tbuckley/cabot-search huggingface dataset:
Symptom assessment in patients with cancer of unknown primary site.
Authors: Benjamin Scheier, Alexander T. Pearson, Joshua Murray Wilfong, Laurence H. Baker
Journal: Journal of Clinical Oncology (2015)

e20696 Background: Health-related quality of life (HRQOL) assessment is instructive in patients with advanced cancer. Patient self-reported assessments allow for frequent evaluation of physical and psychological distress. There has been no research to our knowledge prospectively and specifically evaluating symptom burden in patients with cancer of unknown primary site (CUP), an entity characterized by a burdensome, aggressive clinical course. Methods: We prospectively gathered symptom assessments from patients with advanced CUP in a clinic setting at the University of Michigan Comprehensive Cancer Center between July 2014 and December 2014, using the Edmonton Symptom Assessment Scale (ESAS), a previously validated tool. In the ESAS, patients rate the severity of nine symptoms: pain, tiredness, drowsiness, nausea, appetite, shortness of breath, depression, anxiety and well-being, on a 10-point scale, with 10 being the worst possible symptom severity. The sum of responses is the ESAS distress score. Patients completed questionnaires voluntarily, anonymously, and on a recurring basis at return visits. Results: A total of 40 questionnaires were completed across 137 consecutive clinic visits. Symptoms of pain, tiredness, poor appetite, depression, anxiety and well-being were moderate to severe in greater than 40% of responses. Well-being disruption was severe in 23% of responses. Only 5% of responses reported a preserved well-being. 55% of assessments rated at least one symptom as severe, and among those, 36% reported at least four as severe. Conclusions: Patient-reported HRQOL assessments allow for rapid and consistent symptom evaluation in advanced CUP. The results from our study highlight the tremendous symptom burden in the CUP population and emphasize the need for frequent and attentive supportive care to address patient distress. This data supports our institutional proposal to integrate a formal palliative care provider team into a multidisciplinary CUP clinic. ESAS Severity Symptom Median None (0) Mild (1-3) Moderate (4-7) Severe (8-10) Pain 3 28% 33% 25% 15% Tiredness 4 10% 33% 30% 28% Appetite 5.5 20% 13% 33% 35% Depression 2 48% 10% 35% 8% Anxiety 3 25% 30% 35% 10% Well-being 5 5% 23% 50% 23% Total Distress Score 32
Assessment of Postdonation Outcomes in US Living Kidney Donors Using Publicly Available Data Sets
Authors: Jieming Chen, Sanchita Bhattacharya, Marina Sirota, Sunisa Laiudompitak, Henry Schaefer, Elizabeth Thomson, Jeff Wiser, Minnie M. Sarwal, Atul J. Butte
Journal: JAMA Network Open (2019)

There are limited resources providing postdonation conditions that can occur in living donors (LDs) of solid-organ transplant. Consequently, it is difficult to visualize and understand possible postdonation outcomes in LDs.To assemble an open access resource that is representative of the demographic characteristics in the US national registry, maintained by the Organ Procurement and Transplantation Network and administered by the United Network for Organ Sharing, but contains more follow-up information to help to examine postdonation outcomes in LDs.Cohort study in which the data for the resource and analyses stemmed from the transplant data set derived from 27 clinical studies from the ImmPort database, which is an open access repository for clinical studies. The studies included data collected from 1963 to 2016. Data from the United Network for Organ Sharing Organ Procurement and Transplantation Network national registry collected from October 1987 to March 2016 were used to determine representativeness. Data analysis took place from June 2016 to May 2018. Data from 20 ImmPort clinical studies (including clinical trials and observational studies) were curated, and a cohort of 11 263 LDs was studied, excluding deceased donors, LDs with 95% or more missing data, and studies without a complete data dictionary. The harmonization process involved the extraction of common features from each clinical study based on categories that included demographic characteristics as well as predonation and postdonation data.Thirty-six postdonation events were identified, represented, and analyzed via a trajectory network analysis.The curated data contained 10 869 living kidney donors (median [interquartile range] age, 39 [31-48] years; 6175 [56.8%] women; and 9133 [86.6%] of European descent). A total of 9558 living kidney donors with postdonation data were analyzed. Overall, 1406 LDs (14.7%) had postdonation events. The 4 most common events were hypertension (806 [8.4%]), diabetes (190 [2.0%]), proteinuria (171 [1.8%]), and postoperative ileus (147 [1.5%]). Relatively few events (n = 269) occurred before the 2-year postdonation mark. Of the 1746 events that took place 2 years or more after donation, 1575 (90.2%) were nonsurgical; nonsurgical conditions tended to occur in the wide range of 2 to 40 years after donation (odds ratio, 38.3; 95% CI, 4.12-1956.9).Most events that occurred more than 2 years after donation were nonsurgical and could occur up to 40 years after donation. Findings support the construction of a national registry for long-term monitoring of LDs and confirm the value of secondary reanalysis of clinical studies.
The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma.
Authors: Hussein Basma, Sandra Ghayad, Nadine Darwiche, Raya Hamad Saab
Journal: Journal of Clinical Oncology (2015)

e21010 Background: Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children. Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, only moderate improvements in survival have been made for patients with advanced disease. Retinoic acid is a differentiation agent that has shown some anti-tumor efficacy in RMS cells in vitro, however the effects are of low magnitude. E-3-(4o-Hydroxyl-3o-adamantylbiphenyl-4-yl) acrylic acid (ST1926) is a novel orally available synthetic atypical retinoid, shown to have more potent activity than retinoic acid in several cancer cell lines. Methods: We usedin vitro and in vivo models of RMS to explore the efficacy of ST1926 as a possible therapeutic agent in rhabdomyosarcoma. Results: We found that, in vitro, ST1926 reduced RMS cell viability in all tested alveolar (ARMS) and embryonal (ERMS) rhabdomyosarcoma cell lines, at readily achievable in vivo concentrations. ST1926 induced an early DNA damage response, which led to increase in apoptosis, in addition to S-phase cell cycle arrest and a reduction in protein levels of the cell cycle kinase Cdk1. Effects were irrespective of TP53 mutational status. Interestingly, in ARMS cells, ST1926 treatment decreased levels of PAX3-FOXO1 fusion oncoprotein, and this suppression occurred at a post-translational level. In vivo, ST1926 was effective in inhibiting growth of ARMS and ERMS xenografts, and induced a prominent DNA damage response. Conclusions: We conclude that ST1926 has preclinical efficacy against RMS, and should be further investigated in this disease in clinical trials.
Successful international collaboration establishing a regional retinoblastoma program.
Authors: Raya Hamad Saab, Christiane Al Haddad, Tarek El Khoury, Rasha Al Youssef, Peter Noun, Roula Farah, Lina Farah, Riad Ma'luf, Rami Mahfouz, Ziad Bashour, Layal Bayram, Rachel Christine Brennan, Matthew W. Wilson, Sima Jeha, Hassan Mohamed El Solh
Journal: Journal of Clinical Oncology (2015)

e21024 Background: Survival of patients with intraocular retinoblastoma approaches 100% in developed countries, with salvage of the eye in more than 80%. Outcomes in developing countries are poorer, primarily due to delayed presentation, cost barriers, and lack of specialized personnel and equipment. Methods: A collaborative program was established to allow referral of children with newly diagnosed intraocular retinoblastoma in Lebanon and surrounding countries to the Children’s Cancer Center of Lebanon (CCCL). Disease staging was centralized and treatment was planned in a multidisciplinary setting. Patients received chemotherapy at the local hospital, while examination under anesthesia, focal therapy, enucleation, and radiation therapy were at CCCL at no cost to families through a program development initiative by St Jude Children’s Research Hospital (SJCRH) in Memphis, TN, USA. Challenging cases were discussed with SJCRH team via teleconference. Results: Over 2.5 years, 27 patients were evaluated; retinoblastoma was confirmed in 25. Nationalities were Lebanese (8), Syrian (16), and Iraqi (1). Two patients refused treatment. Twelve of the remaining 23 had unilateral disease; 11 underwent enucleation for Group D-E tumors. In 11 patients with bilateral disease, 12/22 eyes were eventually enucleated, 11 of which had presented with group D-E tumors. Six enucleated eyes had high-risk histologic features. Treatment coordination between the centers was feasible. Seventeen patients received chemotherapy. Twelve patients underwent cryotherapy/ thermotherapy; two patients with bilateral disease required external beam radiation. One child with bilateral disease died of meningeal recurrence. Useful vision was preserved in 19/22 (86%) remaining patients. Conclusions: Facilitating access to specialized multidisciplinary care, resolution of financial barriers, and close coordination among medical teams, all contributed to success of the program and vision salvage in affected children. The high rate of advanced intraocular disease at presentation necessitated frequent enucleation, demonstrating a need for raising awareness among pediatricians and ophthalmologists for earlier diagnosis and referral.
Multifunctional Magnetic Nanoplatform Eliminates Cancer Stem Cells via Inhibiting the Secretion of Extracellular Heat Shock Protein 90
Authors: Yajing Liu, Xiaomin Suo, Haotong Peng, Weixiao Yan, Hongjuan Li, Xinjian Yang, Zhenhua Li, Jinchao Zhang, Dandan Liu
Journal: Advanced Healthcare Materials (2019)

Abstract Cancer stem cells (CSCs) are responsible for malignant tumor initiation, recurrences, and metastasis. Therefore, targeting CSCs is a promising strategy for the development of cancer therapies. A big challenge for CSC‐based cancer therapy is the overexpression of therapeutic stress protein, heat shock protein 90 (Hsp90), which protects CSCs from further therapeutic‐induced damage, leading to the failure of treatment. Thus, efficient strategies to target CSCs are urgently needed for cancer therapy. To this end, a multifunctional nanoparticle (MNP) for CSC‐based combined thermotherapy and chemotherapy is reported. This strategy dramatically suppresses tumor growth in breast CSC xenograft‐bearing mice. Furthermore, a new mechanism is present that the MNP exerts its striking effects on CSCs by inhibiting the secretion of extracellular Hsp90 (eHsp90), resulting in the interruption of several key signaling pathways. These findings open new perspectives on the use of an MNP for effective CSC‐based cancer treatment by inhibiting the function of eHsp90.
Abstract 15562: Loss of Mitochondrial Pyruvate Carrier 1 in Cardiomyocytes Leads to Cardiac Dysfunction and Heart Failure via Hif-1 Activation
Authors: Yuan Zhang, James Cox, Jared Rutter, E. Dale Abel
Journal: Circulation (2015)

Glucose and lactate are important fuel substrates for the heart, particularly during acute hemodynamic stresses such as pressure overload or following exercise training. Cytosolic pyruvate that is generated by glycolytic metabolism of glucose or by conversion of lactate is transported into mitochondria via the recently described mitochondrial pyruvate carrier complex, which has two subunits, MPC1 and MPC2. The role of pyruvate uptake in regulating cardiac function and metabolism is incompletely understood. Thus, we generated cardiomyocyte-restricted MPC1 knockout mice (CMPC1-/-). Loss of MPC1 resulted in degradation of MPC2 leading to functional inactivation of the MPC complex in CMPC1-/- mouse hearts. Cardiac function examined by echocardiography revealed that CMPC1-/- mice exhibited normal cardiac function by the age of 8 weeks but overt systolic dysfunction was noted at the age of 18 weeks. Survival analysis showed that only 61% of CMPC1-/- mice remained alive at the age of 1year while 98% of control mice survived. At the age of 8 weeks, heart weight (HW) and the heart weight to tibia ratio (HW/TL) were significantly increased, as were characteristic transcriptional markers of pathological cardiac hypertrophy, NPPA, NPPB and Acta1. Substrate metabolism measured in isolated working hearts, revealed a 58% reduction in glucose oxidation in CMPC1-/- mice relative to control mice while palmitate oxidation was increased by 35%. Metabolomics analyses revealed accumulation of pyruvate, lactate and alanine. In contrast, malate and glutamate levels were decreased, suggesting a compensatory increase in malate and glutamate utilization. 2-hydroxyglutarate (2-HG) was also increased in CMPC1-/- mouse hearts, which may activate Hif-1α signaling. Indeed, downstream transcriptional targets of Hif-1 (LDHA, PDK1 and PKM2) were increased. These data suggest that mitochondrial pyruvate uptake although dispensable for normal cardiac development and function in non-stressed juvenile hearts ultimately precipitates pathological cardiac hypertrophy and heart failure in CMPC1-/- mice via 2-HG-mediated Hif-1 activation.
Inference of Ancient Whole-Genome Duplications and the Evolution of Gene Duplication and Loss Rates
Authors: Arthur Zwaenepoel, Yves Van de Peer
Journal: Molecular Biology and Evolution (2019)

Gene tree-species tree reconciliation methods have been employed for studying ancient whole-genome duplication (WGD) events across the eukaryotic tree of life. Most approaches have relied on using maximum likelihood trees and the maximum parsimony reconciliation thereof to count duplication events on specific branches of interest in a reference species tree. Such approaches do not account for uncertainty in the gene tree and reconciliation, or do so only heuristically. The effects of these simplifications on the inference of ancient WGDs are unclear. In particular, the effects of variation in gene duplication and loss rates across the species tree have not been considered. Here, we developed a full probabilistic approach for phylogenomic reconciliation-based WGD inference, accounting for both gene tree and reconciliation uncertainty using a method based on the principle of amalgamated likelihood estimation. The model and methods are implemented in a maximum likelihood and Bayesian setting and account for variation of duplication and loss rates across the species tree, using methods inspired by phylogenetic divergence time estimation. We applied our newly developed framework to ancient WGDs in land plants and investigated the effects of duplication and loss rate variation on reconciliation and gene count based assessment of these earlier proposed WGDs.
SAT-311-The PDGFR-beta containing PRTA-score is a novel non-invasive diagnostic algorithm for significant liver fibrosis in patients with viral, alcoholic, and metabolic liver disease
Authors: Joeri Lambrecht, Stefaan Verhulst, Inge Mannaerts, Jan-peter Sowa, Jan Best, Ali Canbay, Hendrik Reynaert, Leo A. van Grunsven
Journal: Journal of Hepatology (2019)
FRI-213-HBV RNA at 6 months predicts HBeAg loss in nucleos (t)ide analogue treated HBeAg positive patients: Demonstration of clinical utility?
Authors: Bo Wang, Jeffrey Gersch, Mary Horner, Mary Kuhns, Gavin Cloherty, Geoffrey Dusheiko, Kosh Agarwal, Ivana Carey
Journal: Journal of Hepatology (2019)
A tracer-based method enables tracking of <i>Plasmodium falciparum</i> malaria parasites during human skin infection
Authors: Béatrice M F Winkel, Clarize M de Korne, Matthias N van Oosterom, Diego Staphorst, Anton Bunschoten, Marijke C C Langenberg, Séverine C Chevalley-Maurel, Chris J Janse, Blandine Franke-Fayard, Fijs W B van Leeuwen, Meta Roestenberg
Journal: Theranostics (2019)

Introduction: The skin stage of malaria is a vital and vulnerable migratory life stage of the parasite. It has been characterised in rodent models, but remains wholly uninvestigated for human malaria parasites. To enable in depth analysis of not genetically modified (non-GMO) Plasmodium falciparum (Pf) sporozoite behaviour in human skin, we devised a labelling technology (Cy5M2, targeting the sporozoite mitochondrion) that supports tracking of individual non-GMO sporozoites in human skin. Methods: Sporozoite labelling with Cy5M2 was performed in vitro as well as via the feed of infected Anopheles mosquitos. Labelling was validated using confocal microscopy and flow cytometry and the fitness of labelled sporozoites was determined by analysis of infectivity to human hepatocytes in vitro, and in vivo in a rodent infection model. Using confocal video microscopy and custom software, single-sporozoite tracking studies in human skin-explants were performed. Results: Both in vitro and in mosquito labelling strategies yielded brightly fluorescent sporozoites of three different Plasmodium species. Cy5M2 uptake colocalized with MitoTracker® green and could be blocked using the known Translocator protein (TSPO)-inhibitor PK11195. This method supported the visualization and subsequent quantitative analysis of the migration patterns of individual non-GMO Pf sporozoites in human skin and did not affect the fitness of sporozoites. Conclusions: The ability to label and image non-GMO Plasmodium sporozoites provides the basis for detailed studies on the human skin stage of malaria with potential for in vivo translation. As such, it is an important tool for development of vaccines based on attenuated sporozoites and their route of administration.
Establishing a need for the inclusion of patient genetic vernacular in informed consent forms.
Authors: Rebecca D. Pentz, Kristopher A Hendershot, Taylor White, Margie Dixon, Travis Ryan Deal
Journal: Journal of Clinical Oncology (2015)

e22234 Background: Given the trajectory into precision medicine, patient understanding of basic genetics is integral to making an informed decision regarding participating in clinical trials involving genetic testing. Patients may be unable to provide adequate consent for these studies due to genetic health illiteracy. Methods: Patients eligible for surgical removal of tumors were asked to donate tissue to a biobank for genetic testing. As part of a national, multisite NCI biobanking study, we interviewed 101 of these patients about the informed consent issues surrounding broad future research use of donated tissues and asked them to define key genetic terminology at the end of the interview. Both the informed consent and interview guide provided explanations of DNA, genes, and genetic testing. DNA was described as ‘what your genes are made of.’ Genes were described as ‘being passed down from parent to child, determining your physical traits, determining whether you get some diseases, and acting like instruction books thatexist in every cell of your body.’ Genetic research was described as ‘helping researchers to learn more about how to prevent and treat diseases.’ Results: 23 (22.8%) subjects defined DNA in a manner similar to the definition provided. However, 28 (27.7%) defined DNA as what is used for individual identification. 47 (46.5%) defined genes as being responsible for physical or behavioral traits, 26 (25.7%) defined them as determining hereditary, 3 (2.97%) defined them as being related to disease, and 2 (1.98%) defined them as being instructions for cells. Last, 19 (18.8%) defined genetic research as being related to diseases or health, but 22 (21.8%) defined it as research about their own genes or makeup. Overall, there were 12 different definitions for DNA, 13 for genes, and 10 for genetic research. Conclusions: Most patients understand these three key genetic concepts in a variety of ways and use different terms than those used by healthcare professionals in the informed consent document. In order to improve informed consent, we propose using definitions in consents that include the terms most frequently cited by patients, thus using consensus patient language to improve understanding.
FRI-291-Glucokinase sensitizes hepatocarcinoma cells to the lipogenic activity of fructose and controls accumulation of lipid droplets and secretion of triglyceride-rich lipoproteins
Authors: Olivier Diaz, Clémence Jacquemin, Baptiste Panthu, Bénédicte Elena-Herrmann, Gilles Rautureau, Patrice Andre, Vincent Lotteau
Journal: Journal of Hepatology (2019)
The Time Has Come!
Authors: Margaret Tempero
Journal: Journal of the National Comprehensive Cancer Network (2019)

The Time Has Come! W hen imatinib was approved by the FDA almost 20 years ago, a passionate prediction arose that, going forward, all targeted therapeutics would be approved without regard for the primary site of disease, based solely on the presumed molecular driver.I said, "No!That won't work."A driver for one cancer may not be a driver for another.There is also the fact that we have successful chemotherapy treatments for many cancers-who would want to mess with that paradigm?Well, of course, I was wrong.And the FDA has been very receptive to the concept of crosscutting approvals.Thank you!With the breakthrough of immuno-oncology, we now have pembrolizumab approved for any patient with a microsatellite instability (MSI)-high or mismatch repair (MMR)-deficient tumor.And now, larotrectinib, an inhibitor of tropomyosin receptor kinase that is highly active against an NTRK gene fusion, has been approved across all disease types.OK, then, wake up!How do we find these patients?The new therapies mean we must perform MSI/MMR testing and molecular profiling of tumor tissue for everyone, at least those with metastatic disease.How else would we find patients eligible for therapy with these new treatments?Then what are the barriers?The first is the adequacy of the diagnostic biopsy sample, which is likely to be accessed for analysis.To begin, we need to make sure our diagnostic biopsies contain enough material for ancillary molecular analyses.This isn't trivial.This will generally require more than the usual fine-needle aspiration squirt of sample that can be used for diagnosis.Increasingly, we are gaining confidence in analyses derived from cell-free DNA in blood or other body fluids.So we should be able to sort this out.The next barrier is cost.However, the beauty of all this is that because of advancing technologies, the cost of these analyses is decreasing and the market competition is robust.We are not testing for single abnormalities but instead for a broad panel of aberrations that could be clinically actionable.Insurance providers will be faced increasingly with this request.Fortunately, NCCN Guidelines are incorporating the need for these studies.This mandates reimbursement at least from the Centers for Medicare & Medicaid Services, and we hope private insurers will follow suit.The other niggling issue here is that, without a doubt, we will find molecular abnormalities in tumors that reflect germline mutations.This obviously leads to the need for genetic counseling and germline testing for mutations.But I consider that a bonus.We can help these families.We just need to be prepared to deal with the increased need for counseling and screening.Without a doubt, the era of precision oncology is here, and I expect many more breakthroughs will come soon.Just as we now order a "chem" panel when we may only need to check bilirubin, we will now order broad molecular diagnostics on a variety of specimens.The time is here.The time is now.