tbuckley/cabot-search huggingface dataset:
Organ Donation and Drug Intoxication–Related Deaths in the United States
Authors: Muthiah Vaduganathan, Sara R Machado, Ersilia M DeFilippis, Navkaranbir Bajaj, Josef Stehlik, Elias Mossialos, John A Jarcho, Mandeep R Mehra
Journal: New England Journal of Medicine (2019)

To the Editor: The drug-overdose epidemic has led to an increase in the number of organ donors dying from drug intoxication 1 ; this pattern is confined to the United States and has not been observed in Europe. 2 Geographic disparity in the rates of death from drug intoxication in the United States 3 led us to explore trends and statewide variation in the number of donor organs recovered from persons who died from drug intoxication.We used data from the Organ Procurement and Transplantation Network (1999Network ( -2017) ) to examine state-specific patterns in the use of donor organs for adult heart transplantation that were recovered from persons who died from drug intoxication.Net annual changes in the size of the heart transplant waiting list (number of new registrations minus the total number of removals) were also determined.Age-adjusted annual rates of drug intoxication-related deaths from 1999 through 2016 were obtained from the Centers for Disease Control and Prevention WONDER online database. 4We calculated the percentage of heart donors among the total number of persons who died from drug intoxication during this period.The age-standardized rate of death from drug intoxication rose from 6.8 per 100,000 persons in 1999 to 20.8 per 100,000 persons in 2016.Among 37,232 U.S. adult donors from whom hearts were recovered for transplantation from 1999 through 2017, the percentage of those who died from drug intoxication increased from 1.5% to 17.6%.Most states had increases in the rates of drug intoxication-related deaths and organ recovery, with major increases in the Northeast, Midwest, and Southwest regions of the United States (Fig. 1A and1B).
Hypoxia improves hair inductivity of dermal papilla cells via nuclear<scp>NADPH</scp>oxidase 4‐mediated reactive oxygen species generation'
Authors: M. Zheng, Y. Jang, N. Choi, D. Y. Kim, T.W. Han, J. H. Yeo, J. Lee, J.‐H. Sung
Journal: British Journal of Dermatology (2019)

BackgroundDermal papilla cells (DPCs) play a key role in hair regeneration and morphogenesis. Therefore, tremendous efforts have been made to promote DPC hair inductivity.
Comparison of real-world treatment patterns, persistence, healthcare resource utilization (HRU) and costs between octreotide and lanreotide for the treatment of neuroendocrine tumors (NET).
Authors: Lynn Huynh, Beilei Cai, Camara Sharperson, Dominique Lejeune, Mei Sheng Duh, Michelle Kang Kim
Journal: Journal of Clinical Oncology (2019)

105 Background: There has been limited research assessing differences between somatostatin analogues (SSAs) as treatments for NET. This study aims to assess treatment pattern, persistence, HRUs and costs among patients (pts) with NET receiving long-acting octreotide versus lanreotide. Methods: Retrospective claims data from Symphony Health Solutions were analyzed for NET pts who initiated octreotide or lanreotide (index date) between 01/2015–11/2017 for ≥ 90 days. Pts with continuous clinical activity (≥ 180 pre and ≥ 90 days post index date) and without prior non-surgical NET treatment were included. A 1:1 propensity score matched sample was used to compare the two SSA groups with respect to treatment persistence (time to treatment discontinuation [TTD] using Kaplan-Meier) and to all cause and NET related HRUs and costs (provider charges for medical services and insurance payments for prescription drugs) using rate ratio (RR) and mean cost difference (CD) with 95% confidence interval (CI). Results: Among 2,043 NET pts identified, a balanced matched cohort of octreotide and lanreotide pts (N = 543 each) was achieved. In both cohorts, mean age was 65 years and baseline Charlson Comorbidity Index was 5.7. Approximately 80% of matched pts initiated monotherapy; others used SSAs in combination with chemo-, targeted or liver-directed therapy as first line therapy. Median TTD was directionally longer but did not reach statistical significance among octreotide vs lanreotide (19.2 vs 17.5 months, p = 0.6). Numerically lower hospitalization rates were observed among octreotide pts (RR [CI]: all cause = 0.87 [0.73, 1.05]; NET related = 0.85 [0.63, 1.15]). Statistically significantly fewer NET related outpatient visits (1.05 vs 1.10 per pts per month [PPPM]; RR [CI]: 0.95 [0.92, 0.99]) and lower total mean costs PPPM were observed for octreotide than lanreotide (CD [CI]: all cause = -$3,701 [-$5,205, -$2,355]; NET related = -$3,752 [-$4,948, -$2,455]). Conclusions: This study shows similar treatment patterns and persistence between SSA cohorts. Octreotide appeared to be associated with less HRU and total costs compared with lanreotide.
Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models
Authors: Jean Cruz Hernández, Oliver Bracko, Calvin Kersbergen, Victorine Muse, Mohammad Haft-Javaherian, Maxime Berg, Laibaik Park, Lindsay Vinarcsik, Iryna Ivasyk, Daniel Rivera, Yiming Kang, Marta Cortes-Canteli, Myriam Peyrounette, Vincent Doyeux, Amy Smith, Joan Zhou, Gabriel Otte, Jeffrey Beverly, Elizabeth Davenport, Yohan Davit, Charles Lin, Sidney Strickland, Costantino Iadecola, Sylvie Lorthois, Nozomi Nishimura, Chris Schaffer
Journal: Nature Neuroscience (2019)
Elucidating the pathogenesis of esophageal adenocarcinoma through meta-analysis of public data.
Authors: Kamal Khorfan, Jihad Aljabban, Saad Syed, Hussam Salhi, Aderinola Adejare, Habeeb Suara, Zahir Allarakhia, Maryam Panahiazar, Dexter Hadley
Journal: Journal of Clinical Oncology (2019)

71 Background: Esophageal adenocarcinoma (EAC) is the sixth most common cause of cancer-related deaths worldwide. It commonly arises in the setting of reflux disease and Barett’s esophagus. It remains incurable and holds a poor prognosis. Dissecting the genetic signature of EAC can pave new therapeutic avenues. Methods: We employed our Search Tag Analyze Resource (STARGEO) platform to conduct meta-analysis using the National Center for Biotechnology’s (NCBI) Gene Expression Omnibus (GEO). We tagged 151 tumor samples from EAC patients and 62 normal esophageal samples as a control. We then analyzed the signature in Ingenuity Pathway Analysis, restricting genes that showed statistical significance (p &lt; 0.05) and an absolute experimental log ratio greater than 0.15 between tumor and control. Results: Our analysis revealed granulocyte adhesion and diapedesis and FXR/RXR signaling as top canonical pathways. TGFB1, TNF, and beta-estradiol were top upstream regulators with predicted activation. TGFB1 and TNF expression have been correlated with poor prognosis in EAC. Also, beta-estradiol has tumorigenic activity in several cancers but has not been investigated in EAC. Among the top upregulated genes were oncogenic genes such as tetraspanin 8, the antiapoptotic factor OLFM4, and the protease cathepsin E (CTSE). SPINK1, a trypsin inhibitor with recently suggested role in cancer, and the choline transporter SLC44A4, a drug target for pancreatic cancer, were also upregulated. The most downregulated genes included alcohol dehydrogenase 7, associated with EAC in alcohol-drinkers, and the pro-apoptotic gene CRCT1. We also found downregulation of the serine peptidase inhibitor SPINK7. SPINK7 is involved in maintaining epithelial-barrier integrity and is implicated in eosinophilic esophagitis pathogenesis. Lastly, there was downregulation of the candidate tumor suppressor gene transglutaminase 3. Conclusions: Despite screening efforts, EAC incidence and mortality continues to increase as does the need for better treatment. This meta-analysis defines the significant gene expression changes within causal disease processes to provide markers for detection, prognostic insight, and therapeutic value for EAC.
Abstract 18406: Race and Ethnicity Significantly Modify the Association Between Hypertensive Disorders of Pregnancy and Heart Failure but Not Myocardial Infarction Among 1.5 Million Women in California
Authors: Leila Y Beach, Gregory Nah, Rima Arnaout, Nisha I Parikh
Journal: Circulation (2017)

Introduction: The hypertensive disorders of pregnancy (HDP) are associated with increased CVD risk in women. The prevalence of both HDP and CVD vary with race/ethnicity. We examined racial/ethnic d...
Outcomes and risk factors of massive and submassive pulmonary embolism in children: a retrospective cohort study
Authors: Marie-Claude Pelland-Marcotte, Catherine Tucker, Alicia Klaassen, Maria Laura Avila, Ali Amid, Nour Amiri, Suzan Williams, Jacqueline Halton, Leonardo R Brandão
Journal: The Lancet Haematology (2019)
Transmission of Procoagulant Properties to Daughter Generations of Endothelial Cells upon Exposure to Cancer Cell-Derived Microparticles. a New Implication of Cancer Derived Microparticles in the Pathogenesis of Cancer Associated Thrombosis
Authors: Rania Amrane, Aurélie Rousseau, Annette Larsen, Patrick Van Dreden, Grigorios T. Gerotziafas
Journal: Blood (2018)
Ligand-binding Domain–activating Mutations of ESR1 Rewire Cellular Metabolism of Breast Cancer Cells
Authors: Lotem Zinger, Keren Merenbakh-Lamin, Anat Klein, Adi Elazar, Shani Journo, Tomer Boldes, Metsada Pasmanik-Chor, Avishay Spitzer, Tami Rubinek, Ido Wolf
Journal: Clinical Cancer Research (2019)

Mutations in the ligand-binding domain (LBD) of estrogen receptor α (ER) confer constitutive transcriptional activity and resistance to endocrine therapies in patients with breast cancer. Accumulating clinical data suggest adverse outcome for patients harboring tumors expressing these mutations. We aimed to elucidate mechanisms conferring this aggressive phenotype.Cells constitutively expressing physiologic levels of ER-harboring activating LBD mutations were generated and characterized for viability, invasiveness, and tumor formation in vivo. Gene expression profile was studied using microarray and RNAseq technologies. Metabolic properties of the cells were assessed using global metabolite screen and direct measurement of metabolic activity.Cells expressing mutated ER showed increased proliferation, migration, and in vivo tumorigenicity compared with cells expressing the wild-type ER (WT-ER), even in the presence of estrogen. Expression of the mutated ER was associated with upregulation of genes involved in invasion and metastases, as well as elevation of genes associated with tumor cell metabolism. Indeed, a metabolic examination revealed four distinct metabolic profiles: WT-ER-expressing cells either untreated or estrogen treated and mutated ER-expressing cells either untreated or estrogen treated. Pathway analyses indicated elevated tricarboxylic acid cycle activity of 537S-ER-expressing cells. Thus, while WT-ER cells were mostly glucose-dependent, 537S-ER were not addicted to glucose and were able to utilize glutamine as an alternative carbon source.Taken together, these data indicate estrogen-independent rewiring of breast cancer cell metabolism by LBD-activating mutations. These unique metabolic activities may serve as a potential vulnerability and aid in the development of novel treatment strategies to overcome endocrine resistance.
Nonobstructive Hypertrophic Cardiomyopathy—The High-Hanging Fruit
Authors: Sharlene M. Day
Journal: JAMA Cardiology (2019)

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Targeted Drug Delivery and Image-Guided Therapy of Heterogeneous Ovarian Cancer Using HER2-Targeted Theranostic Nanoparticles
Authors: Minati Satpathy, Liya Wang, Rafal J Zielinski, Weiping Qian, Y Andrew Wang, Aaron M Mohs, Brad A Kairdolf, Xin Ji, Jacek Capala, Malgorzata Lipowska, Shuming Nie, Hui Mao, Lily Yang
Journal: Theranostics (2019)

Cancer heterogeneity and drug resistance limit the efficacy of cancer therapy. To address this issue, we have developed an integrated treatment protocol for effective treatment of heterogeneous ovarian cancer. Methods: An amphiphilic polymer coated magnetic iron oxide nanoparticle was conjugated with near infrared dye labeled HER2 affibody and chemotherapy drug cisplatin. The effects of the theranostic nanoparticle on targeted drug delivery, therapeutic efficacy, non-invasive magnetic resonance image (MRI)-guided therapy, and optical imaging detection of therapy resistant tumors were examined in an orthotopic human ovarian cancer xenograft model with highly heterogeneous levels of HER2 expression. Results: We found that systemic delivery of HER2-targeted magnetic iron oxide nanoparticles carrying cisplatin significantly inhibited the growth of primary tumor and peritoneal and lung metastases in the ovarian cancer xenograft model in nude mice. Differential delivery of theranostic nanoparticles into individual tumors with heterogeneous levels of HER2 expression and various responses to therapy were detectable by MRI. We further found a stronger therapeutic response in metastatic tumors compared to primary tumors, likely due to a higher level of HER2 expression and a larger number of proliferating cells in metastatic tumor cells. Relatively long-time retention of iron oxide nanoparticles in tumor tissues allowed interrogating the relationship between nanoparticle drug delivery and the presence of resistant residual tumors by in vivo molecular imaging and histological analysis of the tumor tissues. Following therapy, most of the remaining tumors were small, primary tumors that had low levels of HER2 expression and nanoparticle drug accumulation, thereby explaining their lack of therapeutic response. However, a few residual tumors had HER2-expressing tumor cells and detectable nanoparticle drug delivery but failed to respond, suggesting additional intrinsic resistant mechanisms. Nanoparticle retention in the small residual tumors, nevertheless, produced optical signals for detection by spectroscopic imaging. Conclusion: The inability to completely excise peritoneal metastatic tumors by debulking surgery as well as resistance to chemotherapy are the major clinical challenges for ovarian cancer treatment. This targeted cancer therapy has the potential for the development of effective treatment for metastatic ovarian cancer.
Comparative Analysis of Staging Systems in AL Amyloidosis
Authors: Eli Muchtar, Terry Therneau, Dirk Larson, Morie A. Gertz, Martha Q. Lacy, Francis K. Buadi, David Dingli, Suzanne R. Hayman, Prashant Kapoor, Wilson I Gonsalves, Taxiarchis Kourelis, Rahma Warsame, Amie Fonder, Miriam Hobbs, Yi L. Hwa, Nelson Leung, Stephen J. Russell, John A. Lust, Yi Lin, Ronald S. Go, Steven Zeldenrust, Robert A. Kyle, S. Vincent Rajkumar, Shaji K. Kumar, Angela Dispenzieri
Journal: Blood (2018)
Evaluation of safety and tolerability of durvalumab (D) and tremelimumab (T) in combination with first-line chemotherapy in patients (pts) with esophageal squamous-cell carcinoma (ESCC).
Authors: Dae Ho Lee, HyeRyun Kim, Bhumsuk Keam, Ken Kato, Yasutoshi Kuboki, Gordana Vlahovic, Osamu Takahashi, David Fitts, Myung-Ju Ahn
Journal: Journal of Clinical Oncology (2019)

146 Background: Platinum-doublet chemotherapy in first-line (1L) ESCC pts has reached a therapeutic plateau, and new therapeutic strategies are needed. Adding D (anti-PD-L1 mAb) and T (anti-CTLA-4 mAb) to 1L platinum-based chemotherapy may improve outcome in pts with advanced/metastatic ESCC. Methods: In Part A of this Phase 1b study (NCT02658214), dose-limiting toxicities (DLTs) for D+T (D 1.5 g + T 75 mg on d1, q4w) plus 5-FU+cisplatin (5-FU 800 mg/m 2 + cisplatin 80 mg/m 2 d1-5, q4w) were evaluated for the first 4 cycles in pts with advanced/metastatic ESCC who were eligible for 1L chemotherapy. The primary objective was safety and tolerability and exploratory objectives included antitumor activity and biomarker analysis. Results: Pts (N = 6) were enrolled to receive D+T + 5-FU+cisplatin between November 13, 2017, and February 14, 2018. Median age was 56 years, 83% were male, and all were ECOG PS 1. Four pts had recurrent disease and 2 were newly diagnosed with advanced/metastatic disease. All 6 pts had ≥1 treatment-related adverse event (trAE), 3 pts had grade ≥3 trAEs. All pts experienced 5-FU+cisplatin-related AEs. All grade ≥3 trAEs were neutropenia and considered due to 5-FU+cisplatin treatment; 2 were grade 3 and 1 was grade 4, which was the only serious trAE reported. Two pts had D- and/or T-related trAEs. Immune-mediated AEs were grade 1 or 2 and included diarrhea (n = 1), pruritus (n = 1), rash (n = 1), and increased AST (n = 1). There were no trAEs that led to discontinuation or death. Two of the 6 pts had a confirmed partial response that was ongoing at data cutoff (June 29, 2018). Conclusions: For patients in the ESCC DLT evaluation cohort, D+T + 5-FU+cisplatin was tolerable, and no unexpected toxicities occurred. No DLTs were observed for this regimen. The majority of trAEs and all trAEs grade ≥3 were attributed to 5-FU+cisplatin, and all were manageable. AEs related to D and/or T were all grade 1 or 2. No treatment discontinuation or death was attributed to trAEs. The study has been expanded to further evaluate this regimen in additional patients for efficacy, safety, and biomarkers. Clinical trial information: NCT02658214.
The real-world data in patients with advanced gastric cancer treated with ramucirumab combination chemotherapy.
Authors: Akie Kimura, Daisuke Sakai, Toshihiro Kudo, Naohiro Nishida, Aya Katou, Chiaki Inagaki, Toru Otsuru, Koji Tanaka, Yasuhiro Miyazaki, Tomoki Makino, Tsuyoshi Takahashi, Yukinori Kurokawa, Makoto Yamasaki, Yuichiro Doki, Masaki Mori, Taroh Satoh
Journal: Journal of Clinical Oncology (2019)

156 Background: Ramucirumab with paclitaxel or ramucirumab monotherapy have shown the efficacy and safety in second-line chemotherapy for advanced gastric cancer. The previous reports have shown that neutrophil-lymphocyte ratio (NLR) was the prognostic factor for progression free survival. Methods: We conducted a retrospective review of clinical data from patients treated with ramucirumab at our institution between April 2015 to August 2018. Results: Of 90 patients, 81 received ramucirumab plus paclitaxel, and 9 received ramucirumab monotherapy. There was a significant difference of treatment line between combination therapy and monotherapy (mean 2.5 vs. 3.9, p = 0.00127). Response rate among the patients with target lesions was 18.8% (13/69), and disease control rate was 62.3% (43/69). On the other hand, response rate among the patients previously treated with nivolumab or pembrolizumab was 57.1% (4/7). Median overall survival (OS) for combination therapy and monotherapy was 10.8 months (95% confidence interval [CI] 7.1-11.9) and 5.5 months (95% CI 0.89-9.5), respectively. Grade 3 or 4 neutropenia was more common with combination therapy than with monotherapy (53.1 vs. 11.1%). Of 69 patients who received ramucirumab plus paclitaxel as second or third-line chemotherapy, high NLR (&gt; 3) was the significant factor for poor PFS (median PFS, 2.7 vs. 5.4 months, p = 0.00103), but didn’t show the difference about OS (median OS, 9.7 vs. 11.9 months, p = 0.27). Conclusions: In our analysis, efficacy data was comparable with previous reports. In subgroup analysis, good response was observed in the group of prior nivolumab or pembrolizumab. NLR was prognostic factor for PFS, while it wasn’t show the relevance to OS because of the influence of after ramucirumab therapy.
Abstract 20589: Exercise and Mitochondrial Respiration in Mice with Arrhythmogenic Cardiomyopathy
Authors: Stephen Chelko, Angeliki Asimaki, An-Chi Wei, Deeptankar DeMazumder, Djahida Bedja, Rohan Wagle, Nuria Amat, Brian O’Rourke, Jeff Saffitz, Daniel Judge
Journal: Circulation (2014)

Incomplete penetrance of Arrhythmogenic Cardiomyopathy (AC) suggests environmental factors, such as exercise, influence disease progression. We have previously demonstrated that increased PPARγ contributes to apoptosis and fat deposition in a cellular model of AC. Therefore, we examined the effects of exercise training in a mouse model of AC (knock-in desmoglein-2 mutant). Desmoglein-2 homozygous (Dsg2mut/mut, n=12), heterozygous (Dsg2mut/+, n=11) and WT (n=9) mice were forced to swim train at 5 weeks of age (10min/day increments) and by 7 weeks mice swam 90min/day, 5 days/week. At 16 weeks of age echo- and electrocardiographic, mitochondrial, histological, gene expression and protein analysis were performed. Non-exercised Dsg2mut/mut mice showed redistribution of Cx43, Dsg2, GSK3β and nuclear PKG, increased apoptosis and reduced ejection fraction (EF, p&lt;0.001) and fractional shortening (FS, p&lt;0.01) compared to WT controls by 16 weeks of age. Additionally, by 6 weeks of age Dsg2mut/mut mice (n=3/group) demonstrated reduced carnitine-palmitoyltransferase-1 (p=0.029), increased PPARα (p=0.05), FABP4 (p=0.05) and CEBPα (p=0.04) gene expression and decreased State 3 respiration with Complex I substrates (p=0.01) compared to WT mice. In exercise studies, 50% (6/12) of Dsg2mut/mut mice survived to 16 weeks of age, whereas 6 died suddenly while swimming (mean time of death 19.5 ± 3.88 days post-swimming, p=0.03). Exercised Dsg2mut/mut mice (n=6) showed reduced EF and FS compared to Dsg2mut/+ (n=10) and WT mice (n=8, p&lt;0.001 for all comparisons). Dsg2mut/mut mice had longer mean QRS complex duration (23.9 ± 0.03 ms, p=0.05) and isovolumetric relaxation time (IVRT: 31.3 ± 3.5 ms, p=0.02) compared to Dsg2mut/+ and WT mice (n=3/group; QRS: 23.4 ± 0.03 ms, 19.4 ± 0.02 ms; IVRT: 23.8 ± 0.8 ms, 23.3 ± 1.9 ms, respectively). Furthermore, Dsg2mut/mut mice exhibit higher mitochondrial membrane potential (n=3/group, p=0.03) compared to Dsg2mut/+ and WT mice, and a trend towards increased pyruvate oxidation rate and decreased beta-oxidation rate. These data show that Dsg2mut/mut mice are at risk of arrhythmic fatality and demonstrate glycolytic-dominant respiration during exercise.
Heterogeneity in Multi-Organ Expression of HO-1 and PlGF in Sickle Mice Mimic Exposure of Non-Sickle Mice to Extracellular Heme Via Nrf2-Dependent Pathways
Authors: Oluwabukola Gbotosho, Maria G Kapetanaki, Samit Ghosh, Yu Lin, Frances Weidert, Solomon Fiifi Ofori-Acquah, Gregory J. Kato
Journal: Blood (2018)