tbuckley/cabot-search huggingface dataset:
Alterations in Pathways Regulating Phosphatidil Inositol 3 Phosphate (PI3P) Produce Both Cell Proliferation and Therapy Resistance, and Define a Group of Patients with Poor Prognosis in Acute Myeloid Leukemia (AML)
Authors: Giovanni Marconi, Cristina Papayannidis, Maria Chiara Fontana, Antonella Padella, Giorgia Simonetti, Marco Manfrini, Anna Ferrari, Eugenia Franchini, Stefania Paolini, Sarah Parisi, Chiara Sartor, Maria Chiara Abbenante, Silvia Lo Monaco, Francesca Volpato, Elena Tenti, Viviana Guadagnuolo, Margherita Perricone, Maria Teresa Bochicchio, Andrea Ghelli Luserna Di Rora, Carmen Baldazzi, Valentina Robustelli, Nicoletta Testoni, Simona Soverini, Emanuela Ottaviani, Giovanni Martinelli
Journal: Blood (2016)
Electroporation of a nanoparticle-associated DNA vaccine induces higher inflammation and immunity compared to its delivery with microneedle patches in pigs
Authors: Cindy Bernelin-Cottet, Céline Urien, Joanne McCaffrey, Damien Collins, Agnese Donadei, Dennis McDaid, Virginie Jakob, Christophe Barnier-Quer, Nicolas Collin, Edwige Bouguyon, Elise Bordet, Céline Barc, Olivier Boulesteix, Jean-Jacques Leplat, Fany Blanc, Vanessa Contreras, Nicolas Bertho, Anne C. Moore, Isabelle Schwartz-Cornil
Journal: Journal of Controlled Release (2019)

DNA vaccination is an attractive technology, based on its well-established manufacturing process, safety profile, adaptability to rapidly combat pandemic pathogens, and stability at ambient temperature; however an optimal delivery method of DNA remains to be determined. As pigs are a relevant model for humans, we comparatively evaluated the efficiency of vaccine DNA delivery in vivo to pigs using dissolvable microneedle patches, intradermal inoculation with needle (ID), surface electroporation (EP), with DNA associated or not to cationic poly-lactic-co-glycolic acid nanoparticles (NPs). We used a luciferase encoding plasmid (pLuc) as a reporter and vaccine plasmids encoding antigens from the Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), a clinically-significant swine arterivirus. Patches were successful at inducing luciferase expression in skin although at lower level than EP. EP induced the cutaneaous recruitment of granulocytes, of MHC2posCD172Apos myeloid cells and type 1 conventional dendritic cells, in association with local production of IL-1β, IL-8 and IL-17; these local responses were more limited with ID and undetectable with patches. The addition of NP to EP especially promoted the recruitment of the MHC2posCD172Apos CD163int and CD163neg myeloid subsets. Notably we obtained the strongest and broadest IFNγ T-cell response against a panel of PRRSV antigens with DNA + NPs delivered by EP, whereas patches and ID were ineffective. The anti-PRRSV IgG responses were the highest with EP administration independently of NPs, mild with ID, and undetectable with patches. These results contrast with the immunogenicity and efficacy previously induced in mice with patches. This study concludes that successful DNA vaccine administration in skin can be achieved in pigs with electroporation and patches, but only the former induces local inflammation, humoral and cellular immunity, with the highest potency when NPs were used. This finding shows the importance of evaluating the delivery and immunogenicity of DNA vaccines beyond the mouse model in a preclinical model relevant to human such as pig and reveals that EP with DNA combined to NP induces strong immunogenicity.
Abstract 3497: SAMHD1 is a Novel Biomarker and Therapeutic Target for Radiation Therapy and PARP Inhibition in Breast Cancer
Authors: Elizabeth Thompson
Journal: Cancer Research (2019)

Abstract SAMHD1 is a Novel Biomarker and Therapeutic Target for Radiation Therapy and PARP Inhibition in Breast Cancer Ashley Schlafstein, Waaqo Daddacha, David S. Yu Background/Introduction: Patients with breast cancer are often treated by ionizing radiation (IR) and PARP inhibitors; however, the effectiveness of these treatments is often limited by lack of response and/or resistance. Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a deoxyribonucleotide triphosphate (dNTP) triphosphohydrolase with a well-established role in HIV-1 restriction by depleting dNTPs required for reverse transcription and replication. SAMHD1 is also dysregulated in breast and other cancers and in autoimmune disease. In addition to its well-established dNTPase activity, our lab has defined a novel role for SAMHD1 in DNA end resection to facilitate DNA double strand break (DSB) repair by homologous recombination (HR). Because of its role in DNA DSB repair and its link to breast cancer, we hypothesized that SAMHD1 could be used as a novel biomarker and target for breast cancer therapy. Methods: We queried the TCGA database for patients with breast cancer who were treated with or without IR to determine if there was an association of SAMHD1 expression level with clinical outcome. We also determined if targeting SAMHD1 for proteasomal degradation with novel virus like particles (VLPs) containing Vpx, a viral accessory protein, can sensitize breast cancer cells and tumors to DNA damaging agents. Results: In patients with breast cancer treated with IR, low SAMHD1 expression was associated with a statistically significant improvement in overall survival, while for those not treated with IR, no significant difference in association of SAMHD1 expression with outcome was observed. Breast cancer cells and tumors treated with VLPs containing Vpx were hypersensitive to IR and PARP inhibitor. Conclusion: Our results identify SAMHD1 as a novel biomarker for stratifying breast cancer patients for treatment with IR. In addition, targeting SAMHD1 with VLPs containing Vpx may be a novel therapeutic strategy for sensitizing breast cancer to IR, PARP inhibitors, and other agents that induce DNA DSBs. Citation Format: Elizabeth Thompson. SAMHD1 is a Novel Biomarker and Therapeutic Target for Radiation Therapy and PARP Inhibition in 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 3497.
Thrombotic episodes in myeloproliferative neoplasms: A population based study.
Authors: Somedeb Ball, Dhrubajyoti Bandyopadhyay, Adrija Hajra, Raktim K Ghosh, Lukman Aderoju Tijani, Abhishek Maiti
Journal: Journal of Clinical Oncology (2019)

e18554 Background: Myeloproliferative neoplasms (MPN) are complicated with high incidence of thrombotic episodes, often requiring chronic anticoagulation in high risk patients (pts). To improve our knowledge on risk stratification, we undertook a large population study on National Inpatient Sample (NIS) to investigate the demographic and health factors associated with venous thromboembolism (VTE) and acute coronary syndrome (ACS) in pts with MPN. Methods: In this retrospective cohort study using the most recent 2016 NIS, we included all pts with discharge diagnosis (dx) of MPN with or without current or prior dx of VTE and ACS using appropriate ICD-10 codes. Demographic and health characteristics were compared between groups. Multivariate logistic regression was done to compare length of stay and cost of care. STATA 13.0 was used for statistical analysis. Results: Among 162,435 pts with MPN, 3750 (2.3%) had VTE and 2820 (1.73%) had ACS. MPN pts with VTE had significantly higher age (mean 61.3 years) compared to those without VTE (mean 59.3 years). Smoking, obesity, and JAK2 mutation were significantly more common in MPN with VTE group. Pts with MPN and ACS were significantly older than those without ACS (67.85 vs. 59.2 years). These pts were mostly males and more likely to have hypertension, diabetes, smoking, dyslipidemia, obesity, and chronic kidney disease as comorbidities. Total hospital cost was significantly higher in MPN pts with VTE and ACS. Conclusions: In agreement with prior reports, age, smoking, and presence of JAK-2 mutation seem to be an important prognostic factors for both VTE and ACS in MPN. Other common comorbidities mandate critical consideration in assessment of thrombotic risk in MPN pts. [Table: see text]
<i>In vivo</i>observations provide insight into roles of eosinophils and epithelial cells in asthma
Authors: Carl Persson
Journal: European Respiratory Journal (2019)

Observations in vivo in patients, supported by guinea-pig in vivo data, take centre stage in this perspective. Its objective is to highlight dichotomies between asthma features observed in vivo and accepted views involving cell/molecular biology research paradigms. For example, increased bronchial epithelial permeability is now considered a major paradigm and trait of asthma, yet, absorption of inhaled tracers has not been increased in vivo in asthma. Such maintained barrier function in exudative asthma reflects in vivo asymmetry of the epithelial lining as barrier between outside and inside world of molecules and cells. In desquamatory asthma, maintained epithelial tightness may be explained by in vivo demonstrations of exceedingly patchy epithelial loss, prompt creation of plasma-derived provisional barriers, and high-speed epithelial regeneration. Acknowledged protein/peptide secretion by epithelial cells in vitro is contrasted here with a dominant, unidirectional movement in vivo of plasma-derived proteins/peptides (including antimicrobial peptides) to the surface of an intact epithelial lining. Furthermore, longstanding claims that epithelium-produced adenosine is a mediator of asthma are eroded by observations in vivo in asthmatics. Notions concerning activation/fate of mucosal tissue eosinophils illustrate additional distinctions between accepted views and in vivo patient observations. Finally, in vitro -based paradigms preaching defect epithelial regeneration and increased permeability in pathogenesis of asthma are contrasted with experimental in vivo observations of exaggerated epithelial regeneration, which is multipathogenic in its own right. In conclusion, unexpected and challenging in vivo observations in recent decades underpin novel insights into mucosal mechanisms in asthma.
Treatment sequencing patterns for relapsed refractory multiple myeloma (RRMM) in the era of new therapies in a single center institution.
Authors: Alexandre Tungesvik, Praneeth Reddy Sudalagunta, Jessica Huang, Elizabeth Dimaggio, Gabe De Avila, Ankita Tandon, Rebecca Nelson, Laura Olson, Katherine Tobon, Kenneth H. Shain, Jason B. Brayer
Journal: Journal of Clinical Oncology (2019)

e19513 Background: Although there is much to be optimistic about in the multiple myeloma community as the approval of new therapies and regimen-combinations for relapsed refractory disease continues to grow, determining the best option for a patient can be complicated. Both carfilzomib- (C) and daratumumab- (D) based regimens have demonstrated superior efficacy in this setting, but there is a paucity of data supporting which should be selected first, and if regimen sequence influences outcomes. The aim of this study is to describe sequencing patterns in the era of these newer agents and to determine if there is a difference in outcomes for patients with RRMM who received one of the following treatment sequences: C-regimen with a D-regimen given immediately prior (DC); C-regimen without any prior D (C only); D-regimen with a C-regimen given immediately prior (CD); or D-regimen without any prior C (D only). Methods: This is a retrospective analysis of patients with RRMM consecutively treated at Moffitt Cancer Center between 1/1/2015 and 6/25/18. Response to therapy was assessed using the International Myeloma Working Group (IMWG) criteria. Progression-free survival (PFS) was measured in days from the start of therapy to progression. Time to response (TTR) was measured in days from the start of therapy to first response. Results: 132 patients with RRMM who received 1-3 prior lines of therapy with at least one line of therapy containing either C or D were identified. Overall, the majority of patients were treated with C only (n = 101), 10 received DC, 31 received D only, and 35 received CD. In patients that received C only, partial response (PR) was achieved in 38%, very good partial response (VGPR) was 20%, and stringent complete response (sCR) was 2%. In patients that received DC, PR was 20% and VGPR was 10%; no patient achieved a sCR. Of the patients that received D only, PR was 29%, VGPR was 10%, and sCR was 3%. In patients that received CD, PR was 31% and VGPR was 26%; no patient achieved sCR. Median PFS in patients who received C only, DC, D only, and CD was 117 days, 126 days, 104 days, and 190 days, respectively. TTR in patients who received C only, DC, D only, and CD was 82 days, 39 days, 98 days, and 88 days, respectively. Conclusions: The data suggests that RRMM patients who receive either CD or DC appear to have a PFS advantage over those patients who did not. Notably, an early TTR was found in patients that received DC. Further analysis is ongoing.
Abstract MP011: Cardiac Markers and Risk for Hospitalization with Infection: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Junichi Ishigami, Ron Hoogeveen, Christie Ballantyne, Aaron Folsom, Josef Coresh, Elizabeth Selvin, Kunihiro Matsushita
Journal: Circulation (2017)

Background: Clinical cardiovascular disease (CVD) is a risk factor for infection, but the association may be confounded by other comorbidities. To better understand the underlying pathophysiology, we explored whether subclinical cardiac biomarkers were associated with infection risk in the general population. Methods: Using 8,588 individuals free of clinical CVD in the biracial ARIC Study in 1996-98 (mean age 62 years and 22% African American), we assessed the association of high-sensitivity cardiac troponin T (hs-cTnT) and natriuretic peptide (NTproBNP) with risk of hospitalization through 2013 with an infection ICD code anywhere among the listed discharge diagnoses. Cox proportional hazards models were used to estimate hazard ratios (HRs). Results: During follow-up (median, 15.2 years), 3,308 individuals were discharged with an infection ICD code. The incidence rate increased proportionally with higher hs-cTnT and NTproBNP (Table1). The association did not change in multivariable Cox proportional analyses, and was consistent after further accounting for incident CVD during follow-up (Table1) or restricting to hospitalizations with infection as the primary diagnosis. No interaction was observed for subgroup analysis by age, sex, race, and status of diabetes or chronic kidney disease (eGFR &lt;60 vs. ≥60 ml/min/1.73m 2 ). Although both cardiac markers were associated with different types of infection (pneumonia, urinary tract infections, bloodstream infections, and cellulitis), the association appeared strongest for cellulitis (HR, 1.41 [95%CI, 1.00-2.00] for hsTnT ≥4 vs. &lt;3ng/L; and 1.51 [1.08-2.11] for NTproBNP ≥69 vs. &lt;68 pg/mL). Conclusions: Higher hs-cTnT and NTproBNP concentrations were independently associated with increased risk for hospitalization with infection, suggesting a potential relationship between cardiac damage/overload and infection.
Abstract B45: High-throughput label-free isolation and expansion of circulating tumor cells (CTCs) from non-small cell lung cancer (NSCLC) patients for personalized treatments
Authors: Mina Zeinali, Wei Huang, Maggie Lee, Arthi Nadhan, Anvya Mathur, Casey Hedman, Eric Lin, Ramdane Harouaka, Max S. Wicha, Lili Zhao, Nallasivam Palanisamy, Mathias Hafner, Rishindra Reddy, Gregory P. Kalemkerian, Bryan J. Schneider, Khaled A. Hassan, Nithya Ramnath, Sunitha Nagrath
Journal: Clinical Cancer Research (2020)

Abstract Background: Circulating tumor cell (CTC) clusters are emerging as clinically significant harbingers of metastases in solid organ cancers. Prior to engaging these CTC clusters in animal models of metastases, it is imperative for technology to identify them with high sensitivity. These clusters often present heterogeneous surface markers, and current methods for isolation of clusters may fall short. Methods: We have applied the inertial microfluidic Labyrinth device for high-throughput, biomarker-independent, size-based isolation of CTCs and CTC clusters from patients with metastatic non-small cell lung cancer (NSCLC). Results: Using the Labyrinth device, CTCs (PanCK+/DAPI+/CD45-) were isolated from metastatic NSCLC patients (n=25). Heterogeneous CTC populations were detected, including CTCs expressing epithelial (EpCAM), mesenchymal (vimentin), or both markers. CTCs were isolated from 100% of patients (417±1023 CTCs/mL), and CTCs that were EpCAM negative were significantly higher in numbers than EpCAM+ CTCs. Cell clusters of ≥2 CTCs were observed in 96% of patients, of which 75% were negative for EpCAM. Patients with higher number of CTC clusters than single CTCs had worse progression-free survival (PFS) (p=0.05). Recovered CTCs from patients with RET, ROS1, and ALK-rearranged tumors revealed identical genetic aberrations as the primary tumor for each gene using FISH analysis. We have successfully expanded the recovered CTCs from 2 patients and screened for therapeutic targeting. We have found that TPX-0005 might be effective in these patients and would direct them to a clinical trial using this compound. Conclusions: The label-free Labyrinth device demonstrated the capability of collecting recovered CTCs from the device using a continuous processing technique while in a suspension state. This advantage opens the opportunities not only for CTC expansion off-chip, but also for ex vivo drug testing to direct patient-specific therapies. Citation Format: Mina Zeinali, Wei Huang, Maggie Lee, Arthi Nadhan, Anvya Mathur, Casey Hedman, Eric Lin, Ramdane Harouaka, Max S. Wicha, Lili Zhao, Nallasivam Palanisamy, Mathias Hafner, Rishindra Reddy, Gregory P. Kalemkerian, Bryan J. Schneider, Khaled A. Hassan, Nithya Ramnath, Sunitha Nagrath. High-throughput label-free isolation and expansion of circulating tumor cells (CTCs) from non-small cell lung cancer (NSCLC) patients for personalized treatments [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B45.
Abstract 9719: Overexpressed Phoshodiesterase 3A1 Protects the Heart against Angiotensin II-induced Cardiac Injury via Regulating Interaction between β-adrenergic and Angiotensin II Signaling Pathways
Authors: Masayoshi Oikawa, Shoji Iwaya, Chen Yan, Yasuchika Takeishi
Journal: Circulation (2012)

BACKGROUND: Angiotensin II (AngII) has critical roles in progression of cardiac hypertrophy and fibrosis, leading to subsequent heart failure. Accumulating evidence suggests that there are direct interactions between β-adrenergic and AngII signaling pathways, and β-blocker treatment protects hearts against AngII-induced cardiac injury. Phosphodiesterase 3A (PDE3A) inhibits β-adrenergic receptor (βAR)/protein kinase A (PKA) axis by metabolizing cAMP. Therefore, we hypothesized that overexpressed PDE3A has cardioprotective effects against AngII-induced cardiac injury by regulating AngII signaling. METHODS AND RESULTS: To induce cardiac injury, AngII (800 ng/kg/min) was continuously infused using osmotic mini-pump for 10 days in wild-type (WT) mice and transgenic (TG) mice with cardiac-specific expression of exogenous PDE3A1. AngII stimulation increased heart weight/body weight ratio by 32% in WT hearts compared with vehicle hearts (5.6±0.5 mg/g vs. 4.3±0.1 mg/g, P&lt;0.05), whereas by 5% in TG hearts (5.8±0.6 mg/g vs. 5.5±0.8 mg/g, ns). Echocardiography revealed that AngII lead to cardiac hypertrophy in WT hearts compared to vehicle hearts (wall thickness, 12.4±1.5 mm vs. 8.2±0.7 mm, P&lt;0.05), but not in TG hearts (10.4±1.5 mm vs. 9.3±0.3 mm, ns). Moreover, AngII-induced cardiac fibrosis was also inhibited in TG hearts compared to WT hearts (4.2±1.1% vs. 6.9±2.6%, P&lt;0.05). Interestingly, basal expression levels of transforming growth factor-β (TGFβ) as well as phosphorylated-phospholamban were inhibited in TG hearts compared to WT hearts, suggesting that overexpressed PDE3A regulated AngII/TGFβ and βAR/PKA axis. CONCLUSIONS: We thus conclude that PDE3A inhibits AngII-induced cardiac hypertrophy and fibrosis via regulating the interaction between β-AR/PKA and AngII/TGFβ axis.
Comparative safety and efficacy of anti-PD-1 monotherapy, chemotherapy alone, and their combination therapy in advanced nasopharyngeal carcinoma: findings from recent advances in landmark trials
Authors: Jia-Wei Lv, Jun-Yan Li, Lin-Na Luo, Zi-Xian Wang, Yu-Pei Chen
Journal: Journal for ImmunoTherapy of Cancer (2019)

Recent phase 1–2 trials reported manageable safety profiles and promising antitumor activities of anti-PD-1 drugs (pembrolizumab, nivolumab, camrelizumab and JS001) with/without chemotherapy in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC), however head-to-head comparison among these regimens is lacking. We aimed to comprehensively compare the efficacy and safety of different anti-PD-1 drugs, standard chemotherapy, and their combination therapy in RM-NPC. Adverse event (AE) and objective response rate (ORR) were assessed. The pooled incidence rates of grade 1–5/3–5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1–5 AEs whereas camrelizumab and nivolumab regarding grade 3–5 AEs. As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1–positive and PD-L1–negative patients, respectively (<i>P</i>&nbsp;= 0.11). Here, we represent preliminary evidence for the comparative safety and efficacy of existing anti-PD-1 agents with/without chemotherapy in RM-NPC, which indicated that camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in RM-NPC.
Abstract 11560: Clinical Impact of Heart-type Fatty Acid-binding Protein Levels for Predicting the Occurrence of Appropriate Implantable Cardioverter-defibrillator Shocks in Patients With Brugada Syndrome or Idiopathic Ventricular Fibrillation
Authors: Hyuma Daidoji, Takanori Arimoto, Harutoshi Tamura, Mitsunori Ishino, Daisuke Kutsuzawa, Daisuke Ishigaki, Hiroki Takahashi, Tetsuro Shishido, Takehiko Miyashita, Takuya Miyamoto, Tetsu Watanabe, Isao Kubota
Journal: Circulation (2012)

Background The recent studies suggested that there were no reliable predictors of cardiac events except for prior symptoms and spontaneous type 1 ECG in Brugada syndrome (BS) patients. BS has been ...