tbuckley/cabot-search huggingface dataset:
Abstract 120: Notch Signaling Negatively Regulates Vascular Endothelial Cell Senescence
Authors: Yohko Yoshida, Tohru Minamino
Journal: Circulation Research (2012)

Accumulation of senescent vascular cells occurs in aged vessels, which leads to an increase of inflammation and a decline of regenerative potential, thereby promoting vascular dysfunction and atherosclerosis. However, the molecular mechanisms of these age-related changes remain unclear. The Notch pathway is a highly conserved signaling that controls cell fate determination and differentiation during the development of various tissues. In adults, Notch signaling has been reported to be essential for neovascularization and is implicated with the age-associated conditions such as cancer, neuronal disorder and impaired regeneration of skeletal muscle. Here, we show that Notch signaling has a crucial role in endothelial cell senescence. We found that inhibition of Notch signaling, using short hairpin RNA (shRNA) targeting Notch1, reduced the maximum population doublings of human umbilical vein endothelial cells (HUVEC), increased the activity of senescence-associated beta-galactosidase, and up-regulated the expression of aging-associated molecules such as p53, p21, and p16. Knockdown of the Notch ligand Jagged1 resulted in attenuation of Notch signaling, thereby inducing premature senescence in a way similar to knockdown of Notch1. In contrast, over-expression of Notch1 or Jagged1 extended the replicative lifespan of HUVEC and decreased the expression of aging-associated molecules. To elucidate the mechanism how inhibition of Notch signaling induces premature senescence in endothelial cells, we examined expression of various molecules by microarray analysis, and found that the expression of Id1 (inhibitor of DNA binding 1) and MKP1 (MAP kinase phosphatase 1) was significantly down-regulated by knockdown of Notch. Over-expression of Id1 improved Notch1 inhibition-induced premature senescence, which is associated with a decrease of p16 expression. Likewise, treatment with SB203580, an inhibitor of p38 MAPK, extended lifespan of Notch-deleted endothelial cells along with down-regulation of p16. These results suggest that Notch signaling and the downstream molecules (Id1 and p38) regulate endothelial cell senescence presumably via a p16-dependent pathway, and may be a new target of the therapy for age-associated vascular diseases.
Abstract 120: Genome-wide DNA Methylation Analysis Reveals Dynamic Changes in the Cardiac Methylome During Post-natal Heart Development
Authors: Choon Boon Sim, Mark Ziemann, K.N. Harikrishnan, Antony Kaspi, Jenny Ooi, Lisa Chang, Ishant Khurana, Eric N Olson, Assam El-Osta, Enzo R Porrello
Journal: Circulation Research (2014)

Epigenetic modifications have emerged as central players in the coordination of gene expression networks during cardiac development. Much attention has focused on the role of histone modifications during embryonic heart development, but relatively little is known about the epigenetic control mechanisms that guide post-natal heart maturation. Furthermore, few studies have investigated the role of DNA methylation during cardiac development, despite the fundamental importance of this biological process for transcriptional regulation. The purpose of the current study was to determine whether DNA methylation plays an important role in guiding transcription during the neonatal period, which is an important developmental window for cardiac maturation, including cardiomyocyte cell cycle withdrawal and loss of endogenous regenerative capacity. Here, we interrogated genome-wide changes in transcription and CpG methylation during post-natal cardiac maturation in the mouse (P1 vs. P14). CpG sequencing (CpG-seq) identified 2251 differentially methylated regions (DMRs) between P1 and P14. Intersection of DMRs with different genomic features revealed that 1248 DMRs were associated with promoter regions and transcription start sites. Interestingly, increased methylation of genes associated with well-known signalling pathways for muscle development and differentiation, such as the bone morphogenetic protein, fibroblast growth factor, Wnt and Notch signalling pathways, was associated with transcriptional repression of these regulatory networks at P14. To determine the functional significance of these dynamic changes in the cardiac methylome, we inhibited DNA methylation in vivo by administration of the DNA hypomethylating agent 5-azacytidine from P2 to P12. Post-natal inhibition of DNA methylation caused a marked increase in heart size and was associated with increased cardiomyocyte proliferation. This study provides evidence for widespread alterations in DNA methylation during post-natal heart maturation and suggests that DNA methylation may play an important role in the transcriptional silencing of key regulatory networks for muscle development and cardiomyocyte proliferation during neonatal life.
A pilot feasibility study to evaluate the efficacy of lapatinib in eliminating HER2-positive tumor cells circulating in peripheral blood of women with metastatic breast cancer.
Authors: Sofia Agelaki, Antonia Kalykaki, Haris Markomanolaki, Galatea Kallergi, Kostas Kalbakis, Dimitrios Mavroudis, Vassilis Georgoulias
Journal: Journal of Clinical Oncology (2013)

e22105 Background: EGFR and HER2 are expressed on CTCs from pts with breast cancer (BC). In this study we aimed to evaluate the efficacy of lapatinib, a dual EGFR and HER2 TK inhibitor, to eliminate HER2+ CTCs in metastatic BC. Methods: Pts with metastatic disease and HER2+ CTCs detected after disease stabilization or response to prior therapy were eligible. Pts received lapatinib till disease or CTC progression, whichever occurred first. Cytospins of peripheral blood mononuclear cells (PBMCs) were double stained with HER2 or EGFR along with cytokeratin antibody; 10 6 PBMCs/pt were analyzed for each molecule. Results: Twenty-two pts were enrolled; median age was 62.5 yrs, 2 had HER2+ primary, 12 (54.5%) had visceral disease and 8 (36.4%) had received ≥3 lines. Treatment was discontinued in 1 pt before the end of the 1st cycle due to toxicity and 1 withdrew consent after 3 cycles. A total of 119 courses were administered [median 4.0 (range, 0.5-26.0)]; disease evaluation revealed SD in 11 pts and PD in 10. HER2+ CTC counts declined in 18 (85.7%) pts during treatment [median time to nadir 1 mo (range, 1 – 5)]. After the 1st cycle, HER2+ CTCs decreased in 14 (66.7%) pts, increased in 6 (28.6%) and remained stable in 1 (4.7%). At baseline, 3444 HER2+ CTCs were detected (median 130), whereas after the 1 st and 2 nd cycles, 2281 (median 1) and 989 (median 2), respectively, were identified. The difference between baseline and post-1st or post-2 nd cycle CTC counts was significant for all pts and for patients with SD but not in progressing pts. EGFR expression on CTCs was evaluated at the baseline and the end of treatment sample; in 6 of 8 pts with CTCs detected at both time points, the % EGFR+ CTCs/pt increased from a mean of 29.72% to 71.52%. Moreover, the % ratio of EGFR+ among the total CTCs increased from 17.08% to 37.59%. Conclusions: Lapatinib is effective in decreasing HER2+ CTCs in pts with metastatic BC, irrespective of the HER2 status of the primary. EGFR+ CTCs increase during treatment implicating EGFR as a possible resistance mechanism. The above results suggest that tailoring therapy according to targets present on CTCs represents an effective therapeutic strategy in BC. Clinical trial information: NCT00694252.
Phase II study of EL625, a p53 antisense oligonucleotide, and chemotherapy in refractory and relapsed acute myelogenous leukemia (AML)
Authors: E. J. Freireich, H. Kantarjian, G. Garcia-Manero, A. Ferrajoli, C. Koller, Z. Estrov, S. Kornblau, N. Laddie, L. Smith, J. Cortes
Journal: Journal of Clinical Oncology (2005)

6617 EL625, an antisense phosphorothioate, induces RNase H dependent cleavage of p53 transcripts resulting in loss of p53 production. In vitro, EL625 combined with low doses of p53-inducing genome damaging agents, e.g. idarubicin, eliminates self-renewal of AML blast stem cells without adversely affecting normal cells. To determine the safety & efficacy of EL625 in combination with chemotherapy we are conducting a phase II study in patients (pts) with AML who were refractory to induction chemotherapy or had a 1st remission duration of <12 months, & were receiving their first salvage. As previously published, the expected complete remission rate with salvage chemotherapy for pts with these characteristics is 10–20% (Estey et al. Blood 1996; 88: 756). Pts were randomized to 1 of 3 groups. All pts received EL625 (0.1 mg/kg/hr continuous infusion over 4 days [d]) & Idarubicin (12 mg/m2/d x 3 d) starting 24 hrs after the start of EL625. Ara-C was administered starting 24 hrs after the start of EL625 infusion as follows: Arm 1, no Ara-C; Arm 2, 100 mg/m2/d over 7d; Arm 3, 1 g/m2/d x4d (3d if 60 yrs or older). Pts could receive up to 2 courses of induction therapy. We have treated 11 pts (4 in arm 1; 3 in arm 2; 4 in arm 3). Median age is 56 yrs (range, 25–73 yrs). 7 were refractory to induction & 6 had relapsed after median 1st complete remission (CR) duration of 30 wks (range, 4–46). 4 pts had diploid karyotype & 7 had cytogenetic abnormalities (complex -5/-7 in 2, misc 5). 9 pts are evaluable for efficacy & toxicity (2 too early). 5 pts have received 2 courses of therapy. 4 pts (44%) achieved CR (1 arm 1, 2 arm 2, 1 arm 3). CR occurred in 2 pts with refractory disease & 2 with relapse (1st CR 32 & 46 wks, respectively). All 4 pts continue in CR after 6, 5, 4 & 1 month, respectively; 1 received stem cell transplant in CR. 2 other pts had a morphologic leukemia free state as per the International Working Group (Cheson et al, JCO 2003; 21:4642). 1 pt died on course 1, day 15 of pneumonia. Toxicity was as expected with myelosuppression as the most common adverse event and no grade 3–4 toxicity related to EL625. Although preliminary, these results suggest that EL625 in combination with chemotherapy is well tolerated. The early efficacy data is encouraging. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eleos Eleos
Phase I, dose-finding study of AZD8931, an inhibitor of ErbB1, 2, and 3 receptor signaling, in combination with paclitaxel (P).
Authors: J. A. Lopez-Martin, M. Vidal Losada, J. Cortes, B. Bermejo, A. Lluch Fernandez, M. Learoyd, A. Saunders, M. Stuart, J. Baselga
Journal: Journal of Clinical Oncology (2011)

3105 Background: AZD8931 is an oral, equipotent inhibitor of ErbB1, ErbB2 and ErbB3 receptor signaling. Methods: This open-label (3+3 design) study (NCT00900627) evaluated the MTD, safety, tolerability and PK of AZD8931 (40–160 mg bid) combined with P (90 mg/m2 on days 1, 8 and 15 of a 28-day cycle). DLTs were evaluated during Cycle 1. AZD8931 dosing started at 160 mg bid (based on monotherapy study results; NCT00637039). Results: 20 pts with advanced refractory tumors (16 breast) received AZD8931. Median exposure to AZD8931 was 52 days and to P was 3 cycles. In the 160 mg bid cohort, DLTs occurred in 2/6 pts (Gr 3 rash; Gr 3 keratitis and Gr 3 photophobia), leading to lower dose cohorts. DLTs occurred in 1/2 pts at 120 mg bid (Gr 3 diarrhea) and 2/6 pts at 80 mg bid (Gr 3 rash; Gr 3 esophagitis). AZD8931 40 mg bid was the protocol-defined MTD. At AZD8931 40 mg bid + P, skin rash (n=6) and diarrhea (n=5) were the most common dermatology and GI-related AEs; the majority were of short duration, and responded to appropriate management and/or temporary AZD8931 interruption. At 40 mg bid, AZD8931 steady-state concentrations exceeded preclinical IC50s for target receptors. Combination treatment did not alter exposure of AZD8931 or P (preliminary data). Conclusions: AZD8931 40 mg bid was generally well tolerated, considered suitable for chronic administration, and is progressing into phase II. Experience in this study has highlighted the importance of early rash management and robust guidelines have been adopted. The difference in AZD8931 MTD between this and the monotherapy study most probably reflects differences in clinical interpretation of DLT criteria as they pertained to non life-threatening and subjective events such as rash, more long-term exposure in the present study, and the possible augmentation of rash when EGFR inhibition is combined with P. AZD8931 dose (mg bid) 40 (n=6) 80 (n=6) 120 (n=2) 160 (n=6) Total (n=20) Pts with AEs considered related to study treatment, n* Any grade 6 6 2 6 0 Grade ≥3 5 3 2 6 16 SAEs 2 2 0 3 7 Most frequent grade ≥3 AEs considered related to study treatment, n* Rash 1 1 0 2 4 Rash pustular 2 1 0 1 4 Asthenia 0 0 2 1 3 Diarrhea 0 0 1 1 2 Esophagitis 0 1 0 1 2 *During any treatment cycle. DLT evaluation cycle 1 only.
A review of clinical stage 1 testicular cancer mortality in a high-volume center.
Authors: Sophia C. Kamran, Sarah C. Markt, Rowan Miller, Elizabeth O'Donnell, Brandon David Bernard, Stephanie A. Curreri, Laurence K. Albiges, Christopher Sweeney, Clair Beard
Journal: Journal of Clinical Oncology (2015)

390 Background: Clinical stage 1 (CS1) testicular germ-cell tumors (GCT) have an overall survival of nearly 99% regardless of histology. We seek to describe the Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) features of the clinical stage 1 testicular cancer patients who died of testis cancer. Methods: Analyses included 1,095 males treated at DF/BWCC between 1997-2012 with data entered into an IRB-approved database developed from electronic medical record abstraction. Patient, tumor, and treatment characteristics were summarized. Analyses focused on testicular-cancer death among the CS1 participants. Results: 616 CS1 testicular patients (291 seminoma-SEM and 324 non-seminoma- NS) were identified and 4 died from their disease (cause-specific survival of 99.3%). Average age at diagnosis amongst the latter patients was 26.7 years. All 4 patients had NS and 2 were embryonal predominant. Average tumor size was 6.3 cm, 2 patients did not have lymphovascular invasion, and 2 were unknown. Following treatment with orchiectomy, 2 patients received 2 cycles of adjuvant bleomycin, etoposide, cisplatin (BEP) chemotherapy. See table 1 for details. Conclusions: Four of 616 (0.6%) patients died after initial presentation with CS1 NSGCT, having relapsed at 1.25, 5.4, 6.25, and 20.7 years after orchiectomy. All patients had non-seminoma histology, 3 of these patients were late relapses (&gt; 2 years), and 2 cases relapsed despite adjuvant BEP. [Table: see text]
System-justifying motives can lead to both the acceptance and the rejection of innate explanations for group differences
Authors: Eric Luis Uhlmann, Luke Zhu, Victoria L. Brescoll, George E. Newman
Journal: Behavioral and Brain Sciences (2014)

Abstract Recent experimental evidence indicates that intuitions about inherence and system justification are distinct psychological processes, and that the inherence heuristic supplies important explanatory frameworks that are accepted or rejected based on their consistency with one's motivation to justify the system.
Angiotensin II-induced proliferation of cultured murine mesangial cells
Authors: G Wolf, F Thaiss, W Schoeppe, R A Stahl
Journal: Journal of the American Society of Nephrology (1992)

Angiotensin II (ANG II), as a single factor, induces proliferation in a cultured murine mesangial cell line (MMC). This study was undertaken to evaluate a possible influence of atrial natriuretic peptide (ANP) on this ANG II-induced proliferation. ANP (10(-7) M) for 2 min significantly increased intracellular cGMP levels in MMC. This increase in cGMP was totally abolished when cells were preincubated for 5 min with 10(-7) M ANG II. Stimulation of intracellular cGMP formation by sodium nitroprusside was also decreased in the presence of ANG II. The ANG II-mediated inhibition of ANP-stimulated intracellular cGMP levels was blocked by Dupont 753, suggesting signal transduction through ANG II receptors of the AT1 class. ANP (10(-7) M) for 24 h completely abolished the ANG II-induced proliferation in MMC. However, 10(-7) M ANP had no significant effect on mitogenesis induced by platelet-derived growth factor or epidermal growth factor. Furthermore, ANP reduced the ANG II-stimulated expression of the proliferating cell nuclear antigen, a cofactor of polymerase delta that is active in the S-phase of the cell cycle. The addition of 10(-3) M N-monobutyryl-guanosine 3':5'-cyclic monophosphate or 8-bromo-guanosine 3':5'-cyclic monophosphate also blocked the ANG II-induced proliferation. ANP (10(-7)) M for 24 h had no significant influence on the expression (number and dissociation constant) of ANG II receptors as determined by binding assays. These results suggest that, besides the previously shown vasoconstrictive and vasodilating effects, complex interactions between ANG II and ANP exist that can modulate mesangial cell growth.(ABSTRACT TRUNCATED AT 250 WORDS)
Early versus On-Demand Tube Feeding in Pancreatitis
Authors: Olaf J Bakker, Marc G Besselink, Hein G Gooszen
Journal: New England Journal of Medicine (2015)

found no benefit of early enteral nutrition in patients with predicted severe acute pancreatitis.Clinical trials involving patients with this condition are hampered by the low positive predictive value of current prognostic scoring systems, resulting in the inclusion of many patients who ultimately have mild acute pancreatitis and do not require early enteral nutrition. 2A composite end point allowed for sample-size reduction but ultimately resulted in an underpowered study, owing to the inequality between the individual end points. 3Death and infection have vastly different clinical significance, given that persistent organ failure, not infection, is the primary cause of death in patients with severe acute pancreatitis. 4,5 The timing, type, and volume of fluid administered were not detailed in this study.Individual centers across this consortium may have different practices with regard to fluid resuscitation that potentially biased the results toward the null hypothesis.Enteral nutrition has consistently been shown to have a benefit in patients with severe acute pancreatitis, but we are still no closer to optimizing patient selection and the timing of enteral nutrition.
Safety and clinical activity of MK-3475 as initial therapy in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Naiyer A. Rizvi, Edward B. Garon, Amita Patnaik, Leena Gandhi, Natasha B. Leighl, Ani Sarkis Balmanoukian, Jonathan Wade Goldman, Joseph Paul Eder, Elizabeth Johnson, George R. Blumenschein, Matthew A. Gubens, Kyriakos P. Papadopoulos, Gregory M. Lubiniecki, Jin Zhang, Michelle Niewood, Kenneth Emancipator, Marisa Dolled-Filhart, Mary Elizabeth Hanson, Rina Hui
Journal: Journal of Clinical Oncology (2014)

8007 Background: Programmed death-1 (PD-1) receptor-ligand interaction inhibits T cell activation against tumor cells. MK-3475 is a potent and highly selective humanized monoclonal antibody against PD-1 designed to directly block its interaction with its ligands, PD-L1 and PD-L2, thus removing the inhibition of T cell activation against cancer. MK-3475 led to prolonged anti-tumor activity in previously treated NSCLC patients. This Phase I study evaluated the safety, tolerability, and clinical activity of MK-3475 as initial therapy in patients with locally advanced or metastatic NSCLC. Methods: Patients with no prior systemic therapy for metastatic disease whose tumors expressed PD-L1 by a preliminary immunohistochemical assay were randomized to MK-3475 10 mg/kg every 2 or 3 wks (Q3W). The first 11 patients were randomized to 2 mg/kg and 10 mg/kg Q3W. At least 1 measurable tumor lesion, ECOG performance status of 0 to 1, adequate organ function and adequate tumor biopsy were required for enrollment. Prior adjuvant therapy was allowed if it preceded relapse by at least a year. Tumor response was assessed every 9 weeks until confirmed disease progression per immune related response criteria (irRC; investigator review); RECIST 1.1 by independent central review will also be performed. Results: 84 patients submitted tissue for PD-L1 assessment and 57 patients had tumors that expressed PD-L1. Between Feb 2013 and Oct 2013, 45 patients started treatment (n=6 2Q3W, n=23 10Q3W, n=16 10Q2W). Preliminary data indicate an ORR (confirmed and unconfirmed) of 36% (67% 2 mg/kg Q3W, 27% 10 mg/kg Q3W, 35% 10 mg/kg Q2W) by irRC. 25 patients (55%), including all but 2 responders, remain on treatment (treatment duration from 12+ to 48+ wks). 52% of patients experienced a drug-related adverse event (AE), usually grade 1-2 in severity, most commonly fatigue (14%), pruritus (8%), dermatitis acneiform (6%), diarrhea (6%) and dyspnea (6%). There was a single drug-related grade 3-5 AE, a grade 3 pericardial effusion. Conclusions: These data suggest that MK-3475 is generally well-tolerated and provides robust antitumor activity in a first-line setting in patients with locally advanced or metastatic NSCLC that expresses PD-L1. Clinical trial information: NCT01295827.
Increasing Prevalence of Gastroschisis — 14 States, 1995–2012
Authors: Abbey M. Jones, Jennifer Isenburg, Jason L. Salemi, Kathryn E. Arnold, Cara T. Mai, Deepa Aggarwal, William Arias, Gerard E. Carrino, Emily Ferrell, Olakunle Folorunso, Brendan Ibe, Russell S. Kirby, Heidi R. Krapfl, Lisa K. Marengo, Bridget S. Mosley, Amy E. Nance, Paul A. Romitti, Joseph Spadafino, Jennifer Stock, Margaret A. Honein
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Gastroschisis is a serious congenital defect in which the intestines protrude through an opening in the abdominal wall. Gastroschisis requires surgical repair soon after birth and is associated with an increased risk for medical complications and mortality during infancy. Reports from multiple surveillance systems worldwide have documented increasing prevalence of gastroschisis since the 1980s, particularly among younger mothers; however, since publication of a multistate U.S. report that included data through 2005, it is not known whether prevalence has continued to increase. Data on gastroschisis from 14 population-based state surveillance programs were pooled and analyzed to assess the average annual percent change (AAPC) in prevalence and to compare the prevalence during 2006-2012 with that during 1995-2005, stratified by maternal age and race/ethnicity. The pooled data included approximately 29% of U.S. births for the period 1995-2012. During 1995-2012, gastroschisis prevalence increased in every category of maternal age and race/ethnicity, and the AAPC ranged from 3.1% in non-Hispanic white (white) mothers aged <20 years to 7.9% in non-Hispanic black (black) mothers aged <20 years. These corresponded to overall percentage increases during 1995-2012 that ranged from 68% in white mothers aged <20 years to 263% in black mothers aged <20 years. Gastroschisis prevalence increased 30% between the two periods, from 3.6 per 10,000 births during 1995-2005 to 4.9 per 10,000 births during 2006-2012 (prevalence ratio = 1.3, 95% confidence interval [CI]: 1.3-1.4), with the largest increase among black mothers aged <20 years (prevalence ratio = 2.0, 95% CI: 1.6-2.5). Public health research is urgently needed to identify factors contributing to this increase.