg/m 2 on days 1, 8 and 15 of a 28 day schedule were administered. MTD and anti-tumor activity were evaluated. Results: No grade 3 or 4 toxicities at least possibly related to the treatments resulting in DLT were observed on every dose level. The clinical effects were determined in 3 patients with measurable lesions out of 7 cases. There were 2 partial responses, and disease stabilization was seen in one patient. Conclusions: Combination of paclitaxel, cisplatin and 5-fluorouracil (TCF) is considered to be feasible, well tolerated and active in patients with advanced gastric cancer and warrants further examination in a phase II trial. No significant financial relationships to disclose.
PTU-038 Diving into the depths of the black box: is there a role for push enteroscopy in the era of double balloon enteroscopy – a uk single centre experience
Authors: D Rattehalli, DS Sanders, R Sidhu
Journal: Gut (2015)

<h3>Introduction</h3> Enteroscopy is a novel technique that allows mucosal visualisation, tissue sampling and therapeutic intervention in the small bowel. The use of push enteroscopy (PE) has been questioned with the advent of double balloon enteroscopy (DBE). Whilst PE can reach up to 80 cm beyond the ligament of Treitz, DBE allows greater depth of insertion via the anterograde and retrograde approach into the mid-small bowel. We aim to compare the efficacy of both modalities in terms of diagnostic and therapeutic yields, tolerability and management change. <h3>Method</h3> A retrospective review of patients who underwent PE (from January 2002) and DBE (from July 2006) to October 2014 was performed. Data was collected on demographics, indication, yield, complications and management. Tolerability scores were assessed using a validated scoring system (1-no discomfort 2- slight discomfort 3-extremely uncomfortable 4–unbearable). <h3>Results</h3> A total of 294 PE (mean age 55; 58% male) and 399 DBE (mean age 56; 50% male; anterograde n = 256, retrograde n = 143) were performed in this time period. There was no significant difference in the diagnostic yield between the two modalities (PE 43% vs DBE 49%, p = 0.14) however 37% of positive findings on PE were within reach of a gastroscope. The commonest indication for both was obscure bleeding (PE 63% vs DBE 48%, p = 0.02) and DBE was performed more often for suspected Crohn’s (PE 16% vs DBE 50%, p = 0.005). There was no significant difference in therapeutic yield between PE and DBE (21% vs 24% p = 0.4). Argon plasma coagulation was the most common therapeutic intervention done in both groups (PE n = 44; DBE n = 57) followed by haemostasis intervention in PE (n = 9) and polypectomy in DBE (n = 29). The median length of small bowel examined orally for PE was 130 cm vs DBE 170 cm (p &lt; 0.001). Patient discomfort was scored 3 and above in 21% DBE vs 14% PE (p = 0.005) indicating poorer tolerability for DBE. There was a significant difference in the amount of sedation used (median midazolam dose PE 4 mg vs DBE 6 mg, p &lt; 0.001). Few PE patients were given fentanyl (median dose PE 0 mcg vs DBE 100 mcg, p &lt; 0.001). Management was altered by PE in 43% and by DBE in 41% of patients (p = n/s). Whilst there were no complications for PE, the complication rate for DBE was 1.25% (pancreatitis n = 2, respiratory arrest n = 1, pulmonary oedema n = 1 and NSTEMI n = 1). Since the introduction of DBE, the demand for PE has declined significantly (p = 0.03, r = -0.6). <h3>Conclusion</h3> Both modalities have comparable efficacy with regards to diagnostic and therapeutic yield. Although the demand for PE has declined, there remains a role for PE in patients with proximal small bowel pathology requiring histology or therapeutic intervention. <h3>Disclosure of interest</h3> None Declared.
KRAS mutations (MTs) in non-small cell lung cancer (NSCLC) versus colorectal cancer (CRC): Implications for cetuximab therapy.
Authors: K. D. Danenberg, P. P. Grimminger, P. C. Mack, P. V. Danenberg, J. Cooc, C. Stephens, S. K. Reddy, T. Li, D. R. Gandara
Journal: Journal of Clinical Oncology (2010)

10529 Background: KRAS MTs have been associated with a diversity of biologic functions, and have both prognostic and predictive consequences in NSCLC and CRC. Little data exist comparing the specifics of KRAS MTs in the two cancers. In CRC, benefit from the cetuximab is mainly limited to patients whose tumors are KRAS wild-type (WT). However, recent studies show no such predictive value in NSCLC. We hypothesized that the unique molecular biology and tobacco carcinogen-related etiology of NSCLC contribute to a divergence in KRAS MT type and EGFR-related dependency. Here, we compare KRAS and EGFR status in NSCLC versus (vs) CRC in the large Response Genetics (RGI) database. Methods: KRAS MTs were assessed in 2,693 specimens (838 CRC and 1165 NSCLC) using DNA from microdissected formalin fixed paraffin embedded tumor specimens. EGFR MTs were determined in 649 NSCLCs. A PCR approach with direct sequencing was used to detect 7 different base substitutions in KRAS and 28 EGFR MTs. Statistics: Fisher's Exact Test. Results: KRAS MTs were found in 39% of CRC and 23% of NSCLC specimens (p < 0.001). EGFR MTs were identified in 16% of NSCLCs. In 447 specimens with both assays, EGFR and KRAS MTs were largely exclusive; 4 specimens harbored both (p < 0.001). The ratio of base transversions to transitions was 3.27 in NSCLC versus 0.77 in CRC (p < 0.001). With regard to histology, in NSCLC KRAS MTs were observed in 28.7% (186/649) of adenocarcinomas vs 3.5% (7/198) of squamous cell carcinomas (p < 0.001). Tobacco carcinogenesis-associated G>T transversions (codon 12 GGT>TGT plus GGT>GTT) comprised 61% of KRAS MTs in NSCLC vs 39% in CRC (p < 0.001). The GGT>GAT transition was most prevalent in CRC at 33.3%. Conclusions: This analysis of the RGI database demonstrates differences between NSCLC vs CRC in both incidence and type of KRAS MTs. Increased frequencies of DNA KRAS transversions were seen in NSCLC, likely linked to tobacco exposure. Distinct MT patterns and biologic function may contribute to differences in predictive value for cetuximab therapy between NSCLC and CRC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Response Genetics Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Genoptix, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, Response Genetics, sanofi-aventis Response Genetics DxS, Response Genetics Abbott Laboratories, Bristol-Myers Squibb, Genentech, Lilly, Merck, Novartis, OSI, Pfizer
Abstract 14289: Drug Adherence and the Incidence of Coronary Heart Disease- and Stroke-Specific Mortality among Patients Newly Prescribed Antihypertensive Medications: A 5-Year Cohort Study
Authors: Martin C Wong, Wilson W Tam, Clement S Cheung, Harry H Wang, Ellen L Tong, Antonio C Sek, Bryan P Yan, Nt Cheung, Stephen R Leeder, Cm Yu, Sian M Griffiths
Journal: Circulation (2012)

Background: Randomised trials have shown that optimal adherence to antihypertensive could protect against cardiovascular diseases, but whether adherence reduces cardiovascular deaths in community s...
O-007 Neuropilin 1 (NRP1) may be prognostic and identify a subgroup of Patients with Metastatic Colorectal Cancer (mCRC) who Benefit from Tivozanib + mFOLFOX6 compared to Bevacizumab + mFOLFOX6
Authors: A. Benson, A. Krivoshik, C. Van Sant, M. Needle
Journal: Annals of Oncology (2015)
Estrogen turns down “the AIRE”
Authors: Pearl Bakhru, Maureen A. Su
Journal: Journal of Clinical Investigation (2016)

Genetic alterations are known drivers of autoimmune disease; however, there is a much higher incidence of autoimmunity in women, implicating sex-specific factors in disease development. The autoimmune regulator (AIRE) gene contributes to the maintenance of central tolerance, and complete loss of AIRE function results in the development of autoimmune polyendocrinopathy syndrome type 1. In this issue of the JCI, Dragin and colleagues demonstrate that AIRE expression is downregulated in females as the result of estrogen-mediated alterations at the AIRE promoter. The association between estrogen and reduction of AIRE may at least partially account for the elevated incidence of autoimmune disease in women and has potential implications for sex hormone therapy.