tbuckley/cabot-search huggingface dataset:
A phase III randomized clinical trial (RCT) of tandem myeloablative autologous stem cell transplant (ASCT) using peripheral blood stem cell (PBSC) as consolidation therapy for high-risk neuroblastoma (HR-NB): A Children's Oncology Group (COG) study.
Authors: Julie R. Park, Susan G. Kreissman, Wendy B. London, Arlene Naranjo, Susan Lerner Cohn, Michael D. Hogarty, Sheena Cretella Tenney, Daphne Haas-Kogan, Peter John Shaw, James Duncan Geiger, John J Doski, Sandra Wooton Gorges, Geetika Khanna, Stephan D. Voss, John M. Maris, Stephan A. Grupp, Lisa Diller
Journal: Journal of Clinical Oncology (2016)

LBA3 Background: ASCT improves event-free survival (EFS) for HR-NB. Pilot studies suggest that intensification of myeloablative therapy using tandem ASCT further improves outcome for HR-NB. We conducted a multicenter RCT comparing tandem vs. single consolidation in patients with HR-NB. Methods: Between 11/2007 and 2/2012, 652 eligible patients (pts) with newly diagnosed HR-NB received induction therapy: 6 cycles of chemotherapy including initial 2 cycles of dose-intensive cyclophosphamide/topotecan followed by PBSC collection. Randomization occurred at end induction to single ASCT with carboplatin-etoposide-melphalan (CEM) or tandem ASCT with thiotepa–cyclophosphamide ASCT followed by a modified CEM (TC:CEM). HR pts with non-MYCN amplified Stage 3 (age&gt;18mos) or Stage 4 (age 12-18 mos) tumors were non-randomly assigned to single ASCT (CEM). EFS and overall survival (OS) were analyzed as intent-to-treat. Results: Median age at study entry was 3.1 yrs, 88% (n=574 pts) had Stage 4 disease and 38.2% (n=249 tumors) had MYCN amplification. A total of 355 pts were randomized (CEM n=179 pts; TC:CEM n=176 pts) and 27 patients were non-randomly assigned to CEM. Of randomized pts, 249 patients received post-consolidation immunotherapy on COG trials. Treatment-related mortality was 2.6% (Induction n=7 [1%]; Consolidation n=10 [2.8%; n=8 CEM, n=2 TC:CEM]). Rates of severe mucosal, infectious or liver toxicities were similar between arms. 3-year EFS and OS from diagnosis were 51.1±2.0% and 68.2±1.9%, respectively. EFS and OS for randomized cohort are shown in the Table. Conclusions: Tandem myeloablative consolidation therapy improves survival probability in patients with high-risk neuroblastoma, especially in the setting in post-consolidative immunotherapy. Clinical trial information: NCT00567567. [Table: see text]
Abstract 3683: The stress response mediator ATF3 stabilizes p53 by competing with it for MDM2-mediated ubiquitination
Authors: Xingyao Li, Chunhong Yan
Journal: Cancer Research (2016)

Abstract While the tumor suppressor p53 is crucial for the maintenance of genetic integrity upon DNA damage and oncogenic stresses, its level and activity are tightly controlled by a complex network largely mediated by the E3 ubiquitin ligase MDM2. MDM2 catalyzes the addition of ubiqutin chains to the C-terminus of p53 and is the major ubiquitin ligase to promote proteosomal degradation of p53. We previously demonstrated that ATF3, a common stress response mediator, can bind p53 and prevent it from MDM2-mediated ubiquitination. As a consequence, ATF3 can stabilize p53 upon DNA damage and prevent cells from oncogene-induced transformation by promoting p53-mediated senescence, in line with accumulating evidence supporting that ATF3 can act as a tumor suppressor. Interestingly, ATF3 is also a bona fide substrate of MDM2, and thus, the ATF3-MDM2 interaction can fine tune p53 activity in the DNA damage response. However, the mechanism by which ATF3 blocks p53 ubiquitination to activate the latter protein remains largely undefined. Efficient ubiquitination of p53 requires the binding of MDM2 to the N-terminus of p53, and the MDM2 binding to MDMX. Here we show that neither the p53-MDM2 interaction nor the MDM2-MDMX interaction is disrupted by the binding of ATF3 to p53 or MDM2. As both ATF3 and p53 are substrates of MDM2, we explored a possibility that ATF3 competes with p53 for MDM2-mediated ubiquitination. By in-vitro ubiquitination assays, we identified that the 5 lysine residues clustering in aa 100-115 of ATF3 are required for MDM2-mediated ubiquitination. Site-specific mutagenesis indicates that MDM2 mainly ubiquitinates ATF3 at lysine 107 (K107) and lysine 108 (K108) as MDM2 fails to add ubiquitin chains to ATF3 when these two residues were mutated to arginine. Importantly, while mutations at these two residues do not affect the ATF3 binding to MDM2 or p53, the ATF3 mutant devoid of ubiquitination fails to stabilize p53 and prevent p53 from MDM2-mediated ubiquitination. These results thus demonstrate that ATF3 can activate p53 by competing with the tumor suppressor for MDM2-mediated ubiquitination. Citation Format: Xingyao Li, Chunhong Yan. The stress response mediator ATF3 stabilizes p53 by competing with it for MDM2-mediated ubiquitination. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3683.
Abstract 248: Metformin sensitizes endometrial cancer cells to chemotherapy by inhibiting IDH1-TET1 pathway
Authors: Mingzhu Bai, Zhenbo Zhang, Yinhua Yu, Youji Feng
Journal: Cancer Research (2016)

Abstract Chemotherapy-resistance is the major obstacle for endometrial carcinoma patient administration. Accumulated evidences indicate that metformin sensitizes cancers from several different sites to chemotherapy drugs and reverses progestin resistance in endometrial cancer. Our group has demonstrated that metformin reverses progestin resistance and enhances the rate of cell-killing induced by chemotherapeutic agents in endometrial cancer cells by downregulating GloI expression. Recent study has revealed that aberrant expression of IDH1 contribute to chemotherapy resistance. However, the role of IDH1 in metformin induced chemotherapy sensitivity is not well characterized. As a critical enzyme of the tricarboxylic acid (TCA) cycle, IDH1 catalyzes isocitrate to produce α-ketoglutarate (α-KG), a substrate of TET1, which control TET1-mediated epigenetic modulation of the target genes, including the chemotherapy-resistant genes. In the present study, we have found that IDH1 is overexpressed in endometrial cancers compared with benign endometrial lesions and normal endometria by immunohistochemical analysis of specimens (200 cases of endometrial cancers, 10 cases of benign endometrial lesions and 10 cases of normal endometria). Tissue microarray immunohistochemical detection showed the expression of IDH1, TET1 and 5hmc was positively correlated in different pathological types of endometrial tissue. Interestingly, we found that metformin reduces expression of IDH1 at protein levels with a time- and dose-manners in endometrial cancer cells. Furthermore, overexpression of IDH1 increased TET1 at protein level and blocked metformin-sensitized endometrial cancer to chemotherapy drugs, whereas decrease IDH1 expression lessened TET1 expression and paralleled with the attenuated chemotherapy-resistance. Mechanistic investigations revealed that TET1 involved in metformin-enhanced chemotherapy sensitivity via IDH1 by western blotting and DNA dot blotting assays, this may attribute to that reduced production of α-KG resulted from metformin-suppressing IDH1 is not enough to start TET1-mediated epigenetic modulation of chemotherapy resistant genes. Overall, our findings demonstrate that IDH1 regulates α-KG level and TET1 expression, which in turn affecting metformin mediated endometrial cancer chemotherapeutic sensitivity. Our study suggests IDH1 is a potential target to overcome cisplatin and paclitaxel resistance in endometrial cancer. Citation Format: Mingzhu Bai, Zhenbo Zhang, Yinhua Yu, Youji Feng. Metformin sensitizes endometrial cancer cells to chemotherapy by inhibiting IDH1-TET1 pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 248.
Nanofibrillar cellulose wound dressing in skin graft donor site treatment
Authors: T. Hakkarainen, R. Koivuniemi, M. Kosonen, C. Escobedo-Lucea, A. Sanz-Garcia, J. Vuola, J. Valtonen, P. Tammela, A. Mäkitie, K. Luukko, M. Yliperttula, H. Kavola
Journal: Journal of Controlled Release (2016)

Although new therapeutic approaches for burn treatment have made progress, there is still need for better methods to enhance wound healing and recovery especially in severely burned patients. Nanofibrillar cellulose (NFC) has gained attention due to its renewable nature, good biocompatibility and excellent physical properties that are of importance for a range of applications in pharmaceutical and biomedical fields. In the present study, we investigated the potential of a wood based NFC wound dressing in a clinical trial on burn patients. Previously, we have investigated NFC as a topical functionalized wound dressing that contributes to improve wound healing in mice.Wood based NFC wound dressing was tested in split-thickness skin graft donor site treatment for nine burn patients in clinical trials at Helsinki Burn Centre. NFC dressing was applied to split thickness skin graft donor sites. The dressing gradually dehydrated and attached to donor site during the first days. During the clinical trials, physical and mechanical properties of NFC wound dressing were optimized by changing its composition. From patient 5 forward, NFC dressing was compared to commercial lactocapromer dressing, Suprathel® (PMI Polymedics, Germany).Epithelialization of the NFC dressing-covered donor site was faster in comparison to Suprathel®. Healthy epithelialized skin was revealed under the detached NFC dressing. NFC dressing self-detached after 11-21days for patients 1-9, while Suprathel® self-detached after 16-28days for patients 5-9. In comparison studies with patients 5-9, NFC dressing self-detached on average 4days earlier compared with Suprathel®. Lower NFC content in the material was evaluated to influence the enhanced pliability of the dressing and attachment to the wound bed. No allergic reaction or inflammatory response to NFC was observed. NFC dressing did not cause more pain for patients than the traditional methods to treat the skin graft donor sites.Based on the preliminary clinical data, NFC dressing seems to be promising for skin graft donor site treatment since it is biocompatible, attaches easily to wound bed, and remains in place until donor site has renewed. It also detaches from the epithelialized skin by itself.
Treatment of Advanced Systemic Mastocytosis with PKC412: The French Compassionate Use Programme Experience and Historical Comparison
Authors: Marie-Olivia Chandesris, Gandhi Damaj, Danielle Canioni, Chantal Brouzes, Laure Cabaret, Katia Hanssens, Isabelle Durieu, Stéphane Durupt, Sophie Besnard, Odile Beyne-Rauzy, David Launay, Aurélie Schiffmann, Mathilde Niault, Dana Ranta, Philippe Agape, Cyrill Faure, Sylvain P Chantepie, Nicolas Daguindau, Philippe Bourget, Patrice Dubreuil, Olivier Lortholary, Olivier Hermine
Journal: Blood (2014)
Pharmacology of Antisense Drugs
Authors: C. Frank Bennett, Brenda F. Baker, Nguyen Pham, Eric Swayze, Richard S. Geary
Journal: The Annual Review of Pharmacology and Toxicology (2016)

Recent studies have led to a greater appreciation of the diverse roles RNAs play in maintaining normal cellular function and how they contribute to disease pathology, broadening the number of potential therapeutic targets. Antisense oligonucleotides are the most direct means to target RNA in a selective manner and have become an established platform technology for drug discovery. There are multiple molecular mechanisms by which antisense oligonucleotides can be used to modulate RNAs in cells, including promoting the degradation of the targeted RNA or modulating RNA function without degradation. Antisense drugs utilizing various antisense mechanisms are demonstrating therapeutic potential for the treatment of a broad variety of diseases. This review focuses on some of the advances that have taken place in translating antisense technology from the bench to the clinic.
Obesity As a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis
Authors: Charles Guenancia, Annick Lefebvre, Daniela Cardinale, Anthony F. Yu, Sylvain Ladoire, François Ghiringhelli, Marianne Zeller, Luc Rochette, Yves Cottin, Catherine Vergely
Journal: Journal of Clinical Oncology (2016)

Patients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer.
Persistence of Minimal Residual Disease Assessed By Multi-Parameter Flow Cytometry (MFC) at 30 and 90 Days after Achieving Complete Remission Predicts Outcome in Patients with Acute Myeloid Leukemia
Authors: Pramod Pinnamaneni, Jeffrey L. Jorgensen, Hagop M. Kantarjian, Elias Jabbour, Sherry R. Pierce, Mark Brandt, Sa A. Wang, Sergej Konoplev, Marina Konopleva, Steven M. Kornblau, Tapan Kadia, Courtney D. DiNardo, Naveen Pemmaraju, Michael Andreeff, Zeev Estrov, Guillermo Garcia-Manero, Jorge E. Cortes, Farhad Ravandi
Journal: Blood (2014)
Abstract 467: Immunohistochemical multiplex staining strategies with CD8, CD103, PD-1, FOXP3 and pan melanoma cocktail in tumor infiltrating lymphocytes in melanoma
Authors: David E. Tacha, Wei Yuan, Jillian Terrell
Journal: Cancer Research (2016)

Abstract Introduction Tumor-associated immune suppression can lead to defective T-cell mediated antitumor immunity. CD8 T-cells play a critical role in the host defense against cancers and infectious diseases. However, the presence of antigen-specific CD8 T-cells does not always imply that cancers and/or pathogens are efficiently eliminated in the body. In tumor infiltrating lymphocytes (TILS), other markers including CD103, PD-1 and FOXP3 are broadly expressed and have shown a wider range of immunoregulatory and important roles in T-cell activation, T- cell regulatory and programmed cell-death checkpoints. Existing methods can either deliver phenotypic information on homogenous samples such as flow cell cytometry or give immunohistochemical information on single biomarker. However, it would be of advantage to be able to visualize the distributions of multiple biomarkers in TILs that would discriminate stromal cells versus solid tumor. Therefore, a multiplex IHC stain utilizing a melanoma marker as a staining mask that separates the malignant tumor cells from stromal cells maybe a good strategy to facilitate better interpretation. Materials and Methods Monoclonal mouse antibodies to CD8, FOXP3 and PD-1 and rabbit monoclonal antibodies CD8, CD103 and PD-1 were optimally tittered for single, double and triple stains and visualized with HRP DAB/Black chromogens and/or alkaline phosphatase fast red/blue chromogens. A mouse monoclonal pan melanoma cocktail was visualized with a fast red chromogen and was used as a staining mask for melanoma tumors cells, but not stromal cells. Results Single, double and triple stains that included pan melanoma cocktail (mask) and CD8, CD103 FOXP3 and PD-1 were successfully established. All double and triple stains gave comparable results to single stains. The co-expression of TILs including CD8 and CD103 or CD8 or FOXP3 and PD-1 was easily identified with contrasting chromogens. TILs in stroma tissues and in malignant tumors cells were easily discriminated with the pan melanoma (mask) that stained only tumor cells with fast red chromogen, but did not stain TILS or stromal tissues. Conclusion The evaluation of TILS in malignant melanoma was enhanced with multiplex stains. TILs in stromal tissues and melanoma tumors cells were easily distinguished with the Pan Melanoma staining mask. These finding may help facilitate important prognostic information and thus may support the rationale for using immunotherapy strategies. Citation Format: David E. Tacha, Wei Yuan, Jillian Terrell. Immunohistochemical multiplex staining strategies with CD8, CD103, PD-1, FOXP3 and pan melanoma cocktail in tumor infiltrating lymphocytes in melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 467.
Chasing the precursor of functional hematopoietic stem cells at the single cell levels in mouse embryos
Authors: Xiaochen Wang, Yuemin Gong, Hideo Ema
Journal: Journal of Hematology & Oncology (2016)

Adult hematopoietic stem cells (HSCs), the ideal system for regenerative research, were isolated at single cell levels decades ago, whereas studies on embryonic HSCs are much more difficult. Zhou et al identified a new pre-HSC cell surface marker, CD201, by which they isolated pre-HSCs at single cell levels for further analyses. The novel expression pattern of HSC development is revealed, including the fundamental role of mammalian targets of rapamycin (mTOR) signaling pathway in HSCs emergence, and the repopulation potential of S/G2/M phase pre-HSCs. Deeper understandings of the cellular origin and developmental regulatory network of HSCs are essential to develop new strategies of generating HSCs in vitro for clinical application.
Assuring continuous quality improvement using outcomes data: A potential role for cancer registries.
Authors: R. O. Dillman, S. E. McClure
Journal: Journal of Clinical Oncology (2010)

6129 Background: There are increasing demands for transparency in health care, including making cost and outcome data more readily available to consumers and payers in order to define the quality of care delivered. Survival is a specific, significant, easily attainable, and relevant metric of the quality of cancer care, that is influenced by early detection procedures, treatment by various cancer specialists, and management of co-morbid medical conditions. Survival can be reliably measured because the date of diagnosis of invasive cancer can be ascertained from pathology reports and date of death is a well-documented vital statistic. Methods: We used the cancer registry of a 498-bed not-for-profit community hospital to identify the cohort of patients diagnosed with invasive cancer during 1989 to 2003. Standard computerized reports were generated for the entire cohort and for each of 24 specific tumor types, using computer software designed for this purpose (Electronic Registry Systems, Inc., Cincinnati, OH). Data included demographics, histology, stage, treatment, and actuarial survival curves. Timely follow-up was maintained on more than 90% of patients for 5 years after diagnosis. Results: In the internal benchmark comparison for the years 1989-1995 and 1996-2003, observed 5-year survival rates increased by 6 percentage points for the entire population, were higher for 18 of 24 specific tumor types, and unchanged for two. This improvement was associated with earlier diagnosis and increased use of systemic therapy. 5-year relative survival rates were higher than published Surveillance, Epidemiologic, and End Result (SEER) rates overall, and for 23 of 24 specific tumor types during 1996-2003 compared to 17 of 24 during 1989-1995. Survival for cancer patients improved over time and at a faster rate than observed nationally. Conclusions: Cancer registry data can be used to assess survival as an outcome measure and for comparisons to internal and external benchmarks. Other information routinely collected in cancer registries can be used to suggest which variables have been associated with changes in outcomes over time. When combined with cost data, survival could be used to determine the cost/benefit, or value of care. No significant financial relationships to disclose.
Treatment of Opioid-Use Disorders
Authors: Marc A. Schuckit
Journal: New England Journal of Medicine (2016)

T his article provides an overview of the current treatment of opioid-related conditions, including treatments provided by general practitioners and by specialists in substance-use disorders.The recent dramatic increase in misuse of prescription analgesics, the easy accessibility of opioids such as heroin on the streets, and the epidemic of opioid overdoses underscore how important it is for physicians to understand more about these drugs and to be able to tell patients about available treatments for substance-use disorders.Opioids include most prescription analgesics as well as products of the poppy plant (e.g., opium, morphine, and codeine). 1Although opioids usually are prescribed to control pain, diminish cough, or relieve diarrhea, they also produce feelings of euphoria, tranquility, and sedation that may lead the patient to continue to take these drugs despite the development of serious related problems.These problems include the need to escalate doses in order to achieve these desired effects; such levels of opioids can overwhelm respiratory drive and lead to death. 1,2pioid-use disorders are seen in persons from all educational and socioeconomic backgrounds.][5] By some estimates, almost 17,000 deaths per year are related to opioids; drug poisoning is one of the leading causes of accidental death in the United States.Approximately 3 million persons in the United States and almost 16 million worldwide have a current or past opioid-use disorder. 6The global burden of disease from opioid-related conditions approaches 11 million life-years lost from health problems, disabilities, and early death. 7n the 2013 Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (Table 1), an opioid-use disorder is defined as the repeated occurrence within a 12-month period of 2 or more of 11 problems, including withdrawal, giving up important life events in order to use opioids, and excessive time spent using opioids.A cluster of 6 or more items indicates a severe con dition. 4,8he clinical course of opioid-use disorders involves periods of exacerbation and remission, but the underlying vulnerability never disappears. 1 This pattern is similar to that of other chronic relapsing conditions (e.g., diabetes and hypertension) in which perfect control of symptoms is difficult and patient adherence to treatment is often incomplete.Although persons with opioid problems are likely to have extended periods of abstinence from opioids and often do well, 9 the risk of early death, primarily from an accidental overdose, trauma, suicide, or an infectious disease (e.g., human immunodeficiency virus [HIV] infection), is increased by a factor of 20. [10][11][12][13][14][15] Legal problems are especially likely in persons with criminal records and high impulsivity. 13The risk of adverse outcomes decreases markedly with abstinence from opioids. 9,16
Case 41-1973
Authors: Richard C. Cabot, Benjamin Castleman, Robert E. Scully, Betty U. McNeely, William H. Baker, Max L. Goodman
Journal: New England Journal of Medicine (1973)

Presentation of CaseA 24-year-old woman was admitted to the Massachusetts Eye and Ear Infirmary because of nasal obstruction.She was well until five months previously, when a sore throat developed, followed by nasal obstruction. A physician prescribed antibiotics, which gave no benefit. Three months before admission she was examined by an otolaryngologist, who found a large, necrotic nasopharyngeal mass. Antifungal agents were given, without improvement. A biopsy revealed a necrotizing granuloma. One month later bilateral otitis media developed, with drainage from both ears. Triamcinolone and nasopharyngeal douches were prescribed. Smears and cultures for bacteria, including tubercle bacilli, and for . . .