tbuckley/cabot-search huggingface dataset:
Emergence of Multiple <i>EGFR</i> Extracellular Mutations during Cetuximab Treatment in Colorectal Cancer
Authors: Sabrina Arena, Beatriz Bellosillo, Giulia Siravegna, Alejandro Martínez, Israel Cañadas, Luca Lazzari, Noelia Ferruz, Mariangela Russo, Sandra Misale, Iria González, Mar Iglesias, Elena Gavilan, Giorgio Corti, Sebastijan Hobor, Giovanni Crisafulli, Marta Salido, Juan Sánchez, Alba Dalmases, Joaquim Bellmunt, Gianni De Fabritiis, Ana Rovira, Federica Di Nicolantonio, Joan Albanell, Alberto Bardelli, Clara Montagut
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Patients with colorectal cancer who respond to the anti-EGFR antibody cetuximab often develop resistance within several months of initiating therapy. To design new lines of treatment, the molecular landscape of resistant tumors must be ascertained. We investigated the role of mutations in the EGFR signaling axis on the acquisition of resistance to cetuximab in patients and cellular models. Experimental Design: Tissue samples were obtained from 37 patients with colorectal cancer who became refractory to cetuximab. Colorectal cancer cells sensitive to cetuximab were treated until resistant derivatives emerged. Mutational profiling of biopsies and cell lines was performed. Structural modeling and functional analyses were performed to causally associate the alleles to resistance. Results: The genetic profile of tumor specimens obtained after cetuximab treatment revealed the emergence of a complex pattern of mutations in EGFR, KRAS, NRAS, BRAF, and PIK3CA genes, including two novel EGFR ectodomain mutations (R451C and K467T). Mutational profiling of cetuximab-resistant cells recapitulated the molecular landscape observed in clinical samples and revealed three additional EGFR alleles: S464L, G465R, and I491M. Structurally, these mutations are located in the cetuximab-binding region, except for the R451C mutant. Functionally, EGFR ectodomain mutations prevent binding to cetuximab but a subset is permissive for interaction with panitumumab. Conclusions: Colorectal tumors evade EGFR blockade by constitutive activation of downstream signaling effectors and through mutations affecting receptor–antibody binding. Both mechanisms of resistance may occur concomitantly. Our data have implications for designing additional lines of therapy for patients with colorectal cancer who relapse upon treatment with anti-EGFR antibodies. Clin Cancer Res; 21(9); 2157–66. ©2015 AACR.
Phase III Clinical Trial Development: A Process of Chutes and Ladders
Authors: David M. Dilts, Steven K. Cheng, Joshua S. Crites, Alan B. Sandler, James H. Doroshow
Journal: Clinical Cancer Research (2010)

The Institute of Medicine report on cooperative groups and the National Cancer Institute (NCI) report from the Operational Efficiency Working Group both recommend changes to the processes for opening a clinical trial. This article provides evidence for the need for such changes by completing the first comprehensive review of all the time and steps required to open a phase III oncology clinical trial and discusses the effect of time to protocol activation on subject accrual.The Dilts and Sandler method was used at four cancer centers, two cooperative groups, and the NCI Cancer Therapy Evaluation Program. Accrual data were also collected.Opening a phase III cooperative group therapeutic trial requires 769 steps, 36 approvals, and a median of approximately 2.5 years from formal concept review to study opening. Time to activation at one group ranged from 435 to 1,604 days, and time to open at one cancer center ranged from 21 to 836 days. At centers, group trials are significantly more likely to have zero accruals (38.8%) than nongroup trials (20.6%; P < 0.0001). Of the closed NCI Cancer Therapy Evaluation Program-approved phase III clinical trials from 2000 to 2007, 39.1% resulted in <21 accruals.The length, variability, and low accrual results demonstrate the need for the NCI clinical trials system to be reengineered. Improvements will be of only limited effectiveness if done in isolation; there is a need to return to the collaborative spirit with all parties creating an efficient and effective system. Recommendations put forth by the Institute of Medicine and Operational Efficiency Working Group reports, if implemented, will aid this renewal.
Why do we have Apocrine and Sebaceous Glands?
Authors: Alan M W Porter
Journal: Journal of the Royal Society of Medicine (2001)

The secretions of sebaceous and apocrine glands fulfil an important thermoregulatory role in cold-stressed and heat-stressed hunter-gatherers. In hot conditions the secretions emulsify eccrine sweat and thus encourage the formation of a sweat sheet and discourage the formation and loss of sweat drops from the skin. In colder conditions sebum changes its nature and repels rain from skin and hair.
Is Cigarette Smoking Associated With Suicidal Ideation Among Young People?
Authors: Rob McGee, Sheila Williams, Shyamala Nada-Raja
Journal: American Journal of Psychiatry (2005)

The authors examined the association between suicidal ideation in early adulthood and daily tobacco smoking in a community sample of adolescents.Participants were enrolled in a longitudinal study of health and development. The factors of disadvantage, impulsiveness, stress, depressed mood, tobacco smoking, other substance use, and parental attachment were included in multivariate modelling of suicidal ideation.Data on tobacco use were available for 764 participants. Early tobacco smoking was significantly predictive of later suicidal ideation, but there was no longer a significant relationship when high levels of stress and depression and low levels of parental attachment in adolescence were included in the multivariate model.Tobacco smoking in adolescence does not appear to elevate the risk of later suicidal ideation.
Optimization of rituximab for the treatment of DLBCL (I): dose-dense rituximab in the DENSE-R-CHOP-14 trial of the DSHNHL
Authors: N. Murawski, M. Pfreundschuh, S. Zeynalova, V. Poeschel, M. Hänel, G. Held, N. Schmitz, A. Viardot, C. Schmidt, M. Hallek, M. Witzens-Harig, L. Trümper, T. Rixecker, C. Zwick
Journal: Annals of Oncology (2014)
Placental Growth Factor Upregulation Is a Host Response to Antiangiogenic Therapy
Authors: Rebecca G. Bagley, Yi Ren, William Weber, Min Yao, Leslie Kurtzberg, Jason Pinckney, Dinesh Bangari, Cokey Nguyen, William Brondyk, Johanne Kaplan, Beverly A. Teicher
Journal: Clinical Cancer Research (2011)

Placental growth factor (PlGF) is an angiogenic protein. Upregulation of PlGF has been observed in the clinic following antiangiogenic regimens targeting the VEGF pathway. PlGF has been proposed as a therapeutic target for oncology. sFLT01 is a novel fusion protein that neutralizes mouse and human PlGF (mPlGF, hPlGF) and mouse and human VEGF-A (mVEGF-A, hVEGF-A). It was tested in syngeneic and xenograft tumor models to evaluate the effects of simultaneously neutralizing PlGF and VEGF-A and to investigate changes observed in the clinic in preclinical models.Production of PlGF and VEGF-A by B16F10 and A673 cancer cells in vitro was assessed. Mice with subcutaneous B16F10 melanoma or A673 sarcoma tumors were treated with sFLT01. Tumor volumes and microvessel density (MVD) were measured to assess efficacy. Serum levels of hVEGF-A, hPlGF, and mPlGF at early and late time points were determined by ELISA.Exposure of cancer cell lines to sFLT01 caused a decrease in VEGF secretion. sFLT01 inhibited tumor growth, prolonged survival, and decreased MVD. Analysis of serum collected from treated mice showed that sFLT01 administration caused a marked increase in circulating mPlGF but not hPlGF or hVEGF. sFLT01 treatment also increased circulating mPlGF levels in non-tumor-bearing mice.With the tumor cell lines and mouse models we used, antiangiogenic therapies that target both PlGF and VEGF may elicit a host response rather than, or in addition to, a malignant cell response that contribute to therapeutic resistance and tumor escape as suggested by others.
Aldosterone Requires Vasopressin V1a Receptors on Intercalated Cells to Mediate Acid-Base Homeostasis
Authors: Yuichiro Izumi, Kahori Hori, Yushi Nakayama, Miho Kimura, Yukiko Hasuike, Masayoshi Nanami, Yukimasa Kohda, Yoshinaga Otaki, Takahiro Kuragano, Masuo Obinata, Katsumasa Kawahara, Akito Tanoue, Kimio Tomita, Takeshi Nakanishi, Hiroshi Nonoguchi
Journal: Journal of the American Society of Nephrology (2011)

Both aldosterone and luminal vasopressin may contribute to the maintenance of acid-base homeostasis, but the functional relationship between these hormones is not well understood. The effects of luminal vasopressin likely result from its interaction with V1a receptors on the luminal membranes of intercalated cells in the collecting duct. Here, we found that mice lacking the V1a receptor exhibit type 4 renal tubular acidosis. The administration of the mineralocorticoid agonist fludrocortisone ameliorated the acidosis by restoring excretion of urinary ammonium via increased expression of Rhcg and H-K-ATPase and decreased expression of H-ATPase. In a cell line of intercalated cells established from transgenic rats expressing the mineralocorticoid and V1a receptors, but not V2 receptors, knockdown of the V1a receptor gene abrogated the effects of aldosterone on H-K-ATPase, Rhcg, and H-ATPase expression. These data suggest that defects in the vasopressin V1a receptor in intercalated cells can cause type 4 renal tubular acidosis and that the tubular effects of aldosterone depend on a functional V1a receptor in the intercalated cells.
High Incidence of Cetuximab-Related Infusion Reactions in Tennessee and North Carolina and the Association With Atopic History
Authors: Bert H. O'Neil, Robert Allen, David R. Spigel, Thomas E. Stinchcombe, Dominic T. Moore, Jordan D. Berlin, Richard M. Goldberg
Journal: Journal of Clinical Oncology (2007)

To confirm the anecdotal observation that patients in North Carolina (NC) and Tennessee (TN) treated with cetuximab experience hypersensitivity reactions (HSR) at a much higher rate than are reported nationally and internationally (<or= 3%).Data from patients treated with cetuximab on clinical trials (n = 88) at three research sites were analyzed for grade 3 or 4 HSR. Additional information was obtained from medical records for patients treated with cetuximab at the University of North Carolina (Chapel Hill, NC) to determine whether history of other significant allergy was a risk factor for HSR to cetuximab.Data for 88 patients on clinical trials and an additional 55 patients treated outside of trials were included in this analysis. Patients had a variety of tumor types. For the clinical trial group (n = 88), the overall rate of grade 3 to 4 HSR was 22%, significantly higher than the rate noted in any large published trial. All HSRs occurred during the first dose. There was a strong relationship between prior allergy history and chance of HSR.At the sites in neighboring NC and TN studied, HSR was far more common than reported in national studies. History of prior allergy is a strong predictor of HSR. Further investigation of more specific predictors of HSR in the US middle south region is warranted, and patients being treated with cetuximab in this area should be observed particularly closely during their first infusion.
CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling
Authors: Feng Jiang, Lei Chen, Ying-Cheng Yang, Xian-ming Wang, Ruo-Yu Wang, Liang Li, Wen Wen, Yan-Xin Chang, Cai-Yang Chen, Jing Tang, Gao-Mi-Yang Liu, Wen-Tao Huang, Lin Xu, Hong-Yang Wang
Journal: Cancer Research (2015)

Abstract CYP3A5 is a cytochrome P450 protein that functions in the liver metabolism of many carcinogens and cancer drugs. However, it has not been thought to directly affect cancer progression. In this study, we challenge this perspective by demonstrating that CYP3A5 is downregulated in many hepatocellular carcinomas (HCC), where it has an important role as a tumor suppressor that antagonizes the malignant phenotype. CYP3A5 was downregulated in multiple cohorts of human HCC examined. Lower CYP3A5 levels were associated with more aggressive vascular invasion, poor differentiation, shorter time to disease recurrence after treatment, and worse overall patient survival. Mechanistic investigations showed that CYP3A5 overexpression limited MMP2/9 function and suppressed HCC migration and invasion in vitro and in vivo by inhibiting AKT signaling. Notably, AKT phosphorylation at Ser473 was inhibited in CYP3A5-overexpressing HCC cells, an event requiring mTORC2 but not Rictor/mTOR complex formation. CYP3A5-induced ROS accumulation was found to be a critical upstream regulator of mTORC2 activity, consistent with evidence of reduced GSH redox activity in most clinical HCC specimens with reduced metastatic capacity. Taken together, our results defined CYP3A5 as a suppressor of HCC pathogenesis and metastasis with potential utility a prognostic biomarker. Cancer Res; 75(7); 1470–81. ©2015 AACR.
Loss of PTEN Expression Is Associated with Poor Prognosis in Patients with Intraductal Papillary Mucinous Neoplasms of the Pancreas
Authors: Dario Garcia-Carracedo, Andrew T. Turk, Stuart A. Fine, Nathan Akhavan, Benjamin C. Tweel, Ramon Parsons, John A. Chabot, John D. Allendorf, Jeanine M. Genkinger, Helen E. Remotti, Gloria H. Su
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Previously, we reported PIK3CA gene mutations in high-grade intraductal papillary mucinous neoplasms (IPMN). However, the contribution of phosphatidylinositol-3 kinase pathway (PI3K) dysregulation to pancreatic carcinogenesis is not fully understood and its prognostic value unknown. We investigated the dysregulation of the PI3K signaling pathway in IPMN and its clinical implication. Experimental Design: Thirty-six IPMN specimens were examined by novel mutant-enriched sequencing methods for hot-spot mutations in the PIK3CA and AKT1 genes. PIK3CA and AKT1 gene amplifications and loss of heterozygosity at the PTEN locus were also evaluated. In addition, the expression levels of PDPK1/PDK1, PTEN, and Ki67 were analyzed by immunohistochemistry. Results: Three cases carrying the E17K mutation in the AKT1 gene and one case harboring the H1047R mutation in the PIK3CA gene were detected among the 36 cases. PDK1 was significantly overexpressed in the high-grade IPMN versus low-grade IPMN (P = 0.034) and in pancreatic and intestinal-type of IPMN versus gastric-type of IPMN (P = 0.020). Loss of PTEN expression was strongly associated with presence of invasive carcinoma and poor survival in these IPMN patients (P = 0.014). Conclusion: This is the first report of AKT1 mutations in IPMN. Our data indicate that oncogenic activation of the PI3K pathway can contribute to the progression of IPMN, in particular loss of PTEN expression. This finding suggests the potential employment of PI3K pathway-targeted therapies for IPMN patients. The incorporation of PTEN expression status in making surgical decisions may also benefit IPMN patients and should warrant further investigation. Clin Cancer Res; 19(24); 6830–41. ©2013 AACR.
SODIUM AND THE RENIN-ANGIOTENSIN SYSTEM IN ESSENTIAL HYPERTENSION AND MINERALOCORTICOID EXCESS
Authors: M. Lebel, J.J. Brown, D. Kremer, J.I.S. Robertsc, M.A. Schalekamp, D.L. Davies, A.F. Lever, N.M. Tree, D.G. Beevers, R. Fraser, J.J. Morton, A. Wilson
Journal: The Lancet (1974)
Sequential Immunogene Therapy with Interleukin-12– and Interleukin-15–Engineered Neuroblastoma Cells Cures Metastatic Disease in Syngeneic Mice
Authors: Michela Croce, Raffaella Meazza, Anna Maria Orengo, Luana Radic', Barbara De Giovanni, Claudio Gambini, Barbara Carlini, Vito Pistoia, Lorenzo Mortara, Roberto S. Accolla, Maria Valeria Corrias, Silvano Ferrini
Journal: Clinical Cancer Research (2005)

To investigate the potential synergistic effects of Neuro2a neuroblastoma cells engineered with IL-12 and/or IL-15 genes in improving survival of syngeneic mice bearing neuroblastoma metastatic disease.Neuro2a cells engineered with interleukin (IL)-12 (Neuro2a/IL-12), IL-15 (Neuro2a/IL-15), or both cytokines (Neuro2a/IL-12/IL-15) were injected s.c. in syngeneic A/J mice challenged i.v. with Neuro2a parental cells (Neuro2apc) using different schedules of administration in either preventive or therapeutic settings.A single injection of Neuro2a/IL-12 or Neuro2a/IL-15 cells induced resistance to a subsequent i.v. Neuro2apc challenge in 45% and 28% of mice, respectively. Neuro2a/IL-12/IL-15 cells protected 28% of mice, showing no synergistic effect. However, sequential vaccination with Neuro2a/IL-12 (day -30) followed by Neuro2a/IL-15 (day -15) protected 71% of mice from subsequent challenge with Neuro2apc. A single dose of Neuro2a/IL-12 prolonged the mean survival time of mice bearing established metastatic neuroblastoma from 21 +/- 3 to 46 +/- 27 days but failed to cure mice, whereas Neuro2a/IL-15 or Neuro2a/IL-12/IL-15 were ineffective. However, sequential vaccination with Neuro2a/IL-12 (day +3) followed by Neuro2a/IL-15 (day +13) cured 43% of mice as assessed by histologic analysis of different organs from long-term surviving mice. CTL activity against Neuro2apc cells was observed in splenocytes from treated mice, and CD8(+) T-cell depletion abrogated the therapeutic effect of vaccination.Sequential vaccination with IL-12- and IL-15-engineered neuroblastoma cells induced optimal preventive and therapeutic effects, which may be related to the Th1 priming effect of IL-12 followed by the enhancement of CD8(+) T-cell responses and their maintenance mediated by IL-15.
Abstract MP90: Carotid Arterial Stiffness is Associated with An Increased Risk of Incident Cerebral Microbleeds in Older People: the Age, Gene/Environment Susceptibility-Reykjavik Study
Authors: Jie Ding, Michiel L Bots, Sigurdur Sigurdsson, Melissa Garcia, Tamara B Harris, Gudny Eiriksdottir, Mark A van Buchem, Vilmundur Gudnason, Lenore J Launer
Journal: Circulation (2015)

Introduction: Cerebral microbleeds (CMBs) resulting from cerebral amyloid angiopathy are predominantly located in lobar regions, whereas those from hypertension are in deep and infratentorial regions. Although age and high blood pressure are major risk factors for CMBs, the underlying mechanisms remain unclear; arterial stiffness may be important. Hypothesis: We hypothesized that carotid arterial stiffness, would be associated with incident CMBs. Given the spatial distributions of the underlying arteriopathies in which hypertensive arteriopathy typically affects the small perforating end-arteries of the deep structures, we further hypothesized that the associations would be more robust for deep CMBs attributed to hypertensive arteriopathy. Methods: In the prospective, population-based Age, Gene/Environment Susceptibility-Reykjavik Study, 2,512 participants aged 66-97 years underwent a baseline brain MRI examination and carotid ultrasound in 2002-2006, and returned for a repeat brain MRI in 2007-2011. Common carotid arterial stiffness was assessed using a standardized protocol and expressed as carotid arterial strain (CAS), distensibility coefficient (DC) and Young’s elastic modulus (YEM). Log-binomial regression was applied to relate carotid arterial stiffness parameters to CMBs incidence. Results: During a mean follow-up of 5.2 years, 463 people (18.4%) developed new CMBs, of whom 292 had CMBs restricted to lobar regions and 171 had CMBs in a deep or infratentorial region. After adjusting for age, sex and brain MRI interval, all arterial stiffness parameters were each significantly associated with incident CMBs (Risk ratio [RR] per SD decrease in CAS, 1.11 [95%CI, 1.02-1.21]; RR per SD decrease in natural log-transformed DC, 1.14[1.05-1.23]; RR per SD decrease in natural log-transformed YEM, 1.13[1.04-1.22]) and deep CMBs (RR, 1.17[1.00-1.36]; 1.24[1.07-1.43]; 1.22[1.06-1.41] respectively) but not with lobar CMBs. When further adjusted for baseline vascular risk factors including blood pressure and use of blood pressure lowering drugs, the presence of carotid plaque, prevalent CMBs, subcortical infarcts and white matter hyperintensities, the associations persisted. Conclusion: Our findings support the hypothesis that localized increases in carotid arterial stiffness may contribute to the development of CMBs, especially those occuring in a deep location.
Determinants of HIV-1 shedding in the genital tract of women
Authors: Andrea Kovacs, Steven S Wasserman, David Burns, David J Wright, Jonathan Cohn, Alan Landay, Kathleen Weber, Mardge Cohen, Alexandra Levine, Howard Minkoff, Paolo Miotti, Joel Palefsky, Mary Young, Patricia Reichelderfer
Journal: The Lancet (2001)
Truncated CXCL10 is associated with failure to achieve spontaneous clearance of acute hepatitis C infection
Authors: Antonio Riva, Melissa Laird, Armanda Casrouge, Arvydas Ambrozaitis, Roger Williams, Nikolai V. Naoumov, Matthew L. Albert, Shilpa Chokshi
Journal: Hepatology (2014)

The pathogenesis of hepatitis C virus (HCV) infection is strongly influenced by the nature of the host's antiviral immunity. Counterintuitively, elevated serum concentrations of C-X-C chemokine 10 (CXCL10), a potent chemoattractant for antiviral T-cells and NK-cells, are associated with poor treatment outcomes in patients with chronic HCV. It has been reported that an N-terminal truncated form of CXCL10, generated by the protease dipeptidylpeptidase 4 (DPP4), can act as chemokine antagonist. We sought to investigate CXCL10 antagonism in the clinical outcome and evolution of acute HCV infection. We collected serial blood samples from 16 patients, at the clinical onset of acute HCV infection and at 12 standardized follow-up timepoints over the first year. Intact and truncated CXCL10 and DPP4 activity were quantified in all longitudinal samples. In addition, NK-cell frequency/phenotype, and HCV-specific T-cell responses were assessed. Subjects developing chronicity (n = 11) had higher concentrations of CXCL10 ( P &lt; 0.001), which was predominantly in a truncated form ( P = 0.036) compared to patients who spontaneously resolved infection (n = 5). Truncated CXCL10 correlated with HCV-RNA ( r = 0.40, P &lt; 0.001) and DPP4 activity ( r = 0.53, P &lt; 0.001). Subjects who resolved infection had a higher frequency of HCV-specific interferon-gamma (IFNγ)-producing T-cells ( P = 0.017) and predominance of cytotoxic NK-cells ( P = 0.005) compared to patients who became chronic. Patients who became persistently infected had higher proportions of cytokine-producing NK-cells, which were correlated with concentrations of truncated CXCL10 ( r = 0.92, P &lt; 0.001). Conclusion : This study provides the first evidence of chemokine antagonism during acute HCV infection. We suggest that the DPP4-CXCL10 axis inhibits antiviral innate and adaptive host immunity and favors establishment of viral persistence. (Hepatology 2014;60:487–496)
Independent Prognostic Value of the 67-kd Laminin Receptor in Human Prostate Cancer
Authors: David Waltregny, Laurence de Leval, Sylvie Ménard, Jean de Leval, Vincent Castronovo
Journal: JNCI Journal of the National Cancer Institute (1997)

Widespread screening for early detection of prostate cancer has resulted in a dramatic rise in the proportion of clinically silent prostate malignant lesions (1‐5).To date, no reliable predictors of the risk for such lesions to progress are available. Therefore, the urologist faces the therapeutic dilemma of whether to perform a radical treatment (prostatectomy or external radiotherapy) with the knowledge that some patients will have treatment complications with uncertain survival benefit or to carefully watch this group of patients with the known risk that some will experience the morbidity of clinically overt disease. Furthermore, for many patients, the extent of their prostate carcinoma is underevaluated and unpredictable, which results in inadequate therapeutic strategies (6‐9).