tbuckley/cabot-search huggingface dataset:
Maintaining light sedation is important: next steps for research
Authors: John W Devlin, Bhavna Seth, Sarah Train, Dale M Needham
Journal: Thorax (2021)

Critically ill adults are frequently administered continuous sedative and/or opioid infusions, based on clinicians’ intentions of optimising comfort, facilitating mechanical ventilation and promoting safety.1 Deep sedation, more prevalent during the current SARS-CoV-2 pandemic,2 is associated with coma, delirium and muscle weakness, with associated impairments in survival and physical, cognitive and mental health.1 The 2013 Pain, Agitation and Delirium (PAD) guidelines made an ungraded statement that using a sedation protocol (SP) to target light levels of sedation or instituting Spontaneous Awakening Trials (SAT) will improve short-term outcomes (eg, duration of mechanical ventilation or ICU stay).3 The 2018 PAD, Immobility and Sleep (PADIS) guidelines make a graded conditional recommendation that light (vs deep) sedation, should be used, regardless of sedative choice, in critically ill, mechanically ventilated adults.1 

The PADIS panel relied on evidence from eight randomised controlled trials (RCTs), published prior to October 2015, where light versus deep sedation was defined a priori and evaluated ≥4 times daily.1 Studies solely evaluating an SAT were excluded as this approach often results in light sedation at only a single time point during the 24-hour day.1 Results from RCTs were prioritised over cohort studies. Four RCTs compared a light (vs deep) sedation approach using the same sedative regimen. The other four RCTs compared a light (vs deep) approach where the light group either received a no (or ‘as needed’) sedation approach (n=2) or dexmedetomidine (n=2). Two RCTs implemented light sedation intervention for …
Abstract 405: The role of GALNT14 in chemoresistant and metastatic osteosarcoma
Authors: Zachary D. Prudowsky, Tajhal Patel, Kimal Rajapakshe, Christian Coarfa, Ryan Shuck, Nino Rainusso, Jason Yustein
Journal: Cancer Research (2021)

Abstract Introduction: Osteosarcoma is the most common bone tumor in children and adolescents. Many patients have disease progression through standard chemotherapy regimens of methotrexate, cisplatin, and doxorubicin. Presently, there are no salvage therapies that have added significant survival benefits, leaving minimal options for relapsed and resistant disease. Additionally, there are no clinically significant biomarkers for this disease that would predict treatment failures. N-acetylgalactosaminyltransferase 14 (GALNT14) is an enzyme that initiates O-linked glycosylation to outer membrane-bound and extracellular proteins. Using transcriptomic analyses, we identified GALNT14 overexpression correlated with poor tumor necrosis and survival outcomes. Therefore, we hypothesize that GALNT14 contributes to metastatic and chemoresistant phenotypes in pediatric osteosarcoma. Methods: Transcriptomic data from the Therapeutically Applicable Research for Generating Effective Treatments (TARGET) database and RNA-sequencing of institutional patient-derived xenografts (PDXs) revealed that overexpression of GALNT14 correlated to poor necrosis rates. Gene Set Enrichment Analysis (GSEA) also identified upregulation of glycosylation pathways. Aberrant expression of GALNT14 was confirmed using quantitative polymerase chain reaction (qPCR) and Western blot analyses in various osteosarcoma cell lines. Transient GALNT14 knockdown and overexpression were then analyzed for effects on proliferation, invasion, migration, and chemotherapy response in vitro. Kaplan-Meier curves demonstrating overall survival (OS) and event-free survival (EFS) were established using data from the TARGET database. Results: GALNT14 expression was higher in both commercial and PDX cell lines that were known to be more prone for chemoresistance and invasiveness. The highest quartile of patients based on GALNT14 overexpression had 40% OS and 25% EFS, compared to 80% (p=0.002) and 75% (p&amp;lt;0.001) for the lowest quartile of expression, respectively. Summary: GALNT14 shows promise as a predictive marker of chemoresistance and metastasis for pediatric osteosarcoma. Future functional genomic studies through gain and loss-of-function assays will evaluate the role of GALNT14 in osteosarcoma chemoresistance and metastatic potential. Citation Format: Zachary D. Prudowsky, Tajhal Patel, Kimal Rajapakshe, Christian Coarfa, Ryan Shuck, Nino Rainusso, Jason Yustein. The role of GALNT14 in chemoresistant and metastatic osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 405.
Single-cell-resolved differentiation of human induced pluripotent stem cells into pancreatic duct-like organoids on a microwell chip
Authors: Sandra Wiedenmann, Markus Breunig, Jessica Merkle, Christine von Toerne, Tihomir Georgiev, Michel Moussus, Lucas Schulte, Thomas Seufferlein, Michael Sterr, Heiko Lickert, Stephanie Ellen Weissinger, Peter Möller, Stefanie M. Hauck, Meike Hohwieler, Alexander Kleger, Matthias Meier
Journal: Nature Biomedical Engineering (2021)
Early surgical outcomes following 400 feminising genital reconstructive surgeries performed by a single urological surgeon
Authors: U. Walters, T.E. Pidgeon, T. Yap, M. Takhar, H. Gresty, M. Bertoncelli Tanaka, A. Dusoye, P.J. Eyskens, M.H. Junejo, K.A. Bell, K. Sahota, R. Crawford, A. Kanthabalan, N. Bedi, F. Hosking-Jervis, R.L. Oliver, T.G. Rashid
Journal: European Urology (2021)
Abstract 1404: Loss of adenomatous polyposis coli induces DOX resistance through upregulation of ABC transporters
Authors: Casey D. Stefanski, Jenifer R. Prosperi, Lauren Milac
Journal: Cancer Research (2021)

Abstract Chemoresistance is a leading cause of breast cancer related deaths. Therefore, understanding the molecular basis for chemoresistance is essential for novel therapeutic advancement improving patient outcome. The Adenomatous Polyposis Coli (APC) tumor suppressor is lost in up to 70% of sporadic breast cancer; however, little is known about how APC loss contributes to chemoresistance. Using mammary tumor cells isolated from the ApcMin/+ mouse crossed to the Polyoma middle T antigen (PyMT) transgenic model, we were the first to show that APC loss decreased doxorubicin (DOX) induced apoptosis. Therefore, we examined the mechanisms contributing to DOX resistance with APC loss to identify combination therapy options. We previously made the novel observation that APC loss in MMTV-PyMT;ApcMin/+ cells activated signal transducer and activator of transcription 3 (STAT3) thereby increasing the expression of the drug efflux pump, multidrug resistance protein 1 (MDR1). ATP-binding cassette (ABC) transporters, such as MDR1, are one of the most well-known contributors to drug resistance. These ABC transporters are capable of exporting drugs from the cell preventing apoptosis. Decreased intracellular DOX accumulation was observed in APC-deficient cells suggesting enhanced drug efflux. To investigate this decreased intracellular DOX accumulation, we measured the expression and activity of the drug export pumps, MDR1 and multidrug resistance protein 1 (MRP1). APC-deficient cells also have increased expression of MRP1. We used a calcein incorporation assay and demonstrated that APC loss increased MDR1 activity, which was restored by an MDR1 inhibitor. In addition, MDR1 inhibition sensitized the MMTV-PyMT;ApcMin/+ cells to DOX-mediated apoptosis. MRP1 inhibition through genetic manipulation will be used to assess MRP1 activity using the calcein AM assay and its contribution to DOX resistance. MDR1 and MRP1 inhibition will also be used to restore intracellular DOX accumulation. Future studies including evaluating human tumor protein lysates will for APC, MDR1, and MRP1 expression. Correlation studies will be used to determine whether loss of APC correlates with either high expression of MDR1 or MRP1. Taken together, APC loss mediates DOX resistance via exporting DOX demonstrating the potential use of combination therapy to overcome chemoresistance. Citation Format: Casey D. Stefanski, Jenifer R. Prosperi, Lauren Milac. Loss of adenomatous polyposis coli induces DOX resistance through upregulation of ABC transporters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1404.
Micropatterns and peptide gradient on the inner surface of a guidance conduit synergistically promotes nerve regeneration in vivo
Authors: Deteng Zhang, Ziming Li, Haifei Shi, Yuejun Yao, Wang Du, Pan Lu, Kejiong Liang, Liangjie Hong, Changyou Gao
Journal: Bioactive Materials (2021)

Both of the surface topographical features and distribution of biochemical cues can influence the cell-substrate interactions and thereby tissue regeneration in vivo. However, they have not been combined simultaneously onto a biodegradable scaffold to demonstrate the synergistic role so far. In this study, a proof-of-concept study is performed to prepare micropatterns and peptide gradient on the inner wall of a poly (D,L-lactide-co-caprolactone) (PLCL) guidance conduit and its advantages in regeneration of peripheral nerve in vivo. After linear ridges/grooves of 20/40 μm in width are created on the PLCL film, its surface is aminolyzed in a kinetically controlled manner to obtain the continuous gradient of amino groups, which are then transferred to CQAASIKVAV peptide density gradient via covalent coupling of glutaraldehyde. The Schwann cells are better aligned along with the stripes, and show a faster migration rate toward the region of higher peptide density. Implantation of the nerve guidance conduit made of the PLCL film having both the micropatterns and peptide gradient can significantly accelerate the regeneration of sciatic nerve in terms of rate, function recovery and microstructures, and reduction of fibrosis in muscle tissues. Moreover, this nerve conduit can also benefit the M2 polarization of macrophages and promote vascularization in vivo.
Myocardial Stiffness by Cardiac Elastography in Hypertrophic Cardiomyopathy
Authors: Jwan A. Naser, Orawan Anupraiwan, Rosalyn O. Adigun, Joseph J. Maleszewski, Sorin V. Pislaru, Patricia A. Pellikka, Cristina Pislaru
Journal: JACC. Cardiovascular imaging (2021)
Novel personalized cancer vaccine platform based on Bacillus Calmette-Guèrin
Authors: Erkko Ylösmäki, Manlio Fusciello, Beatriz Martins, Sara Feola, Firas Hamdan, Jacopo Chiaro, Leena Ylösmäki, Matthew J Vaughan, Tapani Viitala, Prasad S Kulkarni, Vincenzo Cerullo
Journal: Journal for ImmunoTherapy of Cancer (2021)

Intratumoral BCG therapy, one of the earliest immunotherapies, can lead to infiltration of immune cells into a treated tumor. However, an increase in the number of BCG-induced tumor-specific T cells in the tumor microenvironment could lead to enhanced therapeutic effects.Here, we have developed a novel cancer vaccine platform based on BCG that can broaden BCG-induced immune responses to include tumor antigens. By physically attaching tumor-specific peptides onto the mycobacterial outer membrane, we were able to induce strong systemic and intratumoral T cell-specific immune responses toward the attached tumor antigens. These therapeutic peptides can be efficiently attached to the mycobacterial outer membrane using a poly-lysine sequence N-terminally fused to the tumor-specific peptides.Using two mouse models of melanoma and a mouse model of colorectal cancer, we observed that the antitumor immune responses of BCG could be improved by coating the BCG with tumor-specific peptides. In addition, by combining this novel cancer vaccine platform with anti-programmed death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy, the number of responders to anti-PD-1 immunotherapy was markedly increased.This study shows that intratumoral BCG immunotherapy can be improved by coating the bacteria with modified tumor-specific peptides. In addition, this improved BCG immunotherapy can be combined with ICI therapy to obtain enhanced tumor growth control. These results warrant clinical testing of this novel cancer vaccine platform.
Abstract 2408: Targeted bioinformatics analysis identifies high <i>ABAT</i> transcript expression as a multi-cancer marker of favorable patient prognosis
Authors: Erika L. Knott, Nancy J. Leidenheimer
Journal: Cancer Research (2021)

Abstract Unsupervised analysis of γ-aminobutyric acid (GABA) system genes has identified some genes as correlated with indicators of severity in several cancers. Central to GABA system function is the GABA shunt, a series of reactions bypassing two steps of the tricarboxylic acid (TCA) cycle, which encompasses the synthesis and metabolism of the non-proteinaceous amino acid GABA. Here, we have undertaken a targeted bioinformatics study utilizing publicly available databases - including cBioPortal, UALCAN, the Human Protein Atlas, and the Human Cancer Metastasis Database - to evaluate the expression of transcripts encoding GABA shunt enzymes, and their correlation with clinical outcomes, across nearly three dozen cancers from The Cancer Genome Atlas (TCGA) Pan-Cancer Atlas initiative dataset. Of the three genes encoding enzymes of the GABA shunt, we have focused on ABAT, which encodes the GABA-catabolizing enzyme γ-aminobutyrate aminotransferase (ABAT; aka GABA-transaminase or GABA-T). ABAT is widely expressed across all 32 TCGA studies, ranging from moderate to high expression in skin cutaneous melanoma and low-grade glioma (average ± SEM = 6.5 ± 0.08; 13.3 ± 0.03 log2 RSEM), respectively. For the majority of these tissues, the expression of ABAT in tumor is lower than its expression in adjacent normal tissue. Importantly, ABAT expression is prognostic in 11 cancers: upregulation is favorably prognostic for ACC, BLCA, BRCA, and PAAD, while downregulation is unfavorably prognostic for KIRC, KIRP, LGG, LIHC, LUAD, MESO, and SKCM (Kaplan-Meier survival estimates, z-score = 0.5, p &amp;lt; 0.05). A subset of these cancers, as well as 4 other TCGA cancers, show a decrease in ABAT transcript expression with increasing tumor stage (p &amp;lt; 0.05). Furthermore, 7 cancers express lower levels of ABAT transcripts in the primary tumors of patients with metastases vs the primary tumors of patients without metastases. Additionally, metastases of 4 cancers express elevated levels of ABAT transcripts vs their respective primary tumors. These results imply a dynamic regulation of ABAT expression throughout cancer progression. As very few studies have directly addressed the role of ABAT in cancer progression, the identification of ABAT transcript expression as a broadly applicable multi-cancer prognostic marker may ultimately benefit a wide variety of patients. We would like to thank the Feist-Weiller Cancer Center and LSU Health, Shreveport for supporting this work. Citation Format: Erika L. Knott, Nancy J. Leidenheimer. Targeted bioinformatics analysis identifies high ABAT transcript expression as a multi-cancer marker of favorable patient prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2408.
Enzymatic activation of pyruvate kinase increases cytosolic oxaloacetate to inhibit the Warburg effect
Authors: Elizabeth K. Wiese, Sadae Hitosugi, Sharon T. Loa, Annapoorna Sreedhar, Lindsey G. Andres-Beck, Kiran Kurmi, Yuan-Ping Pang, Larry M. Karnitz, Wilson I. Gonsalves, Taro Hitosugi
Journal: Nature Metabolism (2021)
Abstract 2599: Does tumor volume effect the spectroscopic classification of brain cancer patients
Authors: Ashton G. Theakstone, Paul M. Brennan, Matthew J. Baker
Journal: Cancer Research (2021)

Abstract This study focuses on investigating the link between brain tumor volume and the spectroscopic classification between patients with known gliomas and healthy controls. Discrimination of brain cancer vs. non-cancer patients using serum-based ATR-FTIR diagnostics was first developed by Hands et al. achieving sensitivity and specificity values of 92.8% and 91.5% respectively. Cameron et al. then went on to stratifying between specific brain tumor types and was successful in providing a sensitivity of 90.1% and a specificity of 86.3%. Expanding on these studies, it is vital to determine if the size of a tumor has a direct effect on the sensitivity and specificity and whether or not it was only the larger tumors that were being identified as cancerous. A cohort of 90 patients whose tumor volumes were calculated using their MRI images (either T1-weighted contrast enhanced, T2-weighted or FLAIR images), including patients with high-grade glioblastoma multiforme (GBM), and low-grade gliomas such as anaplastic astrocytoma, astrocytoma, oligoastrocytoma and oligodendroglioma, were used for investigation. Utilizing ATR-FTIR spectroscopy coupled with machine learning algorithms these tumor patients were stratified against 87 healthy controls and were classified as either cancer or non-cancer. From these initial findings' sensitivities, specificities and balanced accuracies were greater than 88% and cancer patients with tumor volumes as small as 0.2 cubic cm were correctly identified, demonstrating that classifications are not affected by tumor volume. Both small and low-grade gliomas were identified which shows great promise for this technique to be used as a screening tool or in diagnostics for early detection of brain tumors. Citation Format: Ashton G. Theakstone, Paul M. Brennan, Matthew J. Baker. Does tumor volume effect the spectroscopic classification of brain cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2599.
Cell Line–Specific Network Models of ER+ Breast Cancer Identify Potential PI3Kα Inhibitor Resistance Mechanisms and Drug Combinations
Authors: Jorge Gómez Tejeda Zañudo, Pingping Mao, Clara Alcon, Kailey Kowalski, Gabriela N. Johnson, Guotai Xu, Jose Baselga, Maurizio Scaltriti, Anthony Letai, Joan Montero, Réka Albert, Nikhil Wagle
Journal: Cancer Research (2021)

Abstract Durable control of invasive solid tumors necessitates identifying therapeutic resistance mechanisms and effective drug combinations. In this work, we used a network-based mathematical model to identify sensitivity regulators and drug combinations for the PI3Kα inhibitor alpelisib in estrogen receptor positive (ER+) PIK3CA-mutant breast cancer. The model-predicted efficacious combination of alpelisib and BH3 mimetics, for example, MCL1 inhibitors, was experimentally validated in ER+ breast cancer cell lines. Consistent with the model, FOXO3 downregulation reduced sensitivity to alpelisib, revealing a novel potential resistance mechanism. Cell line–specific sensitivity to combinations of alpelisib and BH3 mimetics depended on which BCL2 family members were highly expressed. On the basis of these results, newly developed cell line–specific network models were able to recapitulate the observed differential response to alpelisib and BH3 mimetics. This approach illustrates how network-based mathematical models can contribute to overcoming the challenge of cancer drug resistance. Significance: Network-based mathematical models of oncogenic signaling and experimental validation of its predictions can identify resistance mechanisms for targeted therapies, as this study demonstrates for PI3Kα-specific inhibitors in breast cancer.
Application of Information Technology to Clinical Trial Evaluation and Enrollment
Authors: Mitchell S. von Itzstein, Melanie Hullings, Helen Mayo, M. Shaalan Beg, Erin L. Williams, David E. Gerber
Journal: JAMA Oncology (2021)

As cancer treatment has become more individualized, oncologic clinical trials have become more complex. Increasingly numerous and stringent eligibility criteria frequently include tumor molecular or genomic characteristics that may not be readily identified in medical records, rendering it difficult to best match clinical trials with clinical sites and to identify potentially eligible patients once a clinical trial has been selected and activated. Partly because of these factors, enrollment rates for cancer clinical trials remain low, creating delays and increased costs for drug development. Information technology (IT) platforms have been applied to the implementation and conduct of clinical trials to improve efficiencies in several medical fields, and these platforms have recently been introduced to oncologic studies.This review summarizes cancer and noncancer studies that used IT platforms for assistance with clinical trial site selection, patient recruitment, and patient screening. The review does not address the use of IT in other aspects of clinical research, such as wearable physical activity monitors or telehealth visits. A large number of IT platforms (which may be patient facing, site or investigator facing, or sponsor facing) are now commercially available. These applications use artificial intelligence and/or natural language processing to identify and summarize protocol eligibility criteria, institutional patient populations, and individual electronic health records. Although there is an expanding body of literature examining the role of this technology, relatively few studies to date have been performed in oncologic settings.This review found that an increasing number and variety of IT platforms were available to assist in the planning and conduct of clinical trials. Because oncologic clinical care and clinical trial protocols are particularly complex, nuanced, and individualized, published experience with this technology in other fields may not be fully applicable to cancer settings. The extent to which these services will overcome ongoing and increasing challenges in cancer clinical research remains unclear.
Edo-S101, a Bendamustine (BDM)/ Histone-Deacetylase Inhibitor (HDACi) Fusion Molecule, Demonstrates Potent Preclinical Activity Against T-Cell Malignancies and Overcomes BDM-Resistance
Authors: Rosaria De Filippi, Stefania Crisci, Sara Mele, Serena Zanotta, Gaetano Corazzelli, Domenico Galati, Davide Coppola, Piera Maiolino, Mariangela Saggese, Francesco Volzone, Emanuela Morelli, Daniela Donnarumma, Gianpaolo Marcacci, Ferdinando Frigeri, Niels Odum, Thomas Mehrling, Antonio Pinto
Journal: Blood (2017)