tbuckley/cabot-search huggingface dataset:
Significance of the estrogen signaling pathway in <i>EGFR </i>wild-type lung adenocarcinoma.
Authors: Kazumi Tanaka, Kimihiro Shimizu, Toshiteru Nagashima, Yoichi Ohtaki, Kyoichi Kaira, Jun Horiguchi, Tetsunari Oyama, Izumi Takeyoshi
Journal: Journal of Clinical Oncology (2014)

7565 Background: Estrogen and growth factor pathways are potential targets for novel preventative and treatment strategies of lung adenocarcinoma. The purpose of this study is to examine the correlation among estrogen receptor (ER), aromatase expression, and other prognostic factors including epidermal growth factor receptor (EGFR) mutation in lung adenocarcinoma. Methods: We evaluated 150 resected primary lung adenocarcinoma specimens. Expression of aromatase, ERα, ERβ, progesterone receptor (PR), and HER2 was evaluated with immunostaining. Aromatase expression was scored from 0 to 3+ according to immunoreactive intensity. EGFR mutation was evaluated with SmartAmp2 method. Overall survival (OS) and recurrence free survival (RFS) was calculated by Kaplan-Meier method, and differences in survival were determined by log-rank test. Cox proportional hazards model was used to evaluate independent prognostic factors. Results: Expression of aromatase, ERα, ERβ, PR, and HER2 were detected in 79.3%, 1.3%, 88.0%, 2.7%, 39.3% of all patients, respectively. In all patients, high aromatase expression (2+, 3+) was an independent predictor of poor OS (Hazard Ratio [HR]=2.3; 95% confidential interval [CI], 1.2-4.4; P= .017), while no prognostic significance was seen in RFS. ERβ was not an independent predictor of OS and RFS. In patients with wild-type EGFR, high aromatase expression was an independent predictor of poor OS (HR=2.6; 95%CI, 1.2-5.9; P= .019) and RFS (HR=2.5; 95%CI, 1.2-5.4; P= .020). Positive ERβ was also an independent predictor of poor RFS (HR=4.0; 95%CI, 1.2-13.2; P= .022). Furthermore, high aromatase expression was a significant predictor of poor survival only in women (OS, P= .010; RFS, P= .007), while positive ERβ was a significant predictor of poor survival only in men (OS, P= .073; RFS, P= .051). No prognostic significance was seen in patients with EGFR mutations. Conclusions: Aromatase and ERβ expression were independent negative prognostic factors in EGFR wild-type adenocarcinoma. We further showed that in patients with wild-type EGFR, high aromatase expression was a significant predictor of poor survival only in women, while ERβ expression was a significant predictor of poor survival only in men.
Favorable Outcome in Patients with Acute Myeloblastic Leukemia (AML) with NPM1 Mutation Who Present an Inadequate Clearance or Relapse of Minimal/Measurable Residual Disease (MRD): Results of a Preemptive Intervention Policy (CETLAM-2012 Protocol)
Authors: Alex Bataller Torralba, Marina Diaz-Beyá, Ana Garrido, Susana Vives, Mar Tormo, Montserrat Arnan Sangerman, Olga Salamero, Antonia Sampol, Rosa Coll, Monica Lopez-Guerra, Marta Pratcorona, Lurdes Zamora, Eva Villamón, Gael Roue, Adoración Blanco, Aina Oliver-Caldes, Josep F Nomdedeu, Dolors Colomer, Salut Brunet, Jorge Sierra, Jordi Esteve
Journal: Blood (2018)
Expression of oncogene PKMzeta in pancreatic adenocarcinoma.
Authors: Hitendra Patel, Charmi Patel, Adam Watson-Hurthig, Sara S Parker, Edward K Mandell, Diana J Uribe, Parminder Singh, Sourav Ghosh
Journal: Journal of Clinical Oncology (2014)

e15235 Background: Loss of cell polarity, tissue organization and epithelial-mesenchymal transition are associated with progression along the adenoma-carcinoma axis in many cancers. Atypical Protein Kinase C (aPKC) isoforms aPKCzeta/iota form a complex with polarity proteins such as Par3/Par6 and establish cell-cell adhesion and epithelial cell polarity. Recently, we have described that a novel isoform of aPKC, PKMzeta, can biochemically compete with aPKCzeta/iota for binding with Par3 and disrupt the aPKCzeta/iota-Par3 complex (Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14450-5. Epub 2013 Aug 12). Methods: We analyzed The Cancer Genome Atlas (TCGA) RNAseq database for PKMzeta expression and tested PKMzeta mRNA levels in Pancreatic Ductal Adenocarcinoma (PDAC) and matched normal tissue. RNA was isolated from formalin-fixed paraffin-embedded tissue and analyzed by quantitative reverse-transcriptase PCR (qRT-PCR). Results: PKMzeta mRNA is detectable in adenocarcinomas including 78% of PDAC in TCGA RNAseq database (n=41). Furthermore, qRT-PCR analyses of PKMzeta expression in 8 matched normal pancreatic versus PDAC tissue samples showed that PKMzeta was expressed on all PDAC cases versus none in matched normal tissue. (paired t-test; p<0.01). We also show that heterologous expression of PKMzeta in Madin Darby Canine Kidney epithelial cells functionally disrupts cell-cell adhesion and cell polarity. Conclusions: Our results suggest that PKMzeta may be a novel oncogene in PDAC, contributing to the loss of cell polarity and carcinoma initiation and/or progression.
Investigating HER2 status and polysomy 17 in gastric adenocarcinoma using multiplex ligation-dependent probe amplification.
Authors: Tao Wang, Yutaka Amemiya, Pauline Henry, Arun K Seth, Wedad Hanna, Eugene T Hsieh
Journal: Journal of Clinical Oncology (2014)

e15042 Background: Targeted therapy in gastric cancer has resulted in routine HER2 evaluation by immunohistochemistry and in situ hybridization (ISH). For ISH, a HER2 to chromosome 17 centromere (CEP17) ratio ≥ 2.0 is amplified. This assumes a diploid centromeric region. But in about 15% of cases, CEP17 counts are ≥3, suggestive of polysomy 17. In these cases, it is uncertain if HER2 is accurately assessed by ISH. It is also unknown if these are true polysomies or pericentromeric amplification. Multiplex ligation-dependent probe amplification (MLPA) is a multi-target polymerase chain reaction technique that can simultaneously quantify many genes. This can distinguish between true polysomy and pericentromeric amplification. Methods: Silver ISH was performed and scored as per manufacturer guidelines (Ventana). We isolated DNA from paraffin blocks of 13 gastric cancers with ISH CEP17 counts ≥ 3, representing ISH polysomy. We collected 4 cases each of non-polysomic HER2 positive and negative controls, and 2 normal controls. We performed MLPA HER2 assay (MCR Holland) targeting 22 genes on chromosome 17. Results were standardized against normals. A MLPA ratio of 1.4 to 1.99 was deemed low amplified, and a ratio ≥ 2.0 was deemed high amplified. Results: One ISH negative polysomic case was highly amplified on MLPA. Conversely 1 ISH positive polysomic case was MLPA negative, and another was only low amplified (Table). This may be due to the focal nature of the amplification or stromal contamination. Overall, 7 of 13 ISH polysomic cases had low amplification of the pericentromeric gene WSB1. This could account for ISH CEP17 counts of ≥ 3.0. No sample showed amplification in the majority of chromosome 17 genes, suggesting that true polysomy is uncommon. Conclusions: Pericentrometric amplification appears to be more common than true polysomy 17 as an explanation for ISH CEP17 counts ≥ 3.0. This has potential implications for the use of HER2/CEP17 ratios in such cases. MLPA versus ISH results MLPA amplification ISH CEP17 ≥ 3 CEP17 < 3 HER2+ HER2- HER2+ HER2- HER2 - high 2 1 2 0 HER2 - low 0 2 1 0 HER2 - non-amplified 0 8 1 4 WSB1 - high (pericentromeric) 0 0 0 0 WSB1 - low 0 7 0 1 WSB1 - non-amplified 2 4 4 3
Subtype analysis from the GEICAM/2003-02 study: High-risk, node-negative breast cancer patients treated with adjuvant fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel.
Authors: Federico Rojo, Ana Lluch, Amparo Ruiz, Manuel Ruiz-Borrego, Agusti Barnadas, Lourdes Calvo, Sonia Gonzalez, Mireia Margeli, Alvaro Rodriguez-Lescure, Antonio Anton, Miguel Angel Seguí, Montserrat Munoz-Mateu, Joan Dorca, Jose Manuel Lopez-Vega, Carlos Jara-Sanchez, Nuria Martin, Maribel Casas, Eva Maria Carrasco, Rosalia Caballero, Miguel Martin
Journal: Journal of Clinical Oncology (2014)

11107 Background: Adding taxanes to standard anthracycline-based adjuvant therapy improves survival outcome in node-negative breast cancer (BC) patients (pts) with high risk of recurrence. Due to the small magnitude of the benefit and to avoid toxicity, biomarker analyses aimed to identify subpopulations benefiting the most from taxanes are warranted. Methods: After surgery, 1,925 node-negative BC pts with at least one high-risk factor for recurrence (St. Gallen 1998 criteria) were randomly assigned to receive 6 FAC cycles or 4 FAC cycles followed by 8 weekly paclitaxel doses (FAC-wP); 108 out of the 181 HER2+ pts did not receive trastuzumab. With a median follow-up of 63.3 months, 93% and 90.3% of pts receiving FAC-wP or FAC, respectively, remained disease free (hazard ratio [HR]: 0.73; 95% CI: 0.54-0.99; log-rank p= 0.04; Martin JCO 2013). We performed central immunohistochemistry (IHC) for ER, PR, Ki-67 and HER2/FISH; pts were grouped in intrinsic BC subtypes according to the Prat et al. classification (JCO 2012): Luminal A: RE+, PR>20%, HER2-, Ki67<14%; Luminal B1: RE+, HER2-, PR≤20% and/or Ki67≥14%; Luminal B2: RE+, PR+/-, HER2+; HER2: RE-, PR-, HER2+; TN: RE-, PR-, HER2-. We report here the correlation between these variables and Distant Metastases-Free Survival (DMFS). Cox regression and log-rank test were used for analysis. Results: Central biomarker expression and subtype classification is currently available for 1,084 and 946 pts, respectively. DMFS in the 1,084 pts were 97.8% vs 94.8% (HR: 0.52; 95% CI: 0.28-0.97; p=0.035). In the univariate analysis, FAC-wP therapy, ER and PR positive status, low Ki67 proliferation and Luminal A and B1 subtypes were significantly associated with better DMFS. Absence of PR and Luminal B1 were predictive for FAC-wP benefit. The multivariate analysis showed that intrinsic subtype classification was predictive of DMFS (p=0.010). Conclusions: Our study suggests that IHC-based intrinsic subtypes provide prognostic value and could identify a subpopulation of node-negative BC pts (the luminal B1) who obtains more benefit from FAC-wP adjuvant therapy.
Histones Induce the Release of Extracellular Hemoglobin and Red Blood Cell-Derived Microvesicles with Procoagulant Activity
Authors: Denis Noubouossie, Juraj Sokol, Mark Gerard Piegore, Anton Ilich, Michael Wayne Henderson, Micah Mooberry, Dougald Monroe, Nigel S. Key
Journal: Blood (2018)
Predictors of progression in patients with high-grade appendiceal or colorectal adenocarcinoma after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
Authors: Joel Micah Baumgartner, Eric Roeland, Laura Tobin, Andrew M. Lowy
Journal: Journal of Clinical Oncology (2014)

e14573 Background: High-grade peritoneal carcinomatosis (PC) secondary to appendiceal or colorectal cancer is marked by short progression-free survival (PFS) and overall survival. Treatment includes systemic chemotherapy (SC), with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in select cases. Predictors of progression after resection and HIPEC are largely unknown. This study examined the effect of SC and other factors on PFS in high-grade PC patients. Methods: This single center, retrospective cohort study included all patients with high-grade PC of colorectal or appendiceal origin treated with CRS/HIPEC from August 2007 to September 2013. Data was collected from electronic medical records and follow-up continued through January 2014. Survival analysis evaluated associations between PFS and predictor variables including: primary cancer site, number of positive LNs, resection status, peritoneal cancer index, and presence and dose of SC. Age and sex were examined as potential confounders. Results: A total of 69 patients were included, 42% had appendiceal and 58% had colorectal cancer. Median PFS for the entire cohort was 9.29 (6.54-13.79) months; 9.69 (5.75-16.88) months and 9.00 (6.37-14.52) months for those with appendiceal and colorectal cancers, respectively. There was no difference in median PFS between those with pre-HIPEC SC (84%) and those without (p=0.55). The number of pre-HIPEC SC treatment cycles was also not associated with PFS (p=0.73). There was no difference in PFS (p=0.94) between patients who received pre-HIPEC SC compared to those who did not (4%). Females (58%) were more at risk for progression than males, HR 2.16 (1.08-4.32), but not after adjusting for the number of positive LNs. Positive LNs were a significant predictor of PFS both alone and after adjusting for sex, with an adjusted HR of 1.19 (1.08-1.30) for every one positive LN. Conclusions: This study suggests a limited role of pre-HIPEC SC on PFS in PC patients undergoing CRS/HIPEC. Neither pre-HIPEC SC nor the number of SC cycles had an effect on PFS. In contrast, positive LNs were a significant adverse factor in PFS.
Disrupted filamin A/αIIbβ3 interaction induces macrothrombocytopenia by increasing RhoA activity
Authors: Alessandro Donada, Nathalie Balayn, Dominika Sliwa, Larissa Lordier, Valentina Ceglia, Francesco Baschieri, Cyril Goizet, Rémi Favier, Lucie Tosca, Gérard Tachdjian, Cecile V. Denis, Isabelle Plo, William Vainchenker, Najet Debili, Jean-Philippe Rosa, Marijke Bryckaert, Hana Raslova
Journal: Blood (2019)
Inotuzumab Ozogamicin (InO) for Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL) in the Global Phase 3 INO-VATE Trial: Efficacy By MLL Status
Authors: Anjali S. Advani, Elias J. Jabbour, Matthias Stelljes, Wendy Stock, Michaela Liedtke, Nicola Goekbuget, Susan M. O'Brien, Jane Liang White, Tao Wang, A. Douglas Laird, Erik Vandendries, Hagop M. Kantarjian
Journal: Blood (2017)
Phase I Study of the Antibody-Drug Conjugate Brentuximab Vedotin Combined with Re-Induction Chemotherapy in Patients with CD30-Expressing Relapsed/Refractory Acute Myeloid Leukemia
Authors: Amir T. Fathi, Traci M. Blonquist, Ashkan Emadi, Andrew M. Brunner, Gabriela S. Hobbs, Hanno Hock, Steven L McAfee, Robert P. Hasserjian, Frederic I. Preffer, Jenna A. Moran, Meghan Bergeron, Julia Foster, Christina Bertoli, Kristin McGregor, Kaitlyn Fishman, Molly Macrae, Meghan Burke, Tanya T. Behnan, Tina T. Som, Aura Y. Ramos, Megan K. Vartanian, Jennifer Lombardi Story, Patricia Lesho, Vu H. Duong, Mason Mann, Christopher Lescinskas, Christine Connolly, Donna S Neuberg, Karen K. Ballen, Philip C. Amrein
Journal: Blood (2018)
Molecular profiling of small-bowel adenocarcinomas.
Authors: Rebecca Feldman, Igor A. Astsaturov, Zoran Gatalica
Journal: Journal of Clinical Oncology (2014)

3647 Background: Small-bowel adenocarcinoma (SBA) is a rare malignancy with limited knowledge of the molecular mechanisms, or clinical evidence-based guidelines for therapy. We conducted a comprehensive analysis of biomarkers with therapeutic relevance for SBA. Methods: We examined the biomarker profiles of 266 SBA cases. Multiplatform biomarker panel included a combination of sequencing (Sanger, NGS), protein expression (IHC) and gene amplification (CISH /FISH). Results: Several biomarkers have been identified by IHC evaluation in ~250 patients: high TOP2A (74%) and low TUBB3 (81%), low ERCC1 (71%), low RRM1 (69%) and low TS (63%)- favorable for chemotherapy drugs such as doxorubicin, taxanes, oxaliplatin, gemcitabine and capecitabine, respectively. A minority of cases were found to express other favorable chemotherapy response biomarkers: low MGMT (alkylating agents, 30%), high SPARC (nab-paclitaxel, 36%) and high TOPO1 (irinotecan, 39%). SBA demonstrated a high prevalence of multidrug resistance gene expression: MRP1 and BCRP (83%) and PGP (51%). Unexpectedly, a number of cases showed genomic alterations associated with activated oncogenic signaling: EGFR (13% or 12/96), TOP2A (12% or 4/33), HER2 (7% or 9/130) and cMET (1.4% or 1/71). Two patients demonstrated co-amplification of TOP2A and HER2, suggesting these patients may benefit from anthracyclines. Evaluation of mutational hotspots demonstrated a high incidence of oncogenic/tumor suppressor mutations in 60% (47/78) of patients. We discovered that mutations in TP53 (51%) and KRAS (46%) were most common. Other genes with notable alterations included: APC (22%), SMAD4 (20%), BRAF (9%), CTNNB1 (7%) and PTEN (5%). Recent data suggest favorable responses to cetuximab in SBA; these results and high frequency of KRAS mutations in our series indicate that KRAS testing may be recommended in SBA. Conclusions: Our data demonstrate the potential utility of a wide range of traditional chemotherapies for SBA, targeted therapies utilized for other cancer types as well as therapies under clinical investigation. SBA exhibits biologically similar tumorigenesis as large-bowel adenocarcinoma, therefore similar treatment guidelines and biomarker testing strategies should be considered.
Survival Improvement of Patients with Chronic Lymphocytic Leukemia (CLL) in Routine Care 1995 - 2017
Authors: Rudolf Weide, Stefan Feiten, Geothy Chakupurakal, Vera Friesenhahn, Kristina Kleboth, Hubert Köppler, Julia Lutschkin, Jörg Thomalla, Christoph van Roye, Jochen Heymanns
Journal: Blood (2018)
Genomic Instability and a Preferential Involvement of Ras Pathway in the Myelodysplastic Syndromes Evolution to Secondary Acute Myeloid Leukemia
Authors: Marta Martín Izquierdo, María Abáigar, Jesus M Hernández-Sánchez, Félix López Cadenas, Fernando Ramos, Eva Lumbreras, Andrés Madinaveitia-Ochoa, Marta Megido, Jorge Labrador, Javier Sánchez del Real, Carmen Olivier, Julio Dávila, Carlos Aguilar, Juan Nicolás Rodríguez, Guillermo Martín-Nuñez, Sandra Santos-Mínguez, Rocio Benito, Consuelo Del Cañizo, María Díez-Campelo, Jesús María Hernández-Rivas
Journal: Blood (2018)
Association of Sickle Cell Trait with Measures of Cognitive Function and Dementia in African Americans
Authors: Chen Nemin, Christina Caruso, Alvaro Alonso, Vimal K. Derebail, Abhijit V Kshirsagar, Richey Sharrett, Nigel S. Key, Rebecca Gottesman, Megan Grove, Jan Bressler, Eric Boerwinkle, B. Gwen Windham, Thomas H Mosley, Hyacinth I Hyacinth
Journal: Blood (2018)
Nanoscavenger provides long-term prophylactic protection against nerve agents in rodents
Authors: Peng Zhang, Erik J. Liu, Caroline Tsao, Shane A. Kasten, Michael V. Boeri, Thuy L. Dao, Sandra J. DeBus, C. Linn Cadieux, Cetara A. Baker, Tamara C. Otto, Douglas M. Cerasoli, Yantao Chen, Priyesh Jain, Fang Sun, Wenchen Li, Hsiang-Chieh Hung, Zhefan Yuan, Jinrong Ma, Andrew N. Bigley, Frank M. Raushel, Shaoyi Jiang
Journal: Science Translational Medicine (2019)

A catalytic nanoscavenger with long blood residence time provides long-term prophylactic protection against nerve agents in animal models.
Follow-up of 1,001 adults and children after fertility preservation for oncologic conditions within a publicly financed health care program.
Authors: Kenny A Rodriguez-Wallberg, Birgit Borgstrom, Emelie Vonheim, Outi Hovatta
Journal: Journal of Clinical Oncology (2014)

9582 Background: Options for fertility preservation (FP) among adults and children are currently available for female and male individuals of all ages. In Sweden, publicly financed health care covers assisted reproduction and freezing of gametes and tissues for medical reasons. Methods: We reviewed clinical data of 1001 cancer patients enrolled in the FP programme at Karolinska University Hospital, Sweden, between 1998 and 2013. Results: This cohort included 945 adults and 56 children. By the time of this report, 95% of women, 90% of men and 77% of children are in the survival cohort. Most common cancer diagnoses were breast cancer, testicular cancer and lymphoma in adults, and leukemia in children.Women and children were counseled by gynecologists and pediatricians. Adult males were counseled by oncologists. All patients had access to FP options within a few days. Female patients (N=478) were offered cryopreservation of embryos, non-fertilized oocytes or pieces of ovarian cortical tissue. Males (N=523) were offered sperm freezing and cryopreservation of adult or pre-pubertal testicular tissue. Nearly one-third of survivors have returned for fertility counseling and treatment. Transfer of frozen-thawed embryos and use of frozen sperm in fertility treatments had resulted in births in over 50% of cases; in vitro fertilization of frozen-thawed oocytes resulted in transfer of embryos, but not in pregnancies. Ovarian function resumed in three women after transplantation of thawed ovarian tissue, with one pregnancy achieved. No signs of cancer recurrence related to the transplantation of ovarian tissue were observed. Five girls, prepubertal at the time of cancer treatment, underwent additionally ovarian stimulation after puberty, and mature eggs were frozen for the future. Conclusions: The utilization rates of cryo-stored gametes and embryos in this cohort are higher than those reported earlier. Although our results are encouraging, the efficacy of FP procedures can only be estimated in the group of cancer survivors who came back for fertility treatment. We have offered counseling and FP within the publicly financed health care. This may not be possible in all countries.
The Expansion of Inosine at the Wobble Position of tRNAs, and Its Role in the Evolution of Proteomes
Authors: Àlbert Rafels-Ybern, Adrian Gabriel Torres, Noelia Camacho, Andrea Herencia-Ropero, Helena Roura Frigolé, Thomas F Wulff, Marina Raboteg, Albert Bordons, Xavier Grau-Bove, Iñaki Ruiz-Trillo, Lluís Ribas de Pouplana
Journal: Molecular Biology and Evolution (2018)

The modification of adenosine to inosine at the first position of transfer RNA (tRNA) anticodons (I34) is widespread among bacteria and eukaryotes. In bacteria, the modification is found in tRNAArg and is catalyzed by tRNA adenosine deaminase A, a homodimeric enzyme. In eukaryotes, I34 is introduced in up to eight different tRNAs by the heterodimeric adenosine deaminase acting on tRNA. This substrate expansion significantly influenced the evolution of eukaryotic genomes in terms of codon usage and tRNA gene composition. However, the selective advantages driving this process remain unclear. Here, we have studied the evolution of I34, tRNA adenosine deaminase A, adenosine deaminase acting on tRNA, and their relevant codons in a large set of bacterial and eukaryotic species. We show that a functional expansion of I34 to tRNAs other than tRNAArg also occurred within bacteria, in a process likely initiated by the emergence of unmodified A34-containing tRNAs. In eukaryotes, we report on a large variability in the use of I34 in protists, in contrast to a more uniform presence in fungi, plans, and animals. Our data support that the eukaryotic expansion of I34-tRNAs was driven by the improvement brought by these tRNAs to the synthesis of proteins highly enriched in certain amino acids.