tbuckley/cabot-search huggingface dataset:
Prevalence and Characteristics of Virginia Hospitals Suing Patients and Garnishing Wages for Unpaid Medical Bills
Authors: William E. Bruhn, Lainie Rutkow, Peiqi Wang, Stephen E. Tinker, Christine Fahim, Heidi N. Overton, Martin A. Makary
Journal: JAMA (2019)

This study uses 2017 court records to characterize how frequently Virginia hospitals take legal action to garnish patients’ wages to recover unpaid medical expenses, and the characteristics of hospitals and patient employers associated with the actions.
Abstract LB-066: BiTE-armored CARs overcome antigen escape in EGFRvIII-targeted therapy for glioblastoma
Authors: Bryan D. Choi, Xiaoling Yu, Ana P. Castano, Amanda A. Bouffard, William T. Curry, Bob S. Carter, Marcela V. Maus
Journal: Cancer Research (2019)

Abstract Glioblastoma (GBM) is a devastating disease with an extremely poor prognosis. Immune therapy with T cells engineered to express chimeric antigen receptors (CARs), represents a promising alternative to conventional therapy, but responses have been limited to date due to heterogeneous target antigen expression and the emergence of immune escape following treatment with CAR T cells directed at a single target. This was observed in clinical studies with CART-EGFRvIII, wherein EGFRvIII-targeted T cells successfully localized to the brain tumor microenvironment, but ultimately failed to prevent disease progression—with post-treatment specimens demonstrating high levels of wild-type EGFR despite reduced expression of EGFRvIII. To help address this therapeutic barrier, we developed a novel CAR construct engineered for local delivery of bispecific T-cell engagers (BiTEs) that target residual tumor. Specifically, EGFRvIII-targeted CAR T cells were engineered to secrete BiTEs against wild-type EGFR, which is not expressed in normal brain but frequently amplified in GBM, recurrent disease and other cancers. Our results demonstrate that human T cells are efficiently transduced with the dual CART.BiTE transgene, and that modified cells successfully secrete biologically active EGFR-specific BiTEs that not only redirect CAR T cells but also recruit and activate untransduced bystander T cells against wild-type EGFR. Recapitulating clinical data, EGFRvIII CAR T cells were unable to completely treat tumors with heterogenous EGFRvIII expression, leading to outgrowth of EGFRvIII-negative, EGFR-positive recurrence. Conversely, CART.BiTE cells mediated potent antitumor efficacy in the setting of heterogeneous tumors and EGFRvIII antigen loss. In these models, infusion of CART.BiTE cells yielded extended survival and cured mice with even late-stage, established intracerebral tumors, including those derived from glioma cell lines and patient-derived glioma neurosphere cultures. Unlike CAR T cells directly targeting EGFR, which caused on-target toxicity against human skin grafts in vivo, secreted BiTE-EGFR was locally effective at exceedingly low concentrations that did not mediate immune responses against healthy human tissue. These results demonstrate that CARs and BiTEs can be combined strategically to mitigate the impact of antigen heterogeneity in GBM, and also provide a unique T-cell-based delivery method for BiTEs to tumors in the brain. Citation Format: Bryan D. Choi, Xiaoling Yu, Ana P. Castano, Amanda A. Bouffard, William T. Curry, Bob S. Carter, Marcela V. Maus. BiTE-armored CARs overcome antigen escape in EGFRvIII-targeted therapy for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-066.
Evidence-Based Clinical Practice Guidelines for Microcystic Adnexal Carcinoma
Authors: Brandon Worley, Joshua L. Owen, Christopher A. Barker, Ramona Behshad, Christopher K. Bichakjian, Diana Bolotin, Jeremy S. Bordeaux, Scott Bradshaw, Todd V. Cartee, Sunandana Chandra, Nancy Cho, Jennifer Choi, M. Laurin Council, Daniel B. Eisen, Nicholas Golda, Conway C. Huang, Sherrif F. Ibrahim, S. I. Brian Jiang, John Kim, Mario Lacutoure, Naomi Lawrence, Erica H. Lee, Justin J. Leitenberger, Ian A. Maher, Margaret Mann, Kira Minkis, Bharat Mittal, Kishwer S. Nehal, Isaac Neuhaus, David M. Ozog, Brian Petersen, Faramarz Samie, Thuzar M. Shin, Joseph F. Sobanko, Ally-Khan Somani, William G. Stebbins, J. Regan Thomas, Valencia Thomas, David Tse, Abigail Waldman, Y. Gloria Xu, Siegrid S. Yu, Nathalie C. Zeitouni, Tim Ramsay, Emily Poon, Murad Alam
Journal: JAMA Dermatology (2019)

Microcystic adnexal carcinoma (MAC) occurs primarily in older adults of white race/ethnicity on sun-exposed skin of the head and neck. There are no formal guiding principles based on expert review of the evidence to assist clinicians in providing the highest-quality care for patients.
Experimental Acute Exposure to Thirdhand Smoke and Changes in the Human Nasal Epithelial Transcriptome
Authors: Giovanna L. Pozuelos, Meenakshi S. Kagda, Suzaynn Schick, Thomas Girke, David C. Volz, Prue Talbot
Journal: JAMA Network Open (2019)

<h3>Importance</h3> No previous studies have shown that acute inhalation of thirdhand smoke (THS) activates stress and survival pathways in the human nasal epithelium. <h3>Objective</h3> To evaluate gene expression in the nasal epithelium of nonsmoking women following acute inhalation of clean air and THS. <h3>Design, Setting, and Participants</h3> Nasal epithelium samples were obtained from participants in a randomized clinical trial (2011-2015) on the health effects of inhaled THS. In a crossover design, participants were exposed, head only, to THS and to conditioned, filtered air in a laboratory setting. The order of exposures was randomized and exposures were separated by at least 21 days. Ribonucleic acid was obtained from a subset of 4 healthy, nonsmoking women. <h3>Exposures</h3> By chance, women in the subset were randomized to receive clean air exposure first and THS exposure second. Exposures lasted 3 hours. <h3>Main Outcomes and Measures</h3> Differentially expressed genes were identified using RNA sequencing with a false-discovery rate less than 0.1. <h3>Results</h3> Participants were 4 healthy, nonsmoking women aged 27 to 49 years (mean [SD] age, 42 [10.2] years) with no chronic diseases. A total of 389 differentially expressed genes were identified in nasal epithelium exposed to THS, while only 2 genes, which were not studied further, were affected by clean air. Enriched gene ontology terms associated with stress-induced mitochondrial hyperfusion were identified, such as respiratory electron transport chain (<i>q</i> = 2.84 × 10<sup>−3</sup>) and mitochondrial inner membrane (<i>q</i> = 7.21 × 10<sup>−6</sup>). Reactome pathway analysis identified terms associated with upregulation of DNA repair mechanisms, such as nucleotide excision repair (<i>q</i> = 1.05 × 10<sup>−2</sup>). Enrichment analyses using ingenuity pathway analysis identified canonical pathways related to stress-induced mitochondrial hyperfusion (eg, increased oxidative phosphorylation) (<i>P</i> = .001), oxidative stress (eg, glutathione depletion phase II reactions) (<i>P</i> = .04), and cell survival (<i>z</i>score = 5.026). <h3>Conclusions and Relevance</h3> This study found that acute inhalation of THS caused cell stress that led to the activation of survival pathways. Some responses were consistent with stress-induced mitochondrial hyperfusion and similar to those demonstrated previously in vitro. These data may be valuable to physicians treating patients exposed to THS and may aid in formulating regulations for the remediation of THS-contaminated environments.
Inotuzumab ozogamicin (InO) treatment in patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL): Outcomes of patients treated in salvage one with a long duration of first remission.
Authors: Hagop M. Kantarjian, Matthias Stelljes, Anjali S. Advani, Daniel J. DeAngelo, David I. Marks, Wendy Stock, Susan Mary O'Brien, Ryan Daniel Cassaday, Tao Wang, Alexander Neuhof, Erik Vandendries, Elias Jabbour
Journal: Journal of Clinical Oncology (2019)

7029 Background: In R/R ALL, data are limited supporting targeted therapies like InO as first salvage in patients (pts) who had a long first complete remission (CR1). InO, a calicheamicin-conjugated antibody, targets CD22 on ALL blasts. Here we report outcomes in pts with ALL in first salvage (S1) who had a long CR1 before receiving InO vs standard of care chemotherapy (SC). Methods: Adults with CD22+ R/R ALL, stratified by salvage and length of remission (CR1 ≥ or &lt; 12 mos), were randomized to receive InO (n = 164) or SC (n = 162). Methods were previously described (Kantarjian et al, NEJM 2016), with data shown up to the last patient last visit (January 4, 2017). Outcomes including complete remission (CR)/CR with incomplete hematologic recovery (CRi) and overall survival (OS) were determined for S1 pts who achieved CR1 ≥ 12 mos and CR1 ≥ 18 mos. Results: For S1 pts with CR1 ≥ 12 mos or CR1 ≥ 18 mos, InO and SC arms had generally comparable baseline characteristics. For S1 pts with CR1 ≥ 12 mos and CR1 ≥ 18 mos, fewer pts had received a prior stem cell transplant in the InO vs SC arm (10.4% vs 25.0% and 9.7% vs 21.4%). For S1 pts with CR1 ≥ 12 mos and CR1 ≥ 18 mos respectively, InO vs SC treatment led to a higher CR/CRi rate (85.4% vs 27.5% [ P&lt; 0.0001] and 83.9% vs 32.1% [ P&lt; 0.0001]) and improved OS (HR = 0.547 [ P= 0.0086] and 0.504 [ P= 0.0163]), with veno-occlusive liver disease reported in 12.5% and 12.9% of InO pts Clinical trial information: NCT01564784. Conclusions: Improved outcomes were seen with InO vs SC among S1 pts who had a long first complete remission (CR1 ≥ 12 mos or CR1 ≥ 18 mos), supporting the benefit of InO vs SC in this population.[Table: see text]
Abstract 2305: Tumor MUC1 glycoprotein-highly specific CAR T cells control triple-negative breast cancer
Authors: Ru Zhou, Mahboubeh Yazdanifar, Lopamudra Das Roy, John Maher, Pinku Mukherjee
Journal: Cancer Research (2019)

Abstract Antibody-derived Chimeric Antigen Receptor (CAR) T cells have great success in reduction of liquid form of tumor, but not solid tumor. Our novel antibody TAB004 can specifically recognize the tumor form of MUC1 (tMUC1) while sparing the normal MUC1 in several subtypes of breast cancers including &amp;gt;95% of triple negative breast cancer (TNBC). In vivo delivery of TAB004 specifically accumulates in the xenograft TNBC tumor only. Therefore, we hypothesize that TNBC can be specifically targeted with TAB004-derived tMUC1-specific CAR T cells. A panel of 45 human breast cancer cell lines were tested for tMUC1 level, and 11 out of 13 TNBC cell lines showed higher frequency of tMUC1 expression compared to that on normal cells. We engineered a 2nd generation human CAR using TAB004 that was coupled to the CD28-CD3zeta, named as MUC28z CAR. MUC28z was well expressed on activated human T cells. Compared to their mock control, MUC28z CAR T cells retained higher CD25 and CD11c, particularly on CD8 T cells. The susceptibility of TNBC cells to MUC28z CAR T cell cytolysis was dramatic while still corresponding to their tMUC1 level. Only the tMUC1-specific MUC28z CAR T cells expressed and released large amount of IFN-gamma after antigen recognition on TNBC cells. However, IFN-gamma was only involved in the tumor killing by MUC28z CAR T cells at lower E:T ratio. The in vivo treatment of TNBC tumor by MUC28z CAR T cells dramatically controlled HCC70 TNBC tumor growth in a xenograft model. Taken together, our TAB004-derived MUC28z CAR T cells are very potent at killing TNBC tumor cells both in vitro and in vivo, which is very promising to provide a safe, effective and tumor antigen-specific novel immunotherapeutic intervention. Citation Format: Ru Zhou, Mahboubeh Yazdanifar, Lopamudra Das Roy, John Maher, Pinku Mukherjee. Tumor MUC1 glycoprotein-highly specific CAR T cells control triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2305.
Abstract 1305: Identification of signal transduction kinases inhibited by pan-RAF inhibitor belvarafenib using FRET imaging technique
Authors: Dong-Jun Bae, Sang-Yeob Kim, JooYun Byun, InHwan Bae, YoungGil Ahn, YoungHoon Kim, Kwee Hyun Suh
Journal: Cancer Research (2019)

Abstract The mitogen-activated protein kinase (MAPK) pathway plays an important role for the survival and proliferation of tumor cells. For example, the activation of the MAPK pathway due to mutations in BRAF, NRAS and KRAS kinases is known to be the causes of various solid tumors and hematologic malignancies. Accordingly, there is a strong need for effective therapeutic drugs for treating cancers caused by genetic mutation of BRAF, NRAS or KRAS. Belvarafenib (HM95573 or GDC5573), currently in Phase 1 clinical trials, is a selective and orally bioavailable pan-RAF kinase inhibitor. When biochemically assayed for hundreds of kinases, Belvarafenib showed selectivity toward RAF family kinases, including strong inhibition activities for BRAF WT, BRAF mutants and CRAF. Previously, we reported that Belvarafenib strongly inhibits the growth of cancer cell lines with BRAF, NRAS or KRAS mutations and also shows excellent anticancer efficacy in animal models using the corresponding cancer cells. In this study, employing fluorescence resonance energy transfer (FRET) imaging, we examined which protein kinases involved in signal transduction are regulated by Belvarafenib and investigated the mechanism of action for the regulation in typical cancer cells harboring BRAF, NRAS or KRAS mutations such as A375 (melamona), SK-MEL-30 (Kwmelamona), HCT116 (CRC), and Calu-6 (NSCLC). Among the various protein kinases that can be involved in signal transduction, we identified with time-lapse FRET imaging that the phosphorylation of ERK, AKT and S6K are inhibited after the treatment of Belvarafenib in the above cancer cells of BRAF, NRAS or KRAS mutations. Of note, BRAF mutant selective inhibitors, Vemurafenib and Dabrafenib were not active in cancer cells of NRAS or KRAS mutations. These results correlate with the in vitro and in vivo anticancer activity in cancer cells of BRAF, NRAS or KRAS mutations. In conclusion, unlike Vemurafenib and Dabrafenib, the pan-RAF inhibitor Belvarafenib could be effective for treating the cancer caused by NRAS or KRAS mutations, as well as BRAF mutations. Citation Format: Dong-Jun Bae, Sang-Yeob Kim, JooYun Byun, InHwan Bae, YoungGil Ahn, YoungHoon Kim, Kwee Hyun Suh. Identification of signal transduction kinases inhibited by pan-RAF inhibitor belvarafenib using FRET imaging technique [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1305.
Abstract 3425: Mutations in DNA repair and microtubule assembly genes found in triple negative breast tumors treated with neoadjuvant chemotherapy
Authors: Michael Grant, George Snipes, Rebecca Halperin, Paul Heaton, Suwon Kim
Journal: Cancer Research (2019)

Abstract Up to 20% of breast cancer is clinically defined as triple-negative breast cancer (TNBC) lacking estrogen, progesterone, and HER2 receptors. Because no targeted therapy is available, cytotoxic chemotherapy is the primary mode of adjuvant TNBC therapy, but is effective in ~30% patients. In order to determine molecular underpinnings of chemotherapy resistance in TNBC, we analyzed 12 TNBC patient tumor samples collected post neoadjuvant chemotherapy using DNA/RNA sequencing. DNA analysis showed two tumors contained TP53 inactivating mutations and two tumors PIK3CA activating mutations. In addition, a number of mutations in the DNA repair pathway genes were identified including XRCC1, XRCC3, and ATXR, suggesting that DNA damaging nature of chemotherapy agents may have enriched these mutations. In addition, we found mutations in the genes involved in microtubule assembly including BUB3 and APC2, suggesting that these gene mutations may confer resistance to taxol, an anti-microtubule chemotherapy agent. RNA sequencing revealed a true heterogeneous nature of TNBE in that unsupervised clustering did not identify any distinct gene signature correlative of chemotherapy resistance. We are currently evaluating phenotypes related to chemotherapy resistance using cells genetically engineered with the BUB3 or APC2 mutations. Citation Format: Michael Grant, George Snipes, Rebecca Halperin, Paul Heaton, Suwon Kim. Mutations in DNA repair and microtubule assembly genes found in triple negative breast tumors treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3425.
The medical AI insurgency: what physicians must know about data to practice with intelligent machines
Authors: D. Douglas Miller
Journal: npj Digital Medicine (2019)

Machine learning (ML) and its parent technology trend, artificial intelligence (AI), are deriving novel insights from ever larger and more complex datasets. Efficient and accurate AI analytics require fastidious data science-the careful curating of knowledge representations in databases, decomposition of data matrices to reduce dimensionality, and preprocessing of datasets to mitigate the confounding effects of messy (i.e., missing, redundant, and outlier) data. Messier, bigger and more dynamic medical datasets create the potential for ML computing systems querying databases to draw erroneous data inferences, portending real-world human health consequences. High-dimensional medical datasets can be static or dynamic. For example, principal component analysis (PCA) used within R computing packages can speed & scale disease association analytics for deriving polygenic risk scores from static gene-expression microarrays. Robust PCA of k-dimensional subspace data accelerates image acquisition and reconstruction of dynamic 4-D magnetic resonance imaging studies, enhancing tracking of organ physiology, tissue relaxation parameters, and contrast agent effects. Unlike other data-dense business and scientific sectors, medical AI users must be aware that input data quality limitations can have health implications, potentially reducing analytic model accuracy for predicting clinical disease risks and patient outcomes. As AI technologies find more health applications, physicians should contribute their health domain expertize to rules-/ML-based computer system development, inform input data provenance and recognize the importance of data preprocessing quality assurance before interpreting the clinical implications of intelligent machine outputs to patients.
Phase II study of neoadjuvant chemotherapy with S-1 plus oxaliplatin at a dose of 130mg/m2 (nacG-SOX130) in clinical(c)Stage III gastric cancer
Authors: S. Konishi, D. Manaka, Y. Ikeda, T. Ota, R. Kudo, H. Ann, K. Kawaguchi, N. Sasaki, S. Hamasu, R. Nishitai
Journal: Annals of Oncology (2019)
Microscopic Colitis Is Characterized by Intestinal Dysbiosis
Authors: David M. Morgan, Yueming Cao, Kaia Miller, Jessica McGoldrick, Danielle Bellavance, Samantha M. Chin, Stefan Halvorsen, Benjamin Maxner, James M. Richter, Slim Sassi, Kristin E. Burke, Joseph C. Yarze, Jonas F. Ludvigsson, Kyle Staller, Daniel C. Chung, Hamed Khalili
Journal: Clinical Gastroenterology and Hepatology (2019)

The critical role of the gut microbiome in microscopic colitis (MC) is evident by the observation that fecal diversion is associated with resolution of mucosal inflammation while restoration of fecal stream is associated with recurrence of disease.1 Characterization of the composition and function of the gut microbiome in MC therefore could provide insights into disease pathogenesis.
Abstract 1302: Targeting hormone receptor-dependent cancers with potent, selective and orally-available small molecule inhibitors of eIF4E
Authors: Gary G. Chiang, Gregory S. Parker, Ivy N. Hung, Vikas K. Goel, Jocelyn Staunton, Maria Barrera, Eric Sung, Ana Parra, Craig R. Stumpf, Joan Chen, Peggy A. Thompson, Andreas Nevarez, Christopher J. Wegerski, Cody Parker, Jeff Clarine, Samuel Sperry, Alan Xiang, Christian Nilewski, Garrick K. Packard, Kaveri Urkalan, Takasuke Mukaiyama, Theo Michels, Justin T. Ernst, Paul A. Sprengeler, Siegfried H. Reich, Kevin R. Webster
Journal: Cancer Research (2019)

Abstract The PI3K/mTOR pathway is commonly dysregulated in many hormone receptor-dependent tumors and plays a key role in promoting tumor growth and mediating drug resistance. In particular, PI3K and mTORC1/2 inhibitors have been intensively studied in the treatment of hormone receptor-dependent cancers and have shown benefit in some clinical settings. However, issues such as dose-limiting toxicities and emergent resistance limit the broader utility of these inhibitors. The translation initiation factor eIF4E is essential for the translation of m7G-capped mRNA and is a key point of convergence for both the PI3K/mTOR and MAPK signaling pathways. We have designed a series of potent, selective and orally-available m7G cap-competitive inhibitors of eIF4E (eFT-4Ei) with favorable drug-like properties. These inhibitors bind to eIF4E either as its free form or with eIF4E-4EBP and eIF4F complexes within tumor cells and downregulate hormone receptor-dependent signaling. Ribosomal profiling of eIF4E inhibitor-treated tumor cells identified a subset of translationally regulated target genes that overlap with mTORC1/2 regulated genes, but also a unique set of translationally regulated target mRNAs. Consistent with this observation, our eIF4E inhibitors show some similarities yet several important differences from existing mTORC1 or mTORC1/2 dual inhibitors in both cellular and physiological assays. Finally, significant anti-tumor efficacy was observed with eIF4E inhibition in vitro and in vivo. Taken together, these results highlight the potential for targeting eIF4E as a novel therapeutic strategy to treat hormone-receptor dependent cancers. Citation Format: Gary G. Chiang, Gregory S. Parker, Ivy N. Hung, Vikas K. Goel, Jocelyn Staunton, Maria Barrera, Eric Sung, Ana Parra, Craig R. Stumpf, Joan Chen, Peggy A. Thompson, Andreas Nevarez, Christopher J. Wegerski, Cody Parker, Jeff Clarine, Samuel Sperry, Alan Xiang, Christian Nilewski, Garrick K. Packard, Kaveri Urkalan, Takasuke Mukaiyama, Theo Michels, Justin T. Ernst, Paul A. Sprengeler, Siegfried H. Reich, Kevin R. Webster. Targeting hormone receptor-dependent cancers with potent, selective and orally-available small molecule inhibitors of eIF4E [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1302.