tbuckley/cabot-search huggingface dataset:
Targeting the Vav3 oncogene enhances docetaxel-induced apoptosis through the inhibition of androgen receptor phosphorylation in LNCaP prostate cancer cells under chronic hypoxia
Authors: Takeo Nomura, Mutsushi Yamasaki, Kenichi Hirai, Toru Inoue, Ryuta Sato, Keiko Matsuura, Masatsugu Moriyama, Fuminori Sato, Hiromitsu Mimata
Journal: Molecular Cancer (2013)

The Vav family of Rho/Rac guanosine nucleotide exchange factors comprises three members in mammalian cells. Vav3 enhances androgen receptor (AR) activity during progression to androgen independence in prostate cancer. We examined Vav3 small interfering RNA (siRNA) effects on cell proliferation and apoptosis in docetaxel-treated LNCaP cells under chronic hypoxia (LNCaPH). We examined individual and combined effects of Vav3 siRNA (si-Vav3) and docetaxel on cell growth and apoptosis under chronic hypoxia by cell proliferation, flow cytometric, DNA fragmentation, and immunoblot analyses. To clarify the molecular basis of si-Vav3- and docetaxel-induced apoptosis, we analyzed alterations in phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-regulate kinase (ERK), c-jun N-terminal kinase (JNK), and AR pathways using kinase inhibitors in LNCaPH cells. The effects of si-Vav3/atelocollagen complex alone or in combination with docetaxel were assessed on xenografts in nude mice by tumor growth delay. Vav3 overexpression was observed in LNCaPH compared with the expression under normoxia. Interrupting Vav3 signaling using siRNA enhanced docetaxel-induced cell growth suppression compared with that induced by docetaxel alone by inhibition of Akt and ERK phosphorylation, resulting in AR phosphorylation inhibition. In addition to increased B-cell lymphoma 2 (Bcl-2) phosphorylation through JNK signaling in response to docetaxel, si-Vav3 enhanced docetaxel-induced apoptosis, as characterized by the accumulation of sub-G1 phase cells and DNA fragmentation, through Bcl-xL/Bcl-2-associated death promoter (Bad) dephosphorylation, resulting in increased caspase-9, caspase-3, and cleaved poly(ADP-ribose) polymerase activation. Xenograft tumor growth was slightly inhibited by si-Vav3/atelocollagen complex injection and combined use of si-Vav3/atelocollagen complex and docetaxel produced a greater effect than docetaxel alone. Interrupting Vav3 signaling enhances docetaxel-induced apoptosis in LNCaP cells under chronic hypoxia by inhibiting the PI3K/Akt, ERK, and AR signaling pathways. Therapy targeting Vav3 in combination with docetaxel may have practical implications for managing castration-resistant prostate cancer.
Posttraumatic Stress and Psychological Growth in Children With Cancer: Has the Traumatic Impact of Cancer Been Overestimated?
Authors: Sean Phipps, James L. Klosky, Alanna Long, Melissa M. Hudson, Qinlei Huang, Hui Zhang, Robert B. Noll
Journal: Journal of Clinical Oncology (2014)

Purpose To examine posttraumatic stress disorder and posttraumatic stress symptoms (PTSD/PTSS) in children with cancer using methods that minimize focusing effects and allow for direct comparison to peers without a history of cancer. Patients and Methods Children with cancer (n = 255) stratified by time since diagnosis, and demographically matched peers (n = 101) were assessed for PTSD using structured diagnostic interviews by both child and parent reports, and survey measures of PTSS and psychological benefit/growth by child report. Results Cancer was identified as a traumatic event by 52.6% of children with cancer, declining to 23.8% in those ≥ 5 years from diagnosis. By diagnostic interview, 0.4% of children with cancer met criteria for current PTSD, and 2.8% met lifetime criteria by self-report. By parent report, 1.6% of children with cancer met current criteria and 5.9% met lifetime criteria for PTSD. These rates did not differ from controls (all Ps &gt;.1). PTSS levels were descriptively lower in children with cancer but did not differ from controls when all were referring to their most traumatic event (P = .067). However, when referring specifically to cancer-related events, PTSS in the cancer group were significantly lower than in controls (P = .002). In contrast, perceived growth was significantly higher in the cancer group when referring to cancer (P &lt; .001). Conclusion These findings suggest no evidence of increased PTSD or PTSS in youths with cancer. Although childhood cancer remains a significant and challenging event, these findings highlight the capacity of children to adjust, and even thrive, in the face of such challenge.
<i>KRAS</i> Codon 12 and 13 Mutations in Relation to Disease-Free Survival in <i>BRAF</i>–Wild-Type Stage III Colon Cancers from an Adjuvant Chemotherapy Trial (N0147 Alliance)
Authors: Harry H. Yoon, David Tougeron, Qian Shi, Steven R. Alberts, Michelle R. Mahoney, Garth D. Nelson, Suresh G. Nair, Stephen N. Thibodeau, Richard M. Goldberg, Daniel J. Sargent, Frank A. Sinicrope
Journal: Clinical Cancer Research (2014)

Abstract Purpose: We examined the prognostic impact of specific KRAS mutations in patients with stage III colon adenocarcinoma receiving adjuvant FOLFOX alone or combined with cetuximab in a phase III trial (N0147). Analysis was restricted to BRAF–wild-type tumors, because BRAF mutation was associated with poor prognosis, and BRAF and KRAS mutations are mutually exclusive. Experimental Design: The seven most common KRAS mutations in codon 12 and codon 13 were examined in 2,478 BRAF–wild-type tumors. Because KRAS mutations in codon 12 (n = 779) or 13 (n = 220) were not predictive of adjuvant cetuximab benefit, study arms were pooled for analysis. Disease-free survival (DFS) was evaluated by HRs using Cox models. Results: KRAS mutations in codon 12 (multivariate HR, 1.52; 95% confidence interval, CI, 1.28–1.80; P &amp;lt; 0.0001) or codon 13 (multivariate HR, 1.36; 95% CI, 1.04–1.77; P = 0.0248) were significantly associated with shorter DFS compared with patients with wild-type KRAS/BRAF tumors, independent of covariates. KRAS codon 12 mutations were independently associated with proficient mismatch repair (P &amp;lt; 0.0001), proximal tumor site (P &amp;lt; 0.0001), low grade, age, and sex, whereas codon 13 mutations were associated with proximal site (P &amp;lt; 0.0001). Conclusion: KRAS mutations in either codon 12 or 13 are associated with inferior survival in patients with resected stage III colon cancer. These data highlight the importance of accurate molecular characterization and the significant role of KRAS mutations in both codons in the progression of this malignancy in the adjuvant setting. Clin Cancer Res; 20(11); 3033–43. ©2014 AACR.
No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B
Authors: Kathryn M. Kitrinos, Amoreena Corsa, Yang Liu, John Flaherty, Andrea Snow-Lampart, Patrick Marcellin, Katyna Borroto-Esoda, Michael D. Miller
Journal: Hepatology (2013)

One major challenge in the treatment of chronic hepatitis B is to maintain long-term viral suppression without promoting the selection of drug-resistant mutations. We analyzed data from 347 hepatitis B e antigen-negative and 238 hepatitis B e antigen positive patients receiving tenofovir disoproxil fumarate (TDF) in an open-label, longterm extension of two phase 3 studies. To date, resistance analyses have been completed for patients receiving up to 288 weeks (6 years) of TDF. Population sequencing of hepatitis B virus (HBV) polymerase/reverse transcriptase (pol/RT) was attempted for all patients at baseline, and any patient who remained viremic (HBV DNA 400 copies/mL [69 IU/mL]) at week 288 or at the end of treatment with TDF (n552) or emtricitabine(FTC)/TDF (n57). Phenotypic analyses were performed in HepG2 cells using recombinant HBV containing patient pol/RT sequences. Approximately half of the patients on open-label treatment who qualified for genotyping had pol/RT sequence changes compared to baseline (23/52 [44%] on TDF, 4/7 [57%] on FTC/TDF). Most changes were at polymorphic sites and none were associated with TDF resistance. Virologic breakthrough occurred infrequently and was associated with nonadherence to study medication in the majority of cases (12/16, 75%). Per protocol, 57 patients (10%)were eligible to switch to FTC/TDF; the majority had HBV DNA <400 copies/mL at their last study visit regardless of whether they switched to FTC/TDF (n534) or maintained TDF monotherapy (n517). No patient exhibited persistent viremia (HBV DNA never <400 copies/mL) after week 240. TDF monotherapy maintains effective suppression of HBV DNA through 288 weeks of treatment with no evidence of TDF resistance.
Logical limitations to the “catastrophe” models of fatigue during exercise in humans
Authors: T D Noakes, A St Clair Gibson
Journal: British Journal of Sports Medicine (2004)

A central debate in the exercise sciences is the cause of the fatigue that develops especially during high intensity exercise of short duration. The most popular theory holds that this form of exercise is limited by a peripherally based, metabolite induced failure of skeletal muscle contractile function, independent of reduced muscle activation by the central nervous system; so-called peripheral fatigue. This theory arose originally from studies undertaken by Nobel Laureate Sir Archibald Vivian Hill and colleagues in Manchester, UK in the 1920s. In turn, their interpretations were crucially influenced by the earlier 1907 findings of Sir Frederick Gowland Hopkins, Nobel Laureate for his discovery of the vitamins, and Walter Morley Fletcher. The original model of Hill and his colleagues proposed that performance during exercise of high intensity was limited by skeletal muscle anaerobiosis that developed as the result of a limiting skeletal muscle blood flow, following the onset of myocardial ischaemia. Such skeletal muscle anaerobiosis ultimately prevented the neutralization of the lactic acid that, Hill believed, initiated muscle contraction. The resulting lactic acid accumulation impaired skeletal muscle relaxation, causing the (involuntary) termination of exercise. The evolutionary progression of this model led to the "catastrophe theory" of Richard Edwards, which posits that exercise terminates when the physiological and biochemical limits of the body are exceeded, causing a catastrophic failure of intracellular homeostasis. This paper addresses six hallmark physiological requirements that must be correct if Hill's cardiovascular/ anaerobic/catastrophic model is the exclusive explanation for the fatigue that develops during maximum exercise to exhaustion. This leads to a review of the evidence supporting other, related "catastrophe" models that have been developed to explain fatigue during exercise of lower intensities and longer durations. It is concluded that there is little published evidence supporting the theory that fatigue occurs only after physiological homeostasis fails according to the prediction of these catastrophe models. Rather, it is proposed that fatigue in any form of exercise may form part of a regulated, anticipatory response co-ordinated in the subconscious brain. The ultimate goal of this regulation is to preserve homeostasis in all physiological systems during exercise, regardless of intensity or duration or the environmental conditions in which it is undertaken.
A Novel Orally Active Small Molecule Potently Induces G1 Arrest in Primary Myeloma Cells and Prevents Tumor Growth by Specific Inhibition of Cyclin-Dependent Kinase 4/6
Authors: Linda B. Baughn, Maurizio Di Liberto, Kaida Wu, Peter L. Toogood, Tracey Louie, Rachel Gottschalk, Ruben Niesvizky, Hearn Cho, Scott Ely, Malcolm A.S. Moore, Selina Chen-Kiang
Journal: Cancer Research (2006)

Abstract Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of cyclin-dependent kinase 4 (Cdk4)-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of bone marrow myeloma cells in vivo. Here, we show that by specific inhibition of Cdk4/6, the orally active small-molecule PD 0332991 potently induces G1 arrest in primary bone marrow myeloma cells ex vivo and prevents tumor growth in disseminated human myeloma xenografts. PD 0332991 inhibits Cdk4/6 proportional to the cycling status of the cells independent of cellular transformation and acts in concert with the physiologic Cdk4/6 inhibitor p18INK4c. Inhibition of Cdk4/6 by PD 0332991 is not accompanied by induction of apoptosis. However, when used in combination with a second agent, such as dexamethasone, PD 0332991 markedly enhances the killing of myeloma cells by dexamethasone. PD 0332991, therefore, represents the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in multiple myeloma and possibly other B-cell cancers. (Cancer Res 2006; 66(15): 7661-7)
Myocardial expression of CC- and CXC-chemokines and their receptors in human end-stage heart failure
Authors: J Damås
Journal: Cardiovascular Research (2000)

Objectives: Chemokines regulate several biological processes, such as chemotaxis, collagen turnover, angiogenesis and apoptosis. Based on the persistent immune activation with elevated circulating levels of chemokines in patients with congestive heart failure (CHF), we have hypothesised a pathogenic role for chemokines in the development of CHF. The objective of this study was to examine mRNA levels and cellular localisation of chemokines and chemokine receptors in human CHF. Methods: We examined explanted hearts from ten patients with end-stage heart failure (all chambers) and in ten organ donors using an RNase protection assays and immunohistochemical techniques. Results: Our main findings were: (i) expression of eight chemokine and nine chemokine receptor genes in both failing and nonfailing myocardium, (ii) particularly high mRNA levels of monocyte chemoattractant protein (MCP)-1 and CXC-chemokine receptor 4 (CXCR4), in both chronic failing and nonfailing myocardium, (iii) decreased mRNA levels of MCP-1 and interleukin (IL)-8 in the failing left ventricles compared to failing left atria, (iv) decreased chemokine (e.g., MCP-1 and IL-8) and increased chemokine receptor (e.g., CCR2, CXCR1) mRNA levels in failing left ventricles and failing left atria compared to corresponding chambers in the nonfailing hearts and (v) immunolocalisation of MCP-1, IL-8 and CXCR4 to cardiomyocytes. Conclusion: The present study demonstrates for the first time chemokine and chemokine receptor gene expression and protein localisation in the human myocardium, introducing a new family of mediators with potentially important effects on the myocardium. The observation of chemokine dysregulation in human end-stage heart failure may represent a previously unknown mechanism involved in progression of chronic heart failure.
Diagnostic value of serum precipitins to mould antigens in active hypersensitivity pneumonitis
Authors: C-M. Fenoglio, G. Reboux, B. Sudre, M. Mercier, S. Roussel, J-F. Cordier, R. Piarroux, J-C. Dalphin
Journal: European Respiratory Journal (2006)

Serum precipitins have a controversial diagnostic value in hypersensitivity pneumonitis (HP). The present authors’ objective was to assess their diagnostic value by developing scores from a panel of specific antigens tested by two techniques (electrosyneresis and double diffusion) to discriminate active HP from other interstitial lung diseases. Consecutive patients presenting with a condition for which HP was considered in the differential diagnosis were included in the study. All patients underwent the same standardised diagnostic procedure, including precipitin tests performed in routine conditions. Clinical manifestations, bronchoalveolar lavage and high-resolution computed tomography defined the presence or absence of HP. Receiver-operating characteristic curves and logistic regression were used to develop the serological scores. A total of 122 patients (including 31 cases of HP) were included in the study. Five antigens from the panel were selected for the serological scores ( Absidia corymbifera, Eurotium amstelodami, Wallemia sebi, Saccharopolyspora rectivirgula and mesophilic Streptomyces sp.). Electrosyneresis was more discriminative than the double-diffusion technique. Predictive negative values varied 81–88% and predictive positive values varied 71–75% for prevalence of HP 20–35%. In conclusion, serological scores using a panel of relevant antigens may guide both biological and clinical practice in areas of high prevalence of hypersensitivity pneumonitis.
Expression of toll-like receptor 2, NOD2 and dectin-1 and stimulatory effects of their ligands and histamine in normal human keratinocytes
Authors: M. Kobayashi, R. Yoshiki, J. Sakabe, K. Kabashima, M. Nakamura, Y. Tokura
Journal: British Journal of Dermatology (2009)

Epidermal keratinocytes are involved in the skin innate immunity and express toll-like receptors (TLRs) and other innate immune proteins. The epidermis is continuously exposed to pathogenic gram-positive bacteria or fungi. However, few studies have examined the function and expression of innate immune proteins in keratinocytes. Histamine, which is well known for itch and allergy, is closely associated with innate immunity, but its influence on epidermal innate immunity is still unclear.To clarify the expression of innate immune proteins in keratinocytes stimulated by ligand pathogen-associated molecules, and the function of histamine in this process.We investigated the effects of lipopeptide (MALP-2, 1-100 ng mL(-1); ligand for TLR2), peptidoglycan (PGN, 0.02-2 microg mL(-1); ligand for NOD2) and beta-glucan (1-100 microg mL(-1); ligand for dectin-1) in the presence or absence of histamine on mRNA expression of TLR2, NOD2 and dectin-1 as well as human beta-defensin 2 by quantitative real-time polymerase chain reaction in cultured normal human epidermal keratinocytes. TLR2 expression was also examined at the cell surface and intracellularly, as determined by flow cytometry and confocal microscopy. The quantities of interleukin (IL)-1alpha and IL-8 produced by keratinocytes were measured using enzyme-linked immunosorbent assay.At the mRNA level, TLR2 was enhanced by PGN but not by its ligand MALP-2 or by beta-glucan; NOD2 was easily induced by all three ligands; and dectin-1 was enhanced by its ligand beta-glucan. These enhanced expressions were further augmented by histamine at 1 microg mL(-1). While the surface expression of TLR2 was barely detectable by flow cytometry even after stimulation, the intracellular expression of TLR2 was apparently elevated by PGN and further promoted by histamine. A confocal microscopic analysis also revealed the enhanced expression of TLR2 in the cytoplasm. The expression of TLR2, NOD2 and dectin-1 was functional, as these pathogen-associated molecules induced the production of IL-1alpha, IL-8 and defensin, and again, histamine greatly enhanced this production.Our study demonstrated that the expression of functional innate immune receptors is augmented by the pathogen-associated molecules in a ligand-feed forward or nonrelated manner in keratinocytes, and histamine promotes their expression and the resultant production of cytokines and defensins.
The Effect of Aging on Nasal Mucociliary Clearance, Beat Frequency, and Ultrastructure of Respiratory Cilia
Authors: JAMES C. HO, KWOK N. CHAN, WAYNE H. HU, WAH K. LAM, LING ZHENG, GEORGE L. TIPOE, JUNE SUN, RAYMOND LEUNG, KENNETH W. TSANG
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

The increased susceptibility of the elderly to lower respiratory tract infection cannot be fully explained. Although mucociliary clearance, which is affected by ciliary beating and ultrastructure, plays a crucial role in the defense of the airways against inhaled microbes, little is known of the effects of aging on these parameters. We studied the nasal mucociliary clearance (NMCC) time, ciliary beat frequency, and ultrastructure of respiratory cilia in a cohort of healthy volunteers (age range 11 to 90 yr). Ciliary beat frequency of ciliated nasal epithelial cells was obtained via an established photometric method, and NMCC time was measured with the saccharine test. There was a correlation of ciliary beat frequency (r = -0.48, p = 0.0001) and NMCC time r = 0.64, p < 0.001) with increasing age. Transmission electron microscopy revealed an increase in the percent of subjects exhibiting microtubular disarrangement and single central microtubules with aging (p = 0.002 and p = 0.005, respectively). Subjects older than 40 yr of age had significantly slower ciliary beat frequency, higher percent of ciliary cross-sections displaying single tubules, and longer NMCC time than their younger counterparts (p < 0.05). These findings may help explain the frequent occurrence of respiratory infection in the elderly.
Lung Cancer Rates in Men and Women With Comparable Histories of Smoking
Authors: C. Bain, D. Feskanich, F. E. Speizer, M. Thun, E. Hertzmark, B. A. Rosner, G. A. Colditz
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Recent case–control studies suggest that, given equal smoking exposure, women may have a higher relative risk of developing lung cancer than men. Despite prospective data that conflict with this hypothesis, mechanistic studies to find a biologic basis for a sex difference continue. Methods: We addressed the hypothesis directly by analyzing prospective data from former and current smokers in two large cohorts—the Nurses' Health Study of women and the Health Professionals Follow-up Study of men. We calculated incidence rates and hazard ratios of lung cancer in women compared with men, adjusting for age, number of cigarettes smoked per day, age at start of smoking, and time since quitting, using Cox proportional hazards models. We also reviewed published results from prospective analyses. Results: From 1986 through 2000, 955 and 311 primary lung cancers were identified among 60 296 women and 25 397 men, respectively, who ranged in age from 40 to 79 years. Incidence rates per 100 000 person-years for women and men were 253 and 232, respectively, among current smokers and 81 and 73, respectively, among former smokers. The hazard ratio in women ever smokers compared with men was 1.11 (95% confidence interval = 0.95 to 1.31). Six published prospective cohort studies allowed assessment of comparative susceptibility to lung cancer by sex. None supported an excess risk of lung cancer for women. Conclusions: Women do not appear to have a greater susceptibility to lung cancer than men, given equal smoking exposure. Research should be focused on enhancing preventive interventions for all.