tbuckley/cabot-search huggingface dataset:
Combinatory antitumor therapy by cascade targeting of a single drug
Authors: Aiyun Liu, Huaisong Wang, Xiaoshuang Hou, Yu Ma, Gongjun Yang, Yanglong Hou, Ya Ding
Journal: Acta Pharmaceutica Sinica B (2019)

Combination therapy has shown its promise in the clinic for enhancing the efficacy of tumor treatment. However, the dose control of multiple drugs and their non-overlapping toxicity from different drugs are still great challenge. In this work, a single model drug, paclitaxel (PTX), is used to realize combination therapy and solve the problems mentioned above. Either PTX or its triphenylphosphine derivative (TPTX) is encapsulated in galactose-modified liposomes (GLips) to obtain GLips-P or GLips-TP, which are simply mixed in different ratios to finely control the proportion of PTX and TPTX. These mixed liposomes, GLips-P/TP, feature a cascade target delivery of PTX, from tissue to cell, and then to organelle. PTX plays a primary role to cause the cytotoxicity by microtubule bindings in cytoplasm, while TPTX is proved to increase the intracellular levels of caspase-3 and caspase-9 that cause apoptosis via a mitochondria-mediated pathway. Notably, GLips-P/TP 3:1 exhibited the significant drug synergy in both cytotoxicity assay of HepG2 cells and the treatment efficacy in Heps xenograft ICR mouse models. This work not only demonstrates the great promise of a cascade targeting delivery for precise tumor treatment, but also offers a novel platform to design combinatory therapy systems using a single drug.
Synthesis and biological evaluation of a series of 2-(((5-akly/aryl-1H-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3H)-ones as potential HIV-1 inhibitors
Authors: Yumeng Wu, Chengrun Tang, Ruomei Rui, Liumeng Yang, Wei Ding, Jiangyuan Wang, Yiming Li, Christopher C. Lai, Yueping Wang, Ronghua Luo, Weilie Xiao, Hongbing Zhang, Yongtang Zheng, Yanping He
Journal: Acta Pharmaceutica Sinica B (2019)

A series of 2-(((5-akly/aryl-1H-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3H)-ones were synthesized and their anti-HIV-1 activities were evaluated. Most of these compounds were highly active against wild-type (WT) HIV-1 strain (IIIB) with EC50 values in the range of 0.0038–0.4759 μmol/L. Among those compounds, I-11 had an EC50 value of 3.8 nmol/L and SI (selectivity index) of up to 25,468 indicating excellent activity against WT HIV-1. In vitro anti-HIV-1 activity and resistance profile studies suggested that compounds I-11 and I-12 displayed potential anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (EC50s range from 4.3 to 63.6 nmol/L and 18.9–219.3 nmol/L, respectively). On the other hand, it was observed that those two compounds were less effective with EC50 values of 2.77 and 4.87 μmol/L for HIV-1A17 (K103N + Y181C). The activity against reverse transcriptase (RT) was also evaluated for those compounds. Both I-11 and I-12 obtained sub-micromolar IC50 values showing their potential in RT inhibition. The pharmacokinetics examination in rats indicated that compound I-11 has acceptable pharmacokinetic properties and bioavailability. Preliminary structure–activity relationships and molecular modeling studies were also discussed.
Multi-institutional analysis of outcomes in patients with dedifferentiated chondrosarcoma (DDCS).
Authors: Nam Bui, Hilary Dietz, Angela C. Hirbe, Kristen N. Ganjoo, Brian Andrew Van Tine, Vicki Leigh Keedy, Elizabeth J. Davis
Journal: Journal of Clinical Oncology (2019)

11028 Background: DDCS is a rare bone tumor with a poor prognosis. While no standard therapy exists, NCCN guidelines recommend osteosarcoma regimens (ORs). Methods: We performed a retrospective review (January 1, 2007-June 1, 2018) at three sarcoma centers and identified 46 patients (pts) with DDCS to evaluate treatments and outcomes. Results: Median age was 62.5 years (23-83); 61% were male. Median tumor size was 10.5cm (2-34). Most pts had localized disease at diagnosis (dx) (80%), extremity primary (76%), and did not receive neo/adjuvant chemotherapy (70%) or radiotherapy (69%). Local and distant recurrences were frequent (35% and 57%, respectively) and rapid (6.6 months (m) and 5.4 m, respectively). Twenty-eight pts received chemotherapy, 9 neo/adjuvant and 19 for metastasis (met) (Table). Response rate to first line ORs was poor (53% progressed). Notably, 11% had a partial response (D/I). Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) led to stable disease. Median overall survival was 22.8 m and 7.2 m; 5-year survival rates were 30% and 0% in localized and metastatic disease, respectively. Median follow-up was 12.5 m (1.4-120). A multivariate cox proportional hazards model (age, sex, location, met at dx) identified met at dx as the only risk factor for worse prognosis (HR 2.8, p=0.026). Conclusions: DDCS is an aggressive malignancy with a poor prognosis. Despite guidelines to treat with ORs, the benefit is unclear, illustrating the need for randomized trials comparing standard regimens to novel agents. [Table: see text]
Routine Measurements of Cardiac Parasympathetic and Sympathetic Nervous Systems assists in Primary and Secondary Risk Stratification and Management of Cardiovascular Clinic Patients
Authors: Gary L. Murray, Joseph Colombo
Journal: Clinical Cardiology and Cardiovascular Interventions (2019)

Objective: To review our studies of the ease and importance of parasympathetic and sympathetic (P&amp;S) measures in managing cardiovascular patients. Background: The autonomic nervous system is responsible for the development or progression of hypertension (HTN), orthostasis, coronary disease (CAD), heart failure (CHF), and arrhythmias. Finally, new technology provides us with rapid, accurate P and S measures critically needed to manage these patients much more successfully. Methods: Using the ANX 3.0 autonomic monitor, P&amp;S activity was recorded in 4 studies: 163 heart failure patients in total, mean follow-up (f/u) 12-24.5 months; 109 orthostasis patients, f/u 2.28 years (yr), and 483 patients with risk factors or known HTN, CAD, or CHF, f/u 4.92 yrs. All were on guideline-driven therapy. Results: Fifty-nine percent (59%) of CHF patients had dangerously high sympathovagal balance(SB) or cardiac autonomic neuropathy (CAN), and Ranolazine markedly improved 90% of these, improved left ventricular ejection fraction in 70% of patients on average 11.3 units, and reduced MACE (acute coronary syndromes, death, acute CHF, ventricular tachycardia/fibrillation[VT/VF]) 40%. Sixty-six-percent (66%) of orthostatic patients corrected with (r) alpha lipoic acid ([r]ALA); non-responders had the lowest S-tone. In the 483 patient study, SB&gt;2.5 best predicted MACE when compared to nuclear stress and echocardiography (sensitivity 0.59, OR 7.03 [CI 4.59-10.78], specificity 0.83, positive predictive value 0.64, and negative predictive value 0.80).
Abstract 15941: Identification of a Novel TPM1 Mutation in Congenital Atrial Septal Defect With Autosomal Dominant Inheritance
Authors: Polakit Teekakirikul, Wenjuan Zhu, Michael X Wang, Amanda M Smith, Honglan Gou, Abha Bais, Omar Khalifa, Maliha Zahid, Stephanie M Ware, Brian Feingold, Cecilia W Lo
Journal: Circulation (2017)

Introduction: Atrial septal defect (ASD) accounts for 10-15% of all congenital heart defects (CHD). While a genetic contribution in ASD is well described, its underlying genetic architecture remain...
TLR9 activation induces aberrant IgA glycosylation via APRIL- and IL-6–mediated pathways in IgA nephropathy
Authors: Yuko Makita, Hitoshi Suzuki, Toshiki Kano, Akiko Takahata, Bruce A. Julian, Jan Novak, Yusuke Suzuki
Journal: Kidney International (2019)

Galactose-deficient IgA1 (Gd-IgA1) plays a crucial role in the development of IgA nephropathy (IgAN). However, the pathogenic mechanisms driving Gd-IgA1 production have not been fully elucidated. Innate-immune activation via Toll-like receptor 9 (TLR9) is known to be involved in Gd-IgA1 production. A proliferation inducing ligand (APRIL) and IL-6 are also known to enhance Gd-IgA1 synthesis in IgAN. With this as background, we investigated how TLR9 activation in IgA secreting cells results in overproduction of nephritogenic IgA in the IgAN-prone ddY mouse and in human IgA1-secreting cells. Injection of the TLR9 ligand CpG-oligonucleotides increased production of aberrantly glycosylated IgA and IgG-IgA immune complexes in ddY mice that, in turn, exacerbated kidney injury. CpG-oligonucleotide-stimulated mice had elevated serum levels of APRIL that correlated with those of aberrantly glycosylated IgA and IgG-IgA immune complexes. In vitro, TLR9 activation enhanced production of the nephritogenic IgA as well as APRIL and IL-6 in splenocytes of ddY mice and in human IgA1-secreting cells. However, siRNA knock-down of APRIL completely suppressed overproduction of Gd-IgA1 induced by IL-6. Neutralization of IL-6 decreased CpG-oligonucleotide-induced overproduction of Gd-IgA1. Furthermore, APRIL and IL-6 pathways each independently mediated TLR9-induced overproduction of Gd-IgA1. Thus, TLR9 activation enhanced synthesis of aberrantly glycosylated IgA that, in a mouse model of IgAN, further enhanced kidney injury. Hence, APRIL and IL-6 synergistically, as well as independently, enhance synthesis of Gd-IgA1.
Correlation of imatinib plasma trough concentrations with adverse reaction in Chinese gastrointestinal stromal tumors patients.
Authors: Yanzhe Xia, Sile Chen, Shirong Cai, Yulong He, Xinhua Zhang
Journal: Journal of Clinical Oncology (2019)

11034 Background: Imatinib is the standard treatment for patients of Gastrointestinal Stromal Tumors (GISTs), but the intra- and inter-variability of imatinib plasma trough concentration (C min ) are significant. Few studies investigated the association between C min and adverse reaction in Chinese GIST patients. The distribution of imatinib C min in different doses and the correlation of imatinib C min with adverse reaction in Chinese GIST patients from a high-volume center were evaluated. Methods: From 1 Jul 2017 to 31 Dec 2018, a total of 400 patients who were under imatinib treatment were prospectively studied. All patients’ informed consents were obtained. Steady state plasma samples were obtained from patients at least administrating 1 month treatment who were taking imatinib 100 to 800 mg/d, with continuous similar timing of daily dosage for more than 14 days. The adverse reaction was recorded during regular follow-up at out-patient clinic, and blood sample was collected 22±2 hours to the next dosage of imatinib. Liquid chromatography tandem mass spectrometry was applied to determine the concentration. Adverse reaction grades were referred to CTCAE v4.0. Results: A total of 368 patients who followed the same dose of imatinib with good compliance, and having at least 2 times of tests were investigated. The imatinib C min was 384±53 ng/mL, 776±337 ng/mL, 986±327 ng/mL, 1078±498 ng/mL, 1309±712 ng/mL, 1620±469 ng/mL, 2117±597 ng/mL and 3844±987 ng/mL in patients who were administrated with 100 mg/d (n = 3), 200 mg/d (n = 15), 250 mg/d (n = 5), 300 mg/d (n = 80), 400 mg/d (n = 235), 500 mg/d (n = 3), 600 mg/d (n = 22) and 800 mg/d (n = 5), respectively. In correlation analysis, imatinib C min was significantly correlated with periorbital and limbs edema (p &lt; 0.01), anemia (p &lt; 0.01) and rush (p &lt; 0.01), correlated with diarrhea and conjunctival hemorrhage but not significant. Much higher C min was observed in severe adverse reaction (≥ grade 3) of periorbital and limbs edema and rash. There was no correlation between C min with leukopenia, nausea, vomiting, muscle cramp or hepatobiliary disorders. Conclusions: In Chinese GIST patients, imatinib C min at steady state was seems higher than Western populations previous reported, especially in higher doses (≥600 mg/d). Imatinib C min was correlated with anemia, periorbital and limbs edema, diarrhea and conjunctival hemorrhage, suggesting that imatinib C min monitor might be considered when patients were subjected to severe adverse reactions which were caused by excessive imatinib plasma concentration.
Ischemic stroke in children and young adults with sickle cell disease in the post‐STOP era
Authors: Janet L. Kwiatkowski, Jenifer H. Voeks, Julie Kanter, Heather J. Fullerton, Ellen Debenham, Lynette Brown, Robert J. Adams
Journal: American Journal of Hematology (2019)

The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) trials established routine transcranial Doppler ultrasound (TCD) screening, with indefinite chronic red cell transfusions (CRCT) for children with abnormal TCD as standard of care. Implementation failures and limitations to the STOP protocol may contribute to continued ischemic stroke occurrence. In the "Post-STOP" study, we sought to assess the impact of the STOP protocol on the incidence of ischemic stroke in a multicenter cohort of former STOP and/or STOP 2 trial participants. A central team abstracted data for 2851 (74%) of the 3835 children who took part in STOP and/or STOP 2. Data included TCD and neuroimaging results, treatment, laboratory data, and detailed clinical information pertaining to the stroke. Two stroke neurologists independently confirmed each stroke using pre-specified imaging and clinical criteria and came to consensus. Among the 2808 patients who were stroke-free at the start of Post-STOP with available follow-up, the incidence of first ischemic stroke was 0.24 per 100 patient-years (95% CI, 0.18, 0.31), with a mean (SD) duration of follow-up of 9.1 (3.4) [median 10.3, range (0-15.4)] years. Most (63%) strokes occurred in patients in whom the STOP protocol had not been properly implemented, either failure to screen appropriately with TCD (38%) or failure to transfuse adequately patients with abnormal TCD (25%). This study shows that substantial opportunities for ischemic stroke prevention remain by more complete implementation of the STOP Protocol.
P11.58 Astrocytic Environment Aid the Evolution of Immunosuppressive Environment in Glioblastoma
Authors: D H Heiland, V M Ravi, S P Behringer, O Schnell
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastomas are referred to as immunologically “cold” tumors since their cellular environment promotes an anti-inflammatory environment leading to an unresolved barrier to immunotherapy. Although the role of reactive astrocytes in other inflammatory diseases has been investigated in several studies, the immunoregulatory functions of astrocytes in the tumor environment remains poorly understood. MATERIAL AND METHODS We purified reactive astrocytes from de-novo glioblastoma and non-infiltrated cortex specimens by immunoprecipitation and analyzed the transcriptional phenotype by RNA sequencing. In order to investigate the origin of astrocytic transformation, we used a microglia loss-of-function model in human organotypic slices. Microglia was depleted by clodronat stimulation. We injected tumor cells and analyzed gene expression of the astrocytes after 7d incubation by RNA sequencing. Environmental cytokines were analyzed by multi-ELISA. Immunostainings of slices were processed by confocal microscopy and 3D reconstruction. RESULTS Here we address the immunological impact of tumor-associated astrocytes, we were able to identify a novel reactive subtype marked by JAK/STAT pathway activation and CD274 expression. Our results show a distinct astrocytic transcriptional phenotype that mutually arises from both microglia and astrocytes of the tumor environment. This interaction leads to a large release of anti-inflammatory cytokines such as TGFß and IL10. The reactive subtype switch of astrocytes was recovered by inhibition of the JAK pathway, which caused an increase of pro-inflammatory environment. CONCLUSION Our results can form the basis for a novel therapeutic approach by directly targeting tumor-associated astrocytes in order to transformimmunologically “cold” into “warm” tumors.
P11.23 Oncolytic adenovirus Delta-24-RGD exerts a potent anti-tumor effect in preclinical models of atypical teratoid/rhabdoid tumors
Authors: M Garcia Moure, M González Huarriz, L Marrodán, A Patiño-García, M M Alonso
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (AT/RTs) are rare pediatric brain tumors affecting mainly infants and young children. However, AT/RTs encompass almost 10% of death caused by pediatric brain tumors, and the 2-year overall survival for these children remains below 20%. For this reason, AT/RT ranks among the deadliest pediatric brain tumors. Therefore, it is clear we need to find out new therapeutic options for these children. Delta-24-RGD is an oncolytic adenovirus that has already demonstrated its efficacy as in Phase I/II clinical trials in adult patients affected by high grade gliomas with no evidence of severe side effects. Of interest for pediatric brain tumors, the safety of Delta-24-RGD is has also been demonstrated in an ongoing Phase I clinical trial for the treatment of DIPGs (NCT03178032). For these reasons, we propose to evaluate the anti-tumor effect of Delta-24-RGD in preclinical models of ATRT. MATERIAL AND METHODS Our studies have been carried out in three stablished AT/RT cell lines (BT-12, CHLA-06 and CHLA-266). In vitro, AT/RT cultures were infected with Delta-24-RGD-GFP to confirm the infectivity of the virus by flow cytometry. Replication of Delta-24-RGD was ensured by titrating the PFUs generated in AT/RT infected cultures. In regard to cytolytic effect, viability assays (MTS) were conducted in AT/RT cultures infected at increasing MOIs of Delta-24-RGD. In vivo, AT/RT cell lines were engrafted in Rag-2 mice in supratentorial and infratentorial locations, and the animals were treated with Delta-24-RGD at 107 or 108 PFU/animal (intra-tumor administration), or PBS. The therapeutic benefit of Delta-24-RGD was evaluated comparing the overall survival obtained for treated and untreated animals using the Log-rank test. We have also generated models of disseminated disease through intraventricular injection of the tumor cells, thus mimicking the lesions found in patients. AT/RT cell lines were transduced with a luc-expressing lentivirus to facilitate the follow up of these tumors. Mice bearing disseminated AT/RT were treated with Delta-24-RGD at 107 or 108 PFU/animal, or PBS (control). The therapeutic effect was monitored by bioluminescence and by comparison of the survival curves (Log-rank). RESULTS The virus was able to infect and replicate in tumor three different cell culture models of AT/RT, inducing a potent cytotoxic effect that resulting in IC50 values below 1 PFU/cell. Administration of the virus in mice bearing localized AT/RT (supratentorial and infratentorial) extended significantly the survival the animals, leading to up to 20% of long-term survivors. In disseminated AT/RT models, light emission reveals reduction of tumor growth in virus treated animals, resulting in an increased overall survival. CONCLUSION In conclusion, these results demonstrate that Delta-24-RGD could be a feasible therapeutic choice for patients affected by AT/RT.
Alcohol, The Sanction for Its Use, Scientifically Established and Popularly Expounded by a Physiologist.
Journal: JAMA (1907)

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P11.51 Repurposing the antipsychotic chlorpromazine for the treatment of glioblastoma multiforme
Authors: M G Paggi, C Abbruzzese, S Matteoni, P Matarrese, D Giannarelli, I Sperduti, V Villani, A Pace
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Background Glioblastoma multiforme (GBM) is characterized by short survival rates, thus generating a compelling need for more effective therapeutic schemes. Therapeutic approaches involving novel drugs must travel a long and expensive way in order to reach the bedside; drug repurposing and repositioning are viable strategies to develop therapies, involving shorter timelines and lower costs. Here we analyzed the activity of the antipsychotic drug chlorpromazine (CPZ) in hindering GBM growth in vitro and in vivo. The safety of this drug springs from six decades of clinical use as an antipsychotic. CPZ has been very recently identified as an inhibitor of the mitotic kinesin KSP/Eg5 and the AKT/mTOR pathway in human glioma cells. MATERIAL AND METHODS To explore CPZ pharmacodynamic properties, we assayed the effects of CPZ on several GBM cell lines growing in an anchorage-dependent manner or as neurospheres (cancer stem cells). Further experimentation using high-throughput proteomic and metabolomic platforms is underway. RESULTS In our hands CPZ, in the low micromolar range, strongly reduced GBM cell viability after 48 h in both anchorage-dependent cells (IC50=10 microM) and neurospheres (IC50=16 microM), cloning efficiency after 15 d (IC 50=4 and 9 microM, respectively), inducing also, at the respective IC50 concentrations for viability, spindle aberrations up to mitotic catastrophe in almost all cells, as highlighted by means of alpha-tubulin immunofluorescent staining. A Phase II clinical trial involving CPZ, in addition to the adjuvant phase of the Stupp protocol, in GBM patients carrying a hypo-methylated MGMT gene is now ongoing. CONCLUSION We proved the effectiveness of CPZ in potently hindering GBM cell growth, without sparing cancer stem cells. This last characteristic is important in order to overcome disease relapse and drug resistance. Recently, many drugs have been repositioned as potentially useful in GBM and for many of these, such as metformin, disulfiram, chloroquine, sirolimus and others, there are clinical trials that challenge them individually combined with the Stupp protocol. On the basis on our results, we consider the choice to undertake a Phase II clinical trial adding CPZ to TMZ in the adjuvant phase of the Stupp protocol as a rational and ethical option to be pursued