tbuckley/cabot-search huggingface dataset:
Abstract CT210: Precision medicine for advanced pancreas cancer: the individualized molecular pancreatic cancer therapy (IMPaCT) trial
Authors: Lorraine Chantrill, Skye Simpson, Amber Johns, Mona Martyn-Smith, Angela Chou, Clare Watson, Adnan Nagrial, Venessa Chin, Lucille Sebastian, Sonia Yip, John Simes, Nick Pavlakis, Peter Grimison, Ray Asghari, Sandra Harvey, Andrew Biankin
Journal: Cancer Research (2015)

Abstract Background: The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial is designed to exploit results from whole genome sequencing of pancreatic cancer collected under the auspices of the ICGC in Australia. Results showed that small subsets of patients had actionable changes in their tumor genome that could be druggable with currently available therapies. Only 7% of cases were found to be KRAS wildtype, and this phenotype may enrich for susceptibility to EGFR inhibition. Her2 positivity occurs in 2% and may confer sensitivity to Her inhibition. Tumors displaying defects in the DNA damage repair pathway (∼5%) respond to DNA damaging chemotherapy. Trial Design: The IMPaCT trial has recently been amended to a single arm pilot study of first line molecularly guided therapy for advanced pancreas cancer. Patients are permitted to begin their first cycle of chemotherapy with gemcitabine with or without nab-paclitaxel while awaiting molecular results. We screen potential patients for the three molecular targets: Her2 amplification: trastuzumab + gemcitabine; KRAS wildtype: erlotinib + gemcitabine; and DNA damage: platinum-based chemotherapy. In our initial cohort of patients who underwent resection with curative intent, 70% recurred. Recurrence occurred 16m after initial surgery. Collection of tissue commenced in 2009. The first site to open was in April 2013 by which time, only 8 patients for whom we had complete sequence data and actionable mutations were still alive, so we changed the trial to screen de novo metastatic patients. Using the WGS data, we constructed a custom sequencing panel to use DNA extracted from FFPE core biopsies to screen in real time for mutations in KRAS, BRCA2, BRCA1, PALB2 and ATM. Her2 screening is undertaken with IHC and FISH. We have screened 89 cases in 18m, 8 have relevant molecular targets. The average time from biopsy to delivery of results is 21d. 2 of the 8 eligible cases have commenced precision therapy on trial. Citation Format: Lorraine Chantrill, Skye Simpson, Amber Johns, Mona Martyn-Smith, Angela Chou, Clare Watson, Adnan Nagrial, Venessa Chin, Lucille Sebastian, Sonia Yip, John Simes, Nick Pavlakis, Peter Grimison, Ray Asghari, Sandra Harvey, Andrew Biankin. Precision medicine for advanced pancreas cancer: the individualized molecular pancreatic cancer therapy (IMPaCT) trial. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT210. doi:10.1158/1538-7445.AM2015-CT210
SPARC-induced migration of glioblastoma cells via uPA-uPAR signaling and activation of small GTPase RhoA
Authors: Sateesh S. Kunigal, Meena Gujrati, Dzung H. Dinh, William C. Olivero, Jasti S. Rao
Journal: Cancer Research (2006)

4360   Secreted acidic protein rich in cysteine (SPARC) has been suggested as a potential glioma invasion promoting gene. SPARC is highly expressed in human gliomas, promotes glioma invasion, and delays tumor growth  in vitro  and  in vivo . cDNA array reports were performed to determine whether SPARC, which interacts at the cell surface, has an impact on intracellular signaling and downstream gene expression changes that might account for some of its effects on invasion and growth. Additional  in vitro  studies demonstrated that SPARC delays growth, increases attachment, and modulates migration of tumor cells in extracellular matrix-specific and concentration-dependent manners. It has been reported that SPARC functionally contributes to brain tumor invasion and delays tumor growth  in vivo , and that the effects of SPARC are related to the level of SPARC secreted into the extracellular matrix. Thus far, the signaling aspects of glioma migration and invasion are not fully understood. As such, we made an attempt here to increase our understanding of the signaling pathways involved in the invasion and migration of two glioblastoma cell lines (U87 and SNB19). We performed RT-PCR analysis to check the upregulation of uPA, its receptor (uPAR), matrix metalloproteinase 2 (MMP-2), and matrix metalloproteinase (MMP-9). Western blot analysis also confirmed the above results. We used zymography to determine the activity of the metalloproteinases and uPA. Downstream of the uPA-uPAR interaction, PI3-K upregulation has been shown to be overexpressed in SPARC cells. Using GST-TRBD, we show the upregulation of active GTP-bound RhoA, but not Rac1 and Cdc42. Inhibition of uPA-uPAR downregulated PI3-K activity and cell migration as shown by the matrigel invasion assay. The results from the dorsal skin fold chamber model in nude mice indicated the high angiogenic activity of SPARC, but the proliferation of the overexpressed SPARC cells was not affected or reduced. Further, results from the dorsal skin fold chamber model using the SPARC overexpressing SNB19 stable cells transfected with puPA, puPAR or pU2 confirmed the requirement of the uPA-uPAR system in the angiogenic activity of SPARC. Our results show that small GTPase RhoA is necessary to mediate invasion and migration via the uPA-uPAR/PI3-K signaling pathway.
Abstract LB-115: Baseline neutrophil to lymphocyte ratio as a selection criterion for ipilimumab treatment in metastatic melanoma patients
Authors: Pier Francesco Ferrucci, Sara Gandini, Angelo Battaglia, Salvatore Alfieri, Laura Pala, Annamaria Di Giacomo, Giovanni Amato, Gian Carlo Antonini Cappellini, Diana Giannarelli, Emilia Cocorocchio, Chiara Martinoli
Journal: Cancer Research (2015)

Abstract Background: Ipilimumab, a recently approved immunomodulatory drug, improves the survival of metastatic melanoma patients. Despite documented, durable objective responses, a significant number of patients fails to obtain clinical benefit from treatment. The aim of this study was to identify a criterion to select patients best suited to receive this drug. Methods: Sixty-nine metastatic melanoma patients treated at the European Institute of Oncology with 3 mg/kg ipilimumab, were evaluated. Neutrophil to lymphocyte ratio (NLR) was calculated from pre-therapy full blood counts. Progression free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox models were applied. Findings were independently validated on a cohort of 27 patients treated with 10 mg/kg ipilimumab at the University Hospital of Siena and on a cohort of 88 treated in Rome. Results: Best overall response and disease control rates were 9% and 27%, respectively. Median PFS and OS were 3 and 5 months, respectively. Pre-therapy NLR was identified as the strongest and independent marker for treatment benefit in univariate and multivariate analyses. Patients with baseline NLR&amp;lt;5 had a significantly improved PFS (HR = 0.38; 95% CI: 0.22-0.66; P = 0.0006) and OS (HR = 0.24; 95% CI: 0.13-0.46; P&amp;lt;0.0001) compared with those with a NLR≥5. Conclusions: Our findings show that baseline NLR is strongly and independently associated with outcome of patients treated with ipilimumab, and may serve as a selection criterion for this therapy. Citation Format: Pier Francesco Ferrucci, Sara Gandini, Angelo Battaglia, Salvatore Alfieri, Laura Pala, Annamaria Di Giacomo, Giovanni Amato, Gian Carlo Antonini Cappellini, Diana Giannarelli, Emilia Cocorocchio, Chiara Martinoli. Baseline neutrophil to lymphocyte ratio as a selection criterion for ipilimumab treatment in metastatic melanoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-115. doi:10.1158/1538-7445.AM2015-LB-115
MK-507 versus Sezolamide
Authors: Erik A. Lippa, Joel S. Schuman, Eve J. Higginbotham, Michael A. Kass, Robert N. Weinreb, Gregory L. Skuta, David L. Epstein, Blake Shaw, Daniel J. Holder, Deni A. Deasy, Jacob T. Wilensky
Journal: Ophthalmology (1991)
Abstract 2514: Activity of a novel Foxp3-tumor cell vaccine in a murine model of renal cell carcinoma
Authors: Li Shen, Ashley Orillion, Remi Adelaiye, Eric Ciamporcero, Swathi Ramakrishnan, Roberto Pili
Journal: Cancer Research (2015)

Abstract Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and represents 80% of the cases. Treatment options for patients with advanced disease are limited. Targeted molecular therapies have shown survival benefit but most patients develop therapy resistance overtime. Preclinical and clinical studies indicate that immunotherapies are effective and may play a role in the treatment of advanced RCC. However, the response rate is ∼ 20%, with a limited number of patients achieving durable remission. A major barrier to vaccine therapy is the presence of immunosuppressive cell populations including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). In the current study, we designed a tumor cell and Tregs dual-targeting vaccine by inducing Foxp3 expression in tumor cells, and tested this vaccine along with an unmodified vaccine in an orthotopic murine model of RCC, RENCA. We observed that both RENCA cell vaccine and RENCA Foxp3 cell vaccine prevented tumor growth in 6 out 10 animals. Interestingly, in an intervention setting, the RENCA Foxp3 tumor cell vaccine was superior to the RENCA tumor cell vaccine with a significant anti-tumor activity (45% inhibition of tumor weights) (p&amp;lt;0.01). Moreover, RENCA Foxp3 tumor cell vaccine reduced the number of tumor infiltrating Tregs (42% reduction, p&amp;lt;0.05) and Treg Foxp3 expression both in peripheral blood and tumor infiltrates. In summary, our results suggest that a strategy targeting Tregs along with vaccine therapy or a dual targeting vaccine strategy may be beneficial in established RCC. We also observed that suppressive myeloid cell (SMCs) populations dominate the established tumor microenvironment and we are currently testing the combination of the dual-targeting vaccine with a SMC-targeting agent. Citation Format: Li Shen, Ashley Orillion, Remi Adelaiye, Eric Ciamporcero, Swathi Ramakrishnan, Roberto Pili. Activity of a novel Foxp3-tumor cell vaccine in a murine model of renal cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2514. doi:10.1158/1538-7445.AM2015-2514
Universal Screening for Familial Hypercholesterolemia in Children
Authors: Gašper Klančar, Urh Grošelj, Jernej Kovač, Nevenka Bratanič, Nataša Bratina, Katarina Trebušak Podkrajšek, Tadej Battelino
Journal: Journal of the American College of Cardiology (2015)

Individuals with familial hypercholesterolemia (FH) who are untreated have up to 100-fold elevated risk for cardiovascular complications compared with those who are unaffected. Data for identification of FH with a universal screening for hypercholesterolemia in children are lacking.This study sought genetic identification of FH from a cohort of children with elevated serum total cholesterol (TC) concentration, detected in a national universal screening for hypercholesterolemia.Slovenian children born between 1989 and 2009 (n = 272) with TC >6 mmol/l (231.7 mg/dl) or >5 mmol/l (193.1 mg/dl) plus a family history positive for premature cardiovascular complications, identified in a national universal screening for hypercholesterolemia at 5 years of age were genotyped for variants in LDLR, PCSK9, APOB, and APOE.Of the referred children, 57.0% carried disease-causing variants for FH: 38.6% in LDLR, 18.4% in APOB, and none in PCSK9. Nine novel disease-causing variants were identified, 8 in LDLR, and 1 in APOB. Of the remaining participants, 43.6% carried the APOE E4 isoform. Estimated detection rate of FH in the universal screening program from 2009 to 2013 was 53.6% (95% confidence interval [CI]: 34.5% to 72.8%), peaking in 2013 with an upper estimated detection rate of 96.3%. Variants in LDLR, APOB, or the APOE E4 isoform occurred in 48.6%, 60.0%, and 76.5%, respectively, of patients with a family history negative for cardiovascular complications.Most participants who were referred from a national database of universal screening results for hypercholesterolemia had genetically confirmed FH. Data for family history may not suffice for reliable identification of patients through selective and cascade screening.
Disconnected
Authors: Anand Vaidya, Christin N Price, Yvonne C Lee
Journal: New England Journal of Medicine (2012)

A 58-year-old white woman presented to the emergency department with palpitations and lightheadedness. While taking a shower that morning, she had sudden onset of lightheadedness, pain in the front of her chest when taking deep breaths, and mild shortness of breath. Her symptoms had resolved spontaneously, and she had gone to work, where the lightheadedness, palpitations, and chest pain . . . .
The Novel Plk Inhibitor Volasertib Overcomes Cytarabine Resistance in Acute Myeloid Leukemia
Authors: Shuang Fu, Kevin R. Kelly, Claudia M. Espitia, Yingchun Han, Hetty E. Carraway, Anjali S. Advani, Jaroslaw P. Maciejewski, Mikkael A. Sekeres, Nawrocki T. Steffan, Jennifer S. Carew
Journal: Blood (2014)
Abstract 338: Immunohistochemical expression of CD44/ERM complex proteins in penile carcinoma
Authors: Juliana B. de Andrade, Fernando A. Soares
Journal: Cancer Research (2015)

Abstract Background: The loco-regional involvement is considered the main complication and cause of death in the natural history of penile carcinoma. Understanding the molecular processes that may be involved in metastatic dissemination would improve the prognostic tools to better evaluate the patients, avoiding the morbidity of unnecessary surgery. Some studies have emphasized the influence of cellular adhesion in the development of tumorigenesis and metastasis as the proteins of complex CD44/ERM (Ezrin/Radixin/Moesin). Therefore, this study aimed to analyze the expression of proteins CD44 and its variant CD44v6, Ezrin and Moesin in squamous cell penile carcinoma, correlating their expression with the clinical-pathological criteria. Material and Methods: Eighty four patients were selected, retrospectively, undergoing surgery for squamous cell penile carcinoma at AC Camargo Cancer Center. The expression evaluation for CD44, CD44v6 Ezrin and Moesin was performed by immunohistochemistry using Ventana® equipment, subsequently analyzed by digital microscopy in Aperio® system. The immunoreactivity of each protein was categorized as positive and negative using a cut-off criteria established by the average percentage obtained. Results: CD44 expression was present in 19 (22.6%) positive cases, CD44v6 in 50 (59.5%), Ezrin in 30 (35.7%) and Moesin in 53 (63.1%). It was observed that the loss of CD44 expression was significantly correlated with recurrence (p = 0.002) and with the glans invasion (p = 0.035); the positive expression of CD44v6 was significantly correlated with the tumor size (p = 0.009) and with recurrence (p = 0.018); the loss of Ezrin expression was significantly correlated with macroscopic invasion (p = 0.028) and with foreskin of invasion (p = 0.015); the positive expression of Moesin was significantly correlated with macroscopic invasion (p = 0.010) and the loss of its expression was significantly correlated with recurrence (p = 0.035). Disease-free survival was significantly influenced by CD44, CD44v6 and Moesin. Conclusion: The expression of CD44, CD44v6, Ezrin and Moesin seems to significantly influence the prognostic factors of penile carcinoma and could be an important molecular marker in the identification of recurrence risk. Citation Format: Juliana B. de Andrade, Fernando A. Soares. Immunohistochemical expression of CD44/ERM complex proteins in penile carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 338. doi:10.1158/1538-7445.AM2015-338
Book: Me, Myself & Irene
Authors: Rita Baron-Faust
Journal: BMJ (2000)

20th Century FoxDirected by Bobby and Peter Farrelly

On worldwide general release; opened in the United Kingdom 22 September

———————

Rating: 0

The premise of Me, Myself & Irene must have seemed irresistibly clever to the film's producers and a natural for the chameleon comic Jim Carrey. A mentally ill motorcycle cop with a “split” personality—one sweetly passive, the other violently aggressive—ends up running from the law to save a pretty blonde from gangsters, while his dual selves battle each other for her affections along the way.

Carrey's character, Charlie Baileygates, is diagnosed with “advanced delusionary schizophrenia with involuntary narcissistic rage,” supposedly brought on by suppressing his anger at being dumped by his wife and being laughed at by the townspeople. One day Charlie simply snaps, changing into the menacing Hank, who defecates on a neighbour's lawn, suckles a breastfeeding woman, terrorises a little girl, and insults and punches nearly everyone he encounters.

Some US audiences enjoyed the joke (the film grossed $90m (£64m) over the summer), but mental health professionals and patients did not see the humour. Advocate groups, such as the National Alliance for the Mentally Ill, have written letters of protest to 20th Century Fox, complaining that the film makes fun of and perpetuates ugly stigmas about mental illness. The writer-directors, who also gave the world Dumb and Dumber, did not seem to see what the fuss was about. It's only a movie—it's only a bit of fun, they argued.

Britain's two largest mental health charities, Mind and the National Schizophrenia Fellowship, have joined with the Royal College of Psychiatrists, to protest against the film. In their joint press release they say that the film considers schizophrenia, its symptoms, and treatments as a joke.

The charities and the college are not calling for a ban but will be handing out leaflets at 300 cinemas and have demanded that the film be given an “18” certificate. The behaviour portrayed in the film, they argue, has nothing whatever to do with schizophrenia.

They also point out that people affected by schizophrenia don't switch from “gentle to mental,” as the billboard advertisements say, but are more often withdrawn. In fact, “split personality” is a totally different condition, a dissociative disorder rather than a psychotic illness.

Me, Myself & Irene is not terribly funny, and it is one more example of how people with mental illness are stigmatised by the media. Charlie/Hank is portrayed as violent, dangerous, and unfit to hold a responsible job. The film perpetuates harmful myths about mental illness. Charlie's illness is blamed on his personal weakness, and he is “cured” not by medication or therapy, but by his own will power and the love of a good woman. Would anyone ever expect a person with diabetes, or any other chronic illness, to overcome their condition by willpower?
A phase II clinical study of interleukin-11 mutein to treat patients with chemotherapy-induced thrombocytopenia.
Authors: Y. Jung, S. Ho, S. Yu, S. Wu, Y. Zhang, L. Xu, Y. Dai, Y. Teng, S. Ma, S. Song
Journal: Journal of Clinical Oncology (2010)

9113 Background: To demonstrate the safety and efficacy of genetically engineered human interleukin-11 mutein (mIL-11) on chemotherapy- induced thrombocytopenia (CIT) patients, a multicenter randomized controlled trial was conducted in China, comparing mIL-11 with the standard recombinant human interleukin-11 (rhIL-11, NEUMEGA) treatment in 83 cancer patients who had experienced platelet counts of ≤75,000/μL during the chemotherapy cycle immediately preceding study entry. Methods: Patients were randomized into either MR or RM group. Group MR represents the subcutaneous administration of mIL-11 (7.5 μ g/kg) once daily for 10 days beginning 72 hours after chemotherapy during a 21-day chemotherapy (cycle 1) followed by once daily subcutaneous administration of rhIL-11 in the clinical dose (25 μ g/kg) for 10 days (cycle 2). Group RM represents vice versa. In between cycle 1 and 2 for both groups, a 7-day wash-out period was assigned. Results: Intent-to-treat populations of mIL-11 (n=70) or rhIL-11 (n=76) were analyzed to evaluate the safety at all visits. Adverse events were mild or moderate, and the incidence of drug-related adverse events of mIL-11 (25.7%) were lower than those of rhIL-11 (40.8%) (p=0.07). None of Gr 3,4 unexpected adverse events nor death was observed during the study. In addition, no patients developed antibodies against the mIL-11 protein during the study. For the evaluation of efficacy, sixty patients were analyzed for their average platelet counts during the study. mIL-11 (7.5 μ g/kg) as well as rhIL- 11 (25 μ g/kg) were effective to increase the nadir platelet counts (62.58 ± 36.59 × 103/μL vs. 60.19 ± 32.09 × 103/μL for mIL-11 vs rhIL-11), as compared with the nontreated control group (40.98 ± 17.90 × 103/μ L) (p<0.0001). There was statistically no difference between mIL-11 and rhIL-11 for their efficacy, including average platelet counts (197.8 ± 123.6 × 103/μ L vs. 202.3 ± 118.9 × 103/μ L), and the platelet recovery rate during the study. Conclusions: mIL- 11 has equivalent thrombopoietic activity and is well tolerated at dose of 7.5 μg/kg, one-third dose of the clinical dose of rhIL-11 (25 μg/kg), suggesting the potential to reduce CIT in this model. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ViroMed Co., Ltd.
Phase II Trial of Cyclophosphamide, Lenalidomide and Dexamethasone (CYCLO-LEN-DEX) for Previously Untreated Patients with Light-Chain Amyloidosis (AL)
Authors: Joan Blade, Albert Oriol, Juan José Lahuerta, Maria-Victoria Mateos, Javier de la Rubia, Miguel T Hernandez, Miquel Granell, Carlos Fernandez de Larrea, Jesus F. San Miguel, M Teresa Cibeira
Journal: Blood (2014)