tbuckley/cabot-search huggingface dataset:
High frequency of submicroscopic hemizygous deletion and loss of expression of PTEN in uveal melanoma is associated with more aggressive tumors
Authors: Mohamed H. Abdel-Rahman, Ying Yang, Elson Craig, Frederick H. Davidorf, Charis Eng
Journal: Cancer Research (2005)

1676  PTEN is a tumor suppressor gene located at 10q 23.3 that encodes a dual specificity phosphatase with lipid and protein phosphatase activity. It has been shown to play an important role in the pathogenesis of a variety of human cancers. Germline mutations in PTEN cause Cowden syndrome (CS), which is characterized by multiple hamartomas and a high risk of breast and thyroid cancers. Frequent loss of heterozygosity at 10q is found in both early and advanced stage sporadic cutaneous melanomas; however, there are no available reports on the frequency of PTEN loss in uveal melanomas. In this study, we examined PTEN expression using immunohistochemistry in 68 unselected sporadic primary uveal melanomas with an average follow up of about 100 months. Expression of PTEN mRNA was also assessed by quantitative reverse transcription PCR (QRT-PCR) in 10 tumors with available fresh frozen tissue. Molecular cytogenetic alterations were studied in 13 tumors using comparative genomic hybridization (CGH). Genotyping was carried out using the nearest microsatellite markers, D10S1765 and D10S541, to the centromeric and telomeric ends of PTEN respectively. Immunostaining revealed no PTEN expression in 22/64 (34%) and low PTEN expression in 26/64 (41%), whereas the rest of the tumors, 16/64 (16%), had high levels of expression. Protein expression correlated with the mRNA expression in the 10 samples with available data on both. Using CGH, only 1/13 (8%) samples showed gross loss of 10q. However, in the 33 tumors with informative genotyping of at least one marker, 27 (81%) showed loss of heterozygosity (LOH) of either one or both markers. Our CGH results correlated with published literature on the low frequency of cytogenetic and molecular cytogenetic loss of chromosome 10q in uveal melanoma. Total loss of PTEN expression, but not decrease in expression, was associated with a decrease in the patients’ survival (p=0.035). Our study is the first to show involvement of PTEN in uveal melanoma tumorogenesis. These results strongly support PTEN as a major tumor suppressor involved in uveal melanoma pathogenesis. Our data also suggest that submicroscopic deletion, but not large deletion, is the major mechanism of loss of PTEN in uveal melanoma. Further, complete PTEN null status, most likely by submicroscopic deletion and epigenetic silencing, may be associated with adverse outcome
Infectious Complications of Daratumumab-Containing Therapy for Multiple Myeloma
Authors: Andrew Johnsrud, Sandra Susanibar, Jorge Jo Kamimoto, Joyce Johnsrud, Atul Kothari, Mary Burgess, Carolina D. Schinke, Sharmilan Thanendrarajan, Maurizio Zangari, Faith E Davies, Gareth J. Morgan, Frits Van Rhee, Juan Carlos Rico Crescencio
Journal: Blood (2017)
<i>In Vivo</i> Modeling of Chemoresistant Neuroblastoma Provides New Insights into Chemorefractory Disease and Metastasis
Authors: Orli Yogev, Gilberto S. Almeida, Karen T. Barker, Sally L. George, Colin Kwok, James Campbell, Magdalena Zarowiecki, Dimitrios Kleftogiannis, Laura M. Smith, Albert Hallsworth, Philip Berry, Till Möcklinghoff, Hannah T. Webber, Laura S. Danielson, Bliss Buttery, Elizabeth A. Calton, Barbara M. da Costa, Evon Poon, Yann Jamin, Stefano Lise, Gareth J. Veal, Neil Sebire, Simon P. Robinson, John Anderson, Louis Chesler
Journal: Cancer Research (2019)

Neuroblastoma is a pediatric cancer that is frequently metastatic and resistant to conventional treatment. In part, a lack of natively metastatic, chemoresistant
The importance of raiding ecology and sex differences in offensive and defensive warfare
Authors: Anthony C. Lopez
Journal: Behavioral and Brain Sciences (2019)

Abstract De Dreu and Gross offer a compelling synthesis of a growing literature on the psychology of attack and defense. I argue that human raiding ecology suggests the need to endogenize attacker-defender move order as well as opportunities for tactical mismatch available to defenders. Perhaps most significantly, I draw attention to the surprising lacunae in sex differences across attack and defense.
Activating mutation in B-RAF disables normal feedback inhibition of MEK and results in increased output of the RAF/MEK/MAPK signaling pathway.
Authors: Christine Pratilas, Barry Taylor, Sven Nelander, Olivera Grbovic-Huezo, Agnes Viale, David Solit, Chris Sander, Neal Rosen
Journal: Cancer Research (2007)

434  The RAF/MEK/MAPK pathway is activated in tumor cells with BRAF mutation and in those with receptor tyrosine kinase (RTK) activation, but only the former are sensitive to inhibition of proliferation by MEK inhibitors. Consensus in vitro and in vivo transcriptional array analysis showed that an 18-gene profile was significantly deregulated in response to MEK inhibition in a panel of tumor cells harboring B-RAF mutation. No such gene signature was identified in a group of tumor cells resistant to MEK inhibition, in which MAPK activation is due to RTK activation. These data suggest that the transcriptional output of the MAPK pathway is selectively elevated in tumors with BRAF mutation, compared to those with RTK activation. In mutant BRAF tumors, the output was comprised of RNAs that encode transcription factors (ETS and FOS family members, MYC, IER3) and proteins involved in the feedback regulation of MAPK signaling, including members of the Sprouty and DUSP families, which are significantly overexpressed. Levels of phosphorylated MAPK are equivalent in tumor cells with mutant BRAF or RTK activation, in contrast to phosphorylated MEK levels, which are only elevated in BRAF mutant cells. Thus in tumor cells, P-MEK, rather than P-MAPK, correlates with elevated MAPK output and with their sensitivity to MEK inhibition. These results suggest that, in mutant BRAF tumor cells, resistance to normal feedback inhibition of RAF activation is associated with increased transcriptional output of the pathway, resulting in increased expression of MAPK phosphatases and elevated P-MEK/P-MAPK ratios. Consistent with this idea, MEK inhibition alleviates feedback inhibition of P-MEK in tumors with RTK activation, but does not further induce P-MEK in tumors with mutant B-RAF.
Predictive factors associated with clinical outcome and safety in Korean patients with metastatic renal cell carcinoma treated with sunitinib
Authors: M. Hong, H. Jeung, H. Chung, J. Ahn, J. Roh, S. Noh, S. Rha
Journal: Journal of Clinical Oncology (2009)

e16111 Background: Sunitinib has become a standard treatment for metastatic renal cell carcinoma (RCC). The research for identifying patients who are more likely to benefit from this agent is quite limited, especially in Asian patients. Methods: In total, 81 histologically proven metastatic RCC patients who were treated with sunitinib were reviewed between Jan 2006 and Dec 2008. Tumor response was evaluated according to the RECIST criteria, and safety was assessed by NCI-CTC (version 3.0). Primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR), and toxicities. Clinical features associated with clinical outcome were identified by univariate analysis; then, a stepwise modeling approach based on Cox's proportional hazards regression was used to identify independent prognostic factors to these endpoints. Results: Median age was 58 years (range, 29 to 73), and 33 patients received sunitinib as first-line systemic treatment. Clear cell type was predominant (85%). Patient distribution was 12% for favorable, 78% for intermediate, and 10% for poor group according to the MSKCC risk group. With the median follow-up of 26 months, median PFS was 16 months (95% CI, 8 –24) and median OS was 24 months (95% CI, 18 –30). ORR was 30% (95% CI, 19–40%) and DCR was 80% (95% CI, 70–89%). The most common grade 3/4 adverse events of sunitinib was thrombocytopenia (32%). Other severe toxicity included neutropenia (21%), anemia (19%), leucopenia (14%), fatigue (10%), stomatitis (10%). In multivariate analysis, the previous exposure to immunotherapy was related to longer PFS (P&lt;.012). Performance status (ECOG 0–1) and corrected Ca level (8.5∼10.5 mg/dl) were associated with favorable ORR (P=.038) and DCR (p=0.008), respectively. Predictive factors for grade 3/4 thrombocytopenia were corrected Ca level (P=.018), poor MSKCC risk group (P=.025), and low WBC count (&lt;4500/ul, P=.041). Conclusions: Compared to western reports, our data demonstrated comparable clinical efficacy in Asian patients, but different safety profile, especially in hematologic toxicities. This approach provides a tailored approach to predictive factors for targeted agents. No significant financial relationships to disclose.
Fluorinated derivatives of N-acetylaspartylglutamate (NAAG) as substrates of prostate specific membrane antigen (PSMA)
Authors: Xinning Wang, Warren Heston, Haibin Tian, Zhenghong Lee
Journal: Cancer Research (2008)

3180  Prostate specific membrane antigen (PSMA) is a type II integral membrane protein. In healthy subjects, PSMA expression is highly prostate specific and its expression is upregulated in poorly differentiated and advanced prostate cancers. Furthermore, PSMA is also expressed on the tumor vascular endothelium of virtually all solid carcinomas and sarcomas, but not on normal vascular endothelium. Therefore, PSMA is a potentially useful target for diagnosis and therapy across a wide spectrum of solid tumors. We are interested in developing low molecular weight ligands against PSMA as imaging agents since antibodies present problems such as limited diffusion into the tumor and non-specific binding in the liver. PSMA is also a hydrolytic enzyme with hydrolytic activity against polygammaglutamated folates, and N-acetylaspartylglutamate (NAAG). It is well recognized that replacing a hydrogen atom by fluorine atom in a chemical entity can bring significant changes in its chemical and biochemical behavior due to its strong electron withdrawing effect. Therefore, we proposed to develop fluorinated derivatives of PSMA substrate aspartylglutamate/NAAG that can be taken up by the tumor cells’ amino acid transporters to provide information about tumor metabolic activity and PSMA protein density. The fluorine containing amino acids 1-4 was synthesized in a manner whereby either N-tert-butoxycarbonyl-aspartic acid-β-benzyl ester [Boc-Asp(OBzl)-OH] or N-tert-butoxycarbonyl-α-fluoro-aspartic acid-β-benzyl ester [Boc-F-Asp(OBzL)-OH] was coupled by the mixed anhydride method with either γ-fluoro-glutamic acid dibenzyl ester [F-Glu(OBzl)-OBzl] or glutamic acid dibenzyl ester [Glu(OBzl)-OBzl] followed by deprotection of the N-tert-butoxycarbonyl (Boc) group and O-Benzyloxyl (OBzl) group. Both the N-acetylated version and the non-acetylated version were made because there has been a discrepancy in the literature as to the Km for the non-acetylated version with two reports having it at 20 nanomolar and one report at 500 nanomolar. Currently we are testing if these fluorinated aspartylglutamate analogues have good binding affinity to PSMA and if they can be take up the tumor cells. Once these properties have been confirmed, we will synthesize F-18 radiolabelled compounds for future positron emission tomography (PET) imaging studies. Financial Support: DOD New Idea Award PC060746.
NSAIDs-induced upper gastrointestinal bleeding in hepatitis B virus-positive patient with acute kidney injury – nonocclusive mesenteric ischemia
Authors: Andrea Lisotti, Sinan Sadalla, Anna Cominardi, Pietro Fusaroli
Journal: Endoscopy (2019)

An 81-year-old woman was admitted to the intensive care unit with pneumonia complicated by acute kidney injury. Her medical history included arterial hypertension and chronic hepatitis B virus infection. The patient was on dual antiplatelet therapy because of recent myocardial infarction. Antibiotic treatment and continuous renal replacement therapy were started.
Disparity of Race Reporting and Representation in Clinical Trials Leading to Cancer Drug Approvals From 2008 to 2018
Authors: Jonathan M. Loree, Seerat Anand, Arvind Dasari, Joseph M. Unger, Anirudh Gothwal, Lee M. Ellis, Gauri Varadhachary, Scott Kopetz, Michael J. Overman, Kanwal Raghav
Journal: JAMA Oncology (2019)

Representative racial/ethnic participation in research, especially in clinical trials that establish standards of care, is necessary to minimize disparities in outcomes and to uphold societal equity in health care.To evaluate the frequency of race reporting and proportional race representation in trials supporting US Food and Drug Administration (FDA) oncology drug approvals.Database study of all reported trials supporting FDA oncology drug approvals granted between July 2008 and June 2018. Primary reports of trials were obtained from PubMed and ClinicalTrials.gov. Food and Drug Administration approvals were identified using the FDA archives. The US population-based cancer estimates by race were calculated using National Cancer Institute-Surveillance, Epidemiology, and End Results and US Census databases.Primary outcomes were the proportion of trials reporting race and the proportion of patients by race participating in trials. Secondary outcomes included race subgroup analyses reporting and gaps between race proportion in trials and the US population. Descriptive statistics, Fisher exact, and χ2 tests were used to analyze the data. Proportions and odds ratios (OR) with 95% CIs were reported.Among 230 trials with a total of 112 293 participants, 145 (63.0%) reported on at least 1 race, 18 (7.8%) documented the 4 major races in the United States (white, Asian, black, and Hispanic), and 58 (25.2%) reported race subgroup analyses. Reporting on white, Asian, black, and Hispanic races was included in 144 (62.6%), 110 (47.8%), 88 (38.2%), and 23 (10.0%) trials, respectively. Between July 2008 and June 2013 vs July 2013 and June 2018, the number of trials reporting race (45 [56.6%] vs 100 [67.1%]; OR, 1.63; 95% CI, 0.93-2.87; P = .09) and race subgroup analysis (13 [16.1%] vs 45 [30.2%]; OR, 2.26, 95% CI, 1.16-4.67; P = .03) changed minimally and varied across races. Whites, Asians, blacks, and Hispanics represented 76.3%, 18.3%, 3.1% and 6.1% of trial participants, respectively, and the proportion for each race enrolled over time changed nominally (blacks, 3.6% vs 2.9% and Hispanics, 5.3% vs 6.7%) from July 2008 to June 2013 vs July 2013 to June 2018. Compared with their proportion of US cancer incidence, blacks (22% of expected) and Hispanics (44% of expected) were underrepresented compared with whites (98% of expected) and Asians (438% of expected).Race and race subgroup analysis reporting occurs infrequently, and black and Hispanic races are consistently underrepresented compared with their burden of cancer incidence in landmark trials that led to FDA oncology drug approvals. Enhanced minority engagement is needed in trials to ensure the validity of results and reliable benefits to all.
WHO grade has no prognostic value in the pediatric high-grade glioma included in the HERBY trial
Authors: Pascale Varlet, Gwénaël Le Teuff, Marie-Cécile Le Deley, Felice Giangaspero, Christine Haberler, Thomas S Jacques, Dominique Figarella-Branger, Torsten Pietsch, Felipe Andreiuolo, Christophe Deroulers, Tim Jaspan, Chris Jones, Jacques Grill
Journal: Neuro-Oncology (2019)

Abstract Background The World Health Organization (WHO) adult glioma grading system is questionable in pediatric high-grade gliomas (pHGGs), which are biologically distinct from adult HGGs. We took advantage of the neuropathological review data obtained during one of the largest prospective randomized pHGG trials, namely HERBY (NCT01390948), to address this issue in children with newly diagnosed non-brainstem HGG. Methods HGG diagnosis was confirmed by pre-randomization, real-time central pathology review using WHO 2007 criteria, followed by a consensus review blinded to clinical factors and outcomes. We evaluated association between WHO 2007 grade and other clinical/radiological/biological characteristics and the prognostic value of WHO 2007 grade, midline location, and selected biomarkers (Ki-67 index/Olig2/CD34/EGFR/p53/H3F3A K27M mutation) on overall survival. Results Real-time central neuropathological review was feasible in a multicenter study, with a mean time of 2.4 days, and led to the rejection of HGG diagnosis in 20 of 163 cases (12.3%). The different grading criteria and resulting WHO grade were not significantly associated with overall survival in the entire population (n = 118) or in midline and non-midline subgroups. H3F3A K27M mutation was significantly associated with poor outcome. No significant prognostic value was observed for grade, even after regrading H3F3A K27M-mutated midline glioma as grade IV (WHO 2016). Midline location and a high Ki-67 index (≥20%) were associated with poor outcome (P = 0.004 and P = 0.04, respectively). A 10% increase in Ki-67 index was associated with a hazard ratio of 1.53 (95% CI: 1.27–1.83; P &amp;lt; 0.0001). Conclusion Our findings suggest that WHO grade III versus IV has no prognostic value in pediatric HGG.
Gene targeting using recombinant adeno-associated viruses: A novel strategy for functional analysis of the BRCT domain of BARD1
Authors: Gandhi Devangini, Hong Xu, Richard Baer
Journal: Cancer Research (2007)

1109  Recent studies suggest that BRCA1, a tumor suppressor implicated in hereditary breast and ovarian cancer, promotes genome integrity by participating in DNA repair processes and cell cycle checkpoint pathways. BRCA1 contains two recognizable motifs: an N-terminal RING domain that mediates E3 ligase activity and two C-terminal BRCT domains that form a surface for phosphoprotein recognition. While most cancer-associated BRCA1 mutations lead to gross truncations of its reading frame, missense mutations in the BRCT motif can also predispose carriers to breast and/or ovarian carcinomas. Indeed, some of these mutations abrogate the interaction of BRCA1 with phospho-dependent binding partners (e.g., BACH1 and CtIP) necessary for BRCA1-mediated checkpoint functions. In vivo, BRCA1 exists as a heterodimer with BARD1, a structurally related protein that also contains an N-terminal RING domain, and two C-terminal copies of the BRCT domain. Recent studies have identified tumor-associated missense mutations in the BRCT domains of BARD1 in patients with breast, ovarian, and endometrial carcinomas. While BARD1 mutations are rare, their existence implies that BARD1 can also serve as a target for genetic lesions that disrupt BRCA1-mediated tumor suppression. To determine how BARD1 missense mutations lead to tumorigenesis we are examining the effects of these mutations on the genome integrity functions of the BRCA1/BARD1 heterodimer, including homology-directed repair of double-strand DNA breaks and cell cycle checkpoint control. For this purpose, BARD1 mutations are introduced by gene targeting with recombinant adeno-associated viruses and by complementation of siRNA-mediated BARD1-depleted cells.
Longitudinal Association of Depression Symptoms With Cognition and Cortical Amyloid Among Community-Dwelling Older Adults
Authors: Jennifer R. Gatchel, Jennifer S. Rabin, Rachel F. Buckley, Joseph J. Locascio, Yakeel T. Quiroz, Hyun-Sik Yang, Patrizia Vannini, Rebecca E. Amariglio, Dorene M. Rentz, Michael Properzi, Nancy J. Donovan, Deborah Blacker, Keith A. Johnson, Reisa A. Sperling, Gad A. Marshall
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Depressive symptoms are prevalent among older adults and may be early manifestations of Alzheimer disease (AD) before onset of mild cognitive impairment. However, it remains unclear whether worsening depressive symptoms in the presence of AD pathology are associated with cognitive decline in older adults. <h3>Objective</h3> To determine the longitudinal association between depressive symptoms, cognition, and cortical amyloid in community-dwelling older adults. <h3>Design, Setting, and Participants</h3> Participants from the Harvard Aging Brain Study, a cohort study, underwent annual assessments of depression and cognition and baseline cortical amyloid measurement (mean, 4.42 years; range, 2-7 years). Data collection was from September 2010 to August 2017 in a convenience sample of community-dwelling adults (276 participants, all cognitively unimpaired) with at most mild depression at entry. <h3>Main Outcomes and Measures</h3> Depression (Geriatric Depression Scale [GDS]), cognition (Preclinical Alzheimer Cognitive Composite [PACC]), and a continuous measure of cortical amyloid (Pittsburgh Compound-B positron emission tomography imaging). Change in GDS and baseline amyloid were examined as interactive predictors of PACC decline in a linear mixed model with backward elimination, adjusting for age, sex, and education. <h3>Results</h3> Participants were 164 women and 112 men (mean [SD] age, 73.5 [6.0] years). At baseline, the mean (SD) GDS score was 3.0 (2.8) (range, 0-12), the mean (SD) PACC score was −0.004 (0.67) (range, −2.32 to 1.88), and the mean (SD) amyloid positron emission tomography distribution volume ratio was 1.16 (0.20) (range, 0.92-1.94). At last follow-up, the mean (SD) GDS score was 3.9 (2.9) (range, 0-12), and the mean (SD) PACC score was −0.09 (1.27) (range, −5.66 to 1.67). The interaction between cortical amyloid and increasing GDS was associated with declining cognition (β = −0.19; 95% CI, −0.27 to −0.12;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> In this study, cortical amyloid moderated the association between worsening depressive symptoms and declining cognition in older adults. While future work is needed to better understand causal associations, these findings may enhance early detection and prevention of AD clinical symptoms.
Combination of Metformin and Gefitinib as First-Line Therapy for Nondiabetic Advanced NSCLC Patients with EGFR Mutations: A Randomized, Double-Blind Phase II Trial
Authors: Li Li, Liyan Jiang, Yubo Wang, Yizhuo Zhao, Xiao-Ju Zhang, Guoming Wu, Xiangdong Zhou, Jianguo Sun, Jun Bai, Biyong Ren, Kun Tian, Zhi Xu, Hua-liang Xiao, Qi Zhou, Rui Han, Hengyi Chen, Haidong Wang, Zhenzhou Yang, Chan Gao, Shangli Cai, Yong He
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Preclinical and retrospective studies suggested a role for metformin in sensitizing patients who have diabetes with non–small cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitors (TKIs). We therefore examined its effects in combination with gefitinib in patients without diabetes harboring EGFR mutations (EGFRm). Patients and Methods: A total of 224 patients without diabetes with treatment-naïve stage IIIB–IV EGFRm NSCLC were randomly assigned in a 1:1 ratio to receive gefitinib plus either metformin or placebo. The primary endpoint was progression-free survival (PFS) rate at 1 year and secondary endpoints included overall survival (OS), PFS, objective response rate (ORR), and safety. Serum levels of IL6 were also examined in an exploratory analysis. Results: The median duration of follow-up was 19.15 months. The estimated 1-year PFS rates were 41.2% [95% confidence interval (CI), 30.0–52.2] with gefitinib plus metformin and 42.9% (95% CI, 32.6–52.7) with gefitinib plus placebo (P = 0.6268). Median PFS (10.3 months vs. 11.4 months) and median OS (22.0 months vs. 27.5 months) were numerically lower in the metformin group, while ORRs were similar between the two arms (66% vs. 66.7%). No significant treatment group differences were detected across all subgroups with respect to PFS, including those with elevated levels of IL6. Metformin combined with gefitinib resulted in a remarkably higher incidence of diarrhea compared with the control arm (78.38% vs. 43.24%). Conclusions: Our study showed that addition of metformin resulted in nonsignificantly worse outcomes and increased toxicity and hence does not support its concurrent use with first-line EGFR-TKI therapy in patients without diabetes with EGFRm NSCLC.