tbuckley/cabot-search huggingface dataset:
Acetyl‐CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents
Authors: Leigh Goedeke, Jamie Bates, Daniel F. Vatner, Rachel J. Perry, Ting Wang, Ricardo Ramirez, Li Li, Matthew W. Ellis, Dongyan Zhang, Kari E. Wong, Carine Beysen, Gary W. Cline, Adrian S. Ray, Gerald I. Shulman
Journal: Hepatology (2018)

Pharmacologic inhibition of acetyl‐CoA carboxylase (ACC) enzymes, ACC1 and ACC2, offers an attractive therapeutic strategy for nonalcoholic fatty liver disease (NAFLD) through simultaneous inhibition of fatty acid synthesis and stimulation of fatty acid oxidation. However, the effects of ACC inhibition on hepatic mitochondrial oxidation, anaplerosis, and ketogenesis in vivo are unknown. Here, we evaluated the effect of a liver‐directed allosteric inhibitor of ACC1 and ACC2 (Compound 1) on these parameters, as well as glucose and lipid metabolism, in control and diet‐induced rodent models of NAFLD. Oral administration of Compound 1 preferentially inhibited ACC enzymatic activity in the liver, reduced hepatic malonyl‐CoA levels, and enhanced hepatic ketogenesis by 50%. Furthermore, administration for 6 days to high‐fructose‐fed rats resulted in a 20% reduction in hepatic de novo lipogenesis. Importantly, long‐term treatment (21 days) significantly reduced high‐fat sucrose diet–induced hepatic steatosis, protein kinase C epsilon activation, and hepatic insulin resistance. ACCi treatment was associated with a significant increase in plasma triglycerides (approximately 30% to 130%, depending on the length of fasting). ACCi‐mediated hypertriglyceridemia could be attributed to approximately a 15% increase in hepatic very low‐density lipoprotein production and approximately a 20% reduction in triglyceride clearance by lipoprotein lipase ( P ≤ 0.05). At the molecular level, these changes were associated with increases in liver X receptor/sterol response element‐binding protein‐1 and decreases in peroxisome proliferator–activated receptor‐α target activation and could be reversed with fenofibrate co‐treatment in a high‐fat diet mouse model. Conclusion: Collectively, these studies warrant further investigation into the therapeutic utility of liver‐directed ACC inhibition for the treatment of NAFLD and hepatic insulin resistance.
Hepatitis B Virus–Upregulated LNC‐HUR1 Promotes Cell Proliferation and Tumorigenesis by Blocking p53 Activity
Authors: Ningning Liu, Qi Liu, Xiaohai Yang, Fang Zhang, Xinda Li, Yuanwu Ma, Feifei Guan, Xin Zhao, Zhiwei Li, Lianfeng Zhang, Xin Ye
Journal: Hepatology (2018)

Recent studies have indicated that a number of long noncoding RNAs (lncRNAs) are dysregulated in hepatocellular carcinoma, while their aberrant expressions are associated with tumorigenesis and poor prognosis. To identify hepatitis B virus (HBV)‐related lncRNAs, we used RNA deep sequencing to quantify the abundances of lncRNAs in HepG2 cells and HBV transgenic HepG2‐4D14 cells. Here, we demonstrate that lnc‐HUR1 is significantly upregulated in HepG2‐4D14 cells. We found that HBV‐encoded hepatitis B x protein can enhance the transcription of lnc‐HUR1. Overexpression of lnc‐HUR1 promotes cell proliferation, whereas knockdown of lnc‐HUR1 inhibits cell growth. We identified that lnc‐HUR1 can interact with p53 and inhibit its transcriptional regulation on downstream genes, such as p21 and B cell lymphoma 2–associated X protein. We generated lnc‐HUR1 transgenic mice and performed the partial hepatectomy (PHx) to examine liver regeneration. The data showed that the ratio of liver weight to body weight in lnc‐HUR1 transgenic mice is higher than that in wild‐type (WT) littermates at day 2 and day 3 following hepatectomy. Consistently, the results of bromodeoxyuridine staining on liver sections following hepatectomy indicate that the ratio of bromodeoxyuridine‐positive cells in lnc‐HUR1 transgenic mice is significantly higher than that in WT mice, suggesting that lnc‐HUR1 promotes cell proliferation during liver regeneration. Next, we performed the experiment of diethylnitrosamine‐induced tumorigenesis. The data demonstrate that tumor number in lnc‐HUR1 transgenic mice is higher compared with control mice, indicating that lnc‐HUR1 enhances diethylnitrosamine‐induced tumorigenesis. Conclusion: We reveal that HBV‐upregulated lnc‐HUR1 promotes cell proliferation and tumorigenesis by interacting with p53 to block downstream gene transcription. Our findings suggest that lnc‐HUR1 plays an important role in HBV‐related hepatocellular carcinoma development and may serve as a therapeutic marker for hepatocellular carcinoma. (H epatology 2018; 00:000‐000).
Abstract A43: Loss of Keap1 promotes KRAS-driven lung cancer and results in genotype-specific vulnerabilities
Authors: Rodrigo Romero, Volkan I. Sayin, Davidson M. Shawn, Matthew Bauer, Simranjit X. Singh, Sarah LeBoeuf, Triantafyllia R. Karakousi, Donald C. Ellis, Arjun Bhutkar, Francisco Sanchez-Rivera, Lakshmipriya Subbaraj, Britney Martinez, Roderick T. Bronson, Justin R. Prigge, Edward E. Schmidt, Craig J. Thomas, Angela Davies, Igor Dolgalev, Adriana Heguy, Viola Allaj, John T. Piorier, Andre L. Moreira, Charles M. Rudin, Harvey I. Pass, Matthew G. Vander Heiden, Tyler Jacks, Thales Papagiannakopoulos
Journal: Cancer Research (2018)

Abstract Treating KRAS mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein1. One approach to addressing this challenge is to define frequently co-occurring mutations with KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS mutant LUAD tumors carry loss-of-function (LOF) mutations in Kelch-like ECH-associated protein 1 (KEAP1)2-4, a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response5-10. The high frequency of mutations in KEAP1, which would be predicted to result in activation of the NRF2 pathway, suggests an important role for the oxidative stress response in lung tumorigenesis. To test this directly, we used a CRISPR/Cas9-based approach in a mouse model of Kras-driven LUAD to examine the effects of loss of KEAP1 function in lung cancer progression. We show that loss of KEAP1 hyper-activates Nrf2 and promotes Kras-driven LUAD. Combining CRISPR/Cas9-based genetic screening and metabolomic analyses, we also show that KEAP1/NRF2 mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacologic inhibition of glutaminase. Finally, we provide a rationale for sub-stratification of human lung cancer patients with KRAS-KEAP1 or -NRF2 mutant tumors as likely to respond to glutaminase inhibition. Citation Format: Rodrigo Romero, Volkan I. Sayin, Davidson M. Shawn, Matthew Bauer, Simranjit X. Singh, Sarah LeBoeuf, Triantafyllia R. Karakousi, Donald C. Ellis, Arjun Bhutkar, Francisco Sanchez-Rivera, Lakshmipriya Subbaraj, Britney Martinez, Roderick T. Bronson, Justin R. Prigge, Edward E. Schmidt, Craig J. Thomas, Angela Davies, Igor Dolgalev, Adriana Heguy, Viola Allaj, John T. Piorier, Andre L. Moreira, Charles M. Rudin, Harvey I. Pass, Matthew G. Vander Heiden, Tyler Jacks, Thales Papagiannakopoulos. Loss of Keap1 promotes KRAS-driven lung cancer and results in genotype-specific vulnerabilities [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A43.
Identification of key lipids critical for platelet activation by comprehensive analysis of the platelet lipidome
Authors: Bing Peng, Sascha Geue, Cristina Coman, Patrick Münzer, Dominik Kopczynski, Canan Has, Nils Hoffmann, Mailin-Christin Manke, Florian Lang, Albert Sickmann, Meinrad Gawaz, Oliver Borst, Robert Ahrends
Journal: Blood (2018)
Abstract B24: Stem cell lineage infidelity drives wound repair and cancer
Authors: Yejing Ge, Elaine Fuchs
Journal: Cancer Research (2018)

Abstract Human adult tissues harbor resident stem cells (SCs) responsible for homeostasis and wound repair. Tumorigenesis arises when normal SCs accumulate mutations that cause them to derail, shifting their homeostatic balance to favor tissue growth at the expense of differentiation. In contrast to wound repair, where the growth:differentiation imbalance is transient, cancers are refractory to tissue restoration cues, seemingly hijacking these normal cellular programs to fuel their molecular thirst for uncontrolled growth. The notion that a “cancer is a wound that never heals” has origins dating back to Rudolf Virchow in the 1800s. Since then, intimate connections between wounds and tumors have also been drawn at the molecular level. Although intriguing, it remains unclear which of the normal SC remodeling pathways are exploited by tumor SCs and how cancers rewire preinstalled regulatory networks to support malignancy. Here, we investigate such a phenomenon in the skin, where during homeostasis, stem cells of epidermis and hair follicle fuel their respective tissues. We find that breakdown of stem cell lineage confinement--granting privileges associated with both fates--is not only a hallmark but also functional in cancer development. We show that lineage plasticity is critical in wound repair, where it operates transiently to redirect fates. Probing the mechanism, we discover that irrespective of cellular origin, lineage infidelity occurs in wounding when stress-responsive enhancers become activated and override homeostatic enhancers that govern lineage specificity. In cancer, stress-responsive transcription factor levels rise, causing lineage commanders to reach excess. When lineage and stress factors collaborate, they activate new oncogenic enhancers that distinguish cancers from wounds. Citation Format: Yejing Ge, Elaine Fuchs. Stem cell lineage infidelity drives wound repair and cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B24.
Treating refractory depression in Parkinson’s disease: a meta-analysis of transcranial magnetic stimulation
Authors: Alexandra M. Lesenskyj, Megan P. Samples, Jill M. Farmer, Christina R. Maxwell
Journal: Translational Neurodegeneration (2018)

Parkinson's disease (PD) is often accompanied by clinically identified depression. Providing effective pharmacotherapies that concomitantly treat both motor and psychological symptoms can pose a challenge to physicians. For this reason, alternatives to standard anti-depressant treatments, such as repetitive transcranial magnetic stimulation (rTMS), have been evaluated within the Parkinson's population. A literature search was conducted on the PubMed database for all studies that evaluated rTMS as a treatment in patients with both depression and PD. A meta-analysis was performed on all studies that reported mean pre- and post-rTMS depression inventory scores. Widely used depression inventories included both self-report and clinician-administered measures. Effect size for individual study groups and across all studies was calculated. Six of 7 studies meeting inclusion criteria reported significantly improved depression scores, large effect sizes, and significant p-values. Total weighted average effect size was calculated at 1.32 across all study groups that applied rTMS. Across all but one study, rTMS appears to effectively reduce depression scores among self-reported and clinician administered inventories. The total weight average effect size showed that, when considering study sample sizes and degree of findings, this form of neurostimulation can relieve PD patients of their depressive symptoms. Further, rTMS is a promising alternative to traditional anti-depressant therapies when treating refractory depression in patients with PD.
Principles of Biomedical Ethics
Authors: D. Mark Mahler
Journal: JAMA (1984)

Recognition that understanding of ethical principles is requisite for analysis of ethical issues in clinical cases underpins the significance of the contribution of Tom L. Beauchamp and James F. Childress in<i>Principles of Biomedical Ethics</i>, (second edition.) The authors provide "a systematic analysis of the moral principles that should apply to biomedicine," focusing on the process of moral reasoning from ethical principles. They ambitiously appeal to health clinicians, researchers, policy makers, philosophers and theologians, and teachers and students. Structurally, the book includes a brief overview of moral reasoning; a general exposition of two broad ethical theoretical frameworks, utilitarianism and deontology; detailed analysis of the fundamental principles of autonomy, nonmaleficence ("Do no harm"), beneficence, and justice; examination of rules of veracity, confidentiality, privacy, and fidelity, in the context of various professional-patient relationships; and consideration of moral attributes of persons (as contrasted with acts); followed by appendices with case histories and professional
Less cholesterol means better tumor killing for cytotoxic T9 cells
Authors: Brad Griesenauer, Sophie Paczesny
Journal: The Journal of Experimental Medicine (2018)

In this issue, Ma et al. (https://doi.org/10.1084/jem.20171576) show that removal of cholesterol from CD8 T cells during type 9 differentiation increases their IL-9 production, persistence in vivo, and cytolytic function against tumors by preventing SUMOylation of liver X receptors.
Fulvestrant (F) plus sorafenib (S) as salvage therapy for hormone receptor positive (HR+) metastatic breast cancer (MBC) failing prior aromatase inhibitor (AI) treatment.
Authors: Kristine H. Lethert, Deirdre J. Nauman, Yolanda Prado, Mark Seligman, Kasra Karamlou, Frederick S. Ey, Stephen Y. Chui
Journal: Journal of Clinical Oncology (2012)

e11042 Background: Upon MBC progression with AI treatment; F, an estrogen receptor (ER) antagonist, is often used. Furthermore, vascular endothelial growth factor (VEGF) remains a potential target in MBC. S is a multi-kinase inhibitor of VEGF, Raf, platelet-derived growth factor receptor beta, Flt-3, and c-KIT. Prior studies of S show activity with chemotherapy and as a single agent. Combination therapy with an anti-estrogen and a VEGF inhibitor may be more effective than either agent alone. This pilot study combines F + S for HR+ MBC. Methods: Upon disease progression with an AI, 8 pts were treated with F. Concurrent S was administered starting day 1 until disease progression or unacceptable toxicity. Assessment of tumor status with computed tomography and/or bone scan was performed at baseline and every 2 cycles until disease progression. Results: Median age = 58; 75 % &lt;65. ER and PR + = 6 pts; ER + and PR - = 2 pts. 6 pts were treated with adjuvant chemotherapy and endocrine therapy, with subsequent AI for MBC. 2 pts were metastatic at presentation and treated with prior AI. Median number of days on treatment = 220; median number of cycles = 7. 75% had grade 2/3 HFS; 50% required S dose modification. However, HFS and rash/desquamation were the only grade 3 toxicities (3 pts) with no additional grade 3/4 toxicities or dose modifications for other toxicities. Other grade 2 toxicities: neutropenia, myalgias, arthralgias, fatigue, pruritis. Only 1 pt discontinued the study at investigator’s decision for grade 3 HFS. There were no deaths on study. The remaining 7 pts continued F + S until disease progression with stable disease over a range of 2 to 22 cycles. Median time to progression was 7.3 months. Conclusions: Upon progression with an AI, treatment with F + S may provide advantage for some HR+ MBC pts beyond treatment with F alone. Future studies involving S in MBC should focus on identifying the population that will benefit the most in exchange for toxicities associated with S. [Table: see text]
Abstract B28: Development of estrogen-dependent and estrogen receptor-negative cervical cancer in HPV transgenic mice
Authors: Jieun Son, Sang-Hyuk Chung
Journal: Cancer Research (2018)

Abstract Estradiol (E2) and human papillomavirus (HPV) cooperate to cause cervical cancer. The role of estrogen receptor α (ERα) in cervical cancer has been underappreciated. Chronic treatment with E2 promotes the development of cervical cancer in K14E7 transgenic mice expressing HPV16 E7 oncoprotein. In the present study, we bred K14E7 to mice with conditional ablation of Esr1 (ERα-coding gene) in the cervical epithelial cells (Wnt7aCre/Esr1f/f; Esr1ed/ed). We found that E2 promoted the development of ERα cervical cancer in K14E7/Esr1ed/ed mice. In addition, proliferation and apoptotic indices of ERα cancer in K14E7/Esr1ed/ed mice were similar to those of ERα+ cancer in K14E7/Esr1f/f mice. We also found that E2 increased the epithelium thickness and epithelial cell proliferation in the cervix of Esr1ed/ed mice. Our published results have demonstrated that deletion of Esr1 in the cervical stroma promotes the regression of cervical precancer lesions in K14E7 mice. In patients, ERα is expressed in the cancer stroma but not cancer epithelial cells. These observations support that stromal ERα, rather than epithelial ERα, mainly mediates oncogenic E2 signaling for cervical cancer. They also suggest that stromal ERα might be an effective therapeutic target for cervical cancer. Note: This abstract was not presented at the conference. Citation Format: Jieun Son, Sang-Hyuk Chung. Development of estrogen-dependent and estrogen receptor-negative cervical cancer in HPV transgenic mice [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B28.
Infusion of Alloanergized Donor Lymphocytes after CD34-selected Haploidentical Myeloablative Hematopoietic Stem Cell Transplantation
Authors: Jeff K. Davies, Lisa L. Brennan, John R. Wingard, Christopher R. Cogle, Neena Kapoor, Ami J. Shah, Bimalangshu R. Dey, Thomas R. Spitzer, Marcos de Lima, Laurence J. Cooper, Peter F. Thall, Richard E. Champlin, Lee M. Nadler, Eva C. Guinan
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Allogeneic hematopoietic stem-cell transplantation (HSCT) is a curative treatment for many hematologic cancers. Use of haploidentical (mismatched) donors increases HSCT availability but is limited by severe graft-versus-host disease (GvHD) and delayed immune reconstitution. Alloanergization of donor T cells is a simple approach to rebuild immunity while limiting GvHD after haploidentical HSCT, but the optimal T-cell dose and impact on immune reconstitution remain unknown. Patients and Methods: We performed a multicenter phase I trial of alloanergized donor lymphocyte infusion (aDLI) after CD34-selected myeloablative haploidentical HSCT. The primary aim was feasibility and safety with secondary aims of assessing the less frequently addressed issue of impact on immune reconstitution. Results: Nineteen patients with high-risk acute leukemia or myelodysplasia were enrolled. Engraftment occurred in 18 of 19 patients (95%). Pre-aDLI, 12 patients (63%) had bacteremia, nine of 17 at-risk patients (53%) reactivated CMV, and one developed acute GvHD. Sixteen patients received aDLI at dose levels 1 (103 T cells/kg, n = 4), 2 (104, n = 8), and 3 (105, n = 4). After aDLI, five patients developed clinically significant acute GvHD, and four of 14 at-risk patients (29%) reactivated CMV. T-cell recovery was significantly greater, and functional virus- and tumor-associated antigen-specific T cells were detectable earlier in patients receiving dose level 2 or 3 versus dose level 1/no aDLI. Alloanergization of donor cells expanded the CD4+ T-regulatory cell frequency within aDLI, which increased further in vivo without impeding expansion of virus- and tumor-associated antigen-specific T cells. Conclusions: These data demonstrate safety and a potential role for aDLI in contributing to immune reconstitution and expanding tolerogenic regulatory T cells in vivo after CD34-selected myeloablative haploidentical HSCT. Clin Cancer Res; 24(17); 4098–109. ©2018 AACR.
Short- and mid-term outcomes of robotic versus laparoscopic distal pancreatosplenectomy for pancreatic ductal adenocarcinoma: A retrospective propensity score-matched study
Authors: Liu Qu, Zhao Zhiming, Tan Xianglong, Gao Yuanxing, Xu Yong, Liu Rong, Lau Wan Yee
Journal: International Journal of Surgery (2018)
Effects of proton pump inhibitors (PPIs) on FOLFOX and XELOX regimens in colorectal cancer (CRC).
Authors: Grace Wong, Vincent Ha, Michael Patvin Chu, Deonne Dersch-Mills, Sunita Ghosh, Carole Chambers, Michael B. Sawyer
Journal: Journal of Clinical Oncology (2018)

621 Title: Effects of Proton Pump Inhibitors (PPIs) on FOLFOX and XELOX Regimens in Colorectal Cancer (CRC) Background: First-line adjuvant chemotherapy options for stage II-III CRC include XELOX (capecitabine (cape), oxaliplatin) and FOLFOX (oxaliplatin, leucovorin, 5FU). Cape is an oral 5FU prodrug, and recent studies suggested that PPIs may detrimentally affect cape efficacy. Conversely, some literature posits that PPIs may negatively impact CRC itself. Our primary objective was to compare 3-year recurrence-free survival (RFS) rates between XELOX-treated PPI-users and non-PPI users, and FOLFOX-treated PPI users and non-PPI users. Our main secondary objective was to compare overall survival (OS). Methods: We conducted a retrospective chart review of 389 stage II-III CRC patients (pts) who received adjuvant XELOX or FOLFOX from a tertiary cancer center in Alberta, Canada between 2004-2013. Information regarding PPI use, cancer treatment, and pt outcomes were gathered and analyzed from pharmacy databases. Results: 23.4% of XELOX-treated pts and 28.0% of FOLFOX -treated pts used PPIs concurrently with treatment. 3-year RFS was significantly lower in XELOX-treated PPI pts than non-PPI pts (69.5 vs. 82.6%, P=0.029). Unadjusted analysis showed that XELOX-treated PPI pts were twice as likely to experience cancer recurrence or death as XELOX-treated non-PPI pts (HR 2.03, P=0.033). FOLFOX-treated PPI pts had a non-significant increase in three-year RFS versus non-PPI pts (82.9 vs. 61.7%, P=0.066), and no significant difference in recurrence or death (HR 0.51, P=0.071). No significant differences were seen in OS. Conclusions: Our results suggest that PPIs negatively impacted RFS in early-stage XELOX-treated CRC pts, and yielded no significant effect amongst FOLFOX-treated patients. Further studies are required to corroborate our findings. [Table: see text]
Association of Comorbidities With Adverse Outcomes After Enterostomy Closure in Premature Neonates
Authors: Donald J. Lucas, Ankush Gosain
Journal: JAMA Surgery (2018)

This study uses the 2012-2015 American College of Surgeons National Surgical Quality Improvement Program–Pediatric database to examine the safety of enterostomy closure in premature neonates weighing less than 2 kg and identify risk factors for adverse outcomes.