tbuckley/cabot-search huggingface dataset:
P17.10 BNCT for the treatment of malignant brain tumors, from reactor to accelerator
Authors: S. Miyatake, S. Kawabata, T. Kuroiwa, M. Suzuki, Y. Sakurai, K. Ono
Journal: Neuro-Oncology (2017)

Boron neutron capture therapy (BNCT) provides a way to selectively destroy malignant cells and spare normal cells. It is based on the nuclear capture and fission reactions that occur when boron-10, which is a nonradioactive constituent of natural elemental boron, is irradiated with low-energy thermal neutrons to yield high LET and high RBE alpha particles and recoiling lithium-7 nuclei. Since the high LET particles have limited path lengths in tissue (5-9 μm), the destructive effects of these particles are limited to boron-containing cells. Most adequate target cancer cells should be infiltrative, like malignant gliomas which are difficult to be controlled by other par1icles. In addition, this cell selectivity has the merit especially in re-irradiation. For successful BNCT, a sufficient amount of 10B must be selectively delivered to the tumor cells. Prior to neutron irradiation, we can simulate 10B uptake by PET imaging. Since January 2002, we applied BNCT for malignant brain tumors. As of May 2014, we have applied reactor-based BNCT for 58 cases of newly diagnosed GBM, 50 cases of recurrent malignant gliomas, 32 cases of recurrent high-grade meningiomas, and so on, totally 148 cases with 167 times BNCT. At first we applied BNCT for recurrent malignant gliomas (rMG). To evaluate this benefit in the low and high risk group of rMG, We adopted the recursive partitioning analysis (RPA) classification for rMG advocated by Carson et al. in a 2007 article in the Journal of Clinical Oncology (JCO), BNCT could prolong the survival of rMG, especially for high risk group markedly. For example, JCO’s original data set showed the MST for high risk group of rMG (class 3+7) was 4.4 months while our BNCT showed the MST as 11 months. As to rMG, all cases received full-dose radiation therapy, prior to BNCT, therefore radiation necrosis was inevitable even after tumor-selective particle radiation, BNCT. Therefore, we applied anti-VEGF antibody, bevacizumab aggressively for the treatment of symptomatic radiation necrosis after BNCT especially for the recurrent cases who had already treated by other radiation modality. This treatment contributed to further improvement of patient survival of recurrent malignant gliomas after BNCT. Also BNCT showed complete or partial response for all high-grade meningiomas. Depending on these experiences of reactor-based BNCT, we started a phase I clinical trial using both new boron compound (BPA) and a new neutron generator, cyclotron-based accelerator, for rMG since 2012. This study was aimed for the safety and tolerability of this treatment. The clinical trial enrolment and observation were finished with a favorable result. Now we are doing a phase II clinical trial for recurrent GBM using the same combination to clarify the effectiveness. In this presentation, let me introduce the protocol and interim analysis of these trials.
Cytochrome P450 reductase is crucial for redox cycling of mitomycin c but does not mediate its cytotoxicity in Chinese hamster ovary cells
Authors: Yun Wang, Joshua Gray, Vladimir Mishin, Diane Heck, Jeffrey Laskin
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

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Mitomycin c is a quinone-containing alkylating agent which is widely used in the clinic for treatment of solid cancers. One mechanism of cytotoxicity of mitomycin c involves its generation of reactive oxygen species (ROS) upon reductive bioactivation by enzymes such as cytochrome P450 reductase under aerobic conditions. To further investigate involvement of cytochrome P450 reductase in mitomycin c-mediated redox cycling and cytotoxicity, we examined these activities of the antibiotic using Chinese hamster ovary cells overexpressing P450 reductase (CHO OR) and the corresponding control cells (CHO WT). Cytochrome P450 reductase activity in CHO OR cells was about 40-fold greater than in CHO WT cells as measured by reduction of cytochrome c in cell lysates. We found that mitomycin c stimulated ROS production, as measured by the formation of hydrogen peroxide using the Amplex Red reaction, in lysates from both CHO cell lines. The Vmax for mitomycin c in lysates from P450 reductase-overexpressing cells was 27-fold greater than in lysates from CHO WT cells (30 nmol H2O2/mg protein/min vs. 1.1 H2O2/mg protein/min), while the Kact value in CHO OR lysates was about 5-fold higher than in CHO WT lysates (382 μM vs. 77 μM). Mitomycin c also stimulated utilization of NADPH. In the presence of 100 μM mitomycin c, the Vmax for the oxidation of NADPH increased 14-fold in CHO OR cell lysates and only 2-fold in CHO WT cell lysates. Mitomycin c also stimulated hydroxyl radical formation in lysates from both cell types, as measured using terephthalate, a hydroxyl radical trapping agent in conjunction with HPLC and fluorescence detection. CHO OR cells formed 5-10 fold more hydroxyl radicals when compared to CHO WT cells in the presence of mitomycin c. In lysates from both cell types, hydroxyl radical formation was inhibited by dimethylsulfoxide and abolished by catalase. In cell growth inhibition assay, mitomycin c was found to be cytotoxic in both cell lines. However, despite increased redox cycling in CHO OR cells, no differences in cytotoxicity were apparent between the two cell types (IC50 = 0.05 in CHO OR and CHO WT cells, respectively). Taken together, these data indicate that cytochrome P450 reductase can mediate redox cycling and ROS formation in CHO cells. However, increased redox cycling does not enhance cytotoxicity of mitomycin c in these cells. These data suggest that either other ROS-related enzymes or alternative targets are important for the cytotoxicity of mitomycin c. (Supported by CA93798 and CA100994.)
Sleep-Time Ambulatory BP Is an Independent Prognostic Marker of CKD
Authors: Ramón C. Hermida, Diana E. Ayala, Artemio Mojón, José R. Fernández
Journal: Journal of the American Society of Nephrology (2017)

The prognostic value of clinic and ambulatory BP in predicting incident CKD and whether CKD risk reduction associates with progressive treatment–induced decrease of clinic, awake, or asleep BP are unknown. We prospectively evaluated 2763 individuals without CKD, 1343 men and 1420 women (mean±SD age: 51.5±14.3 years old), with baseline ambulatory BP ranging from normotension to hypertension. On recruitment and annually thereafter (more frequently if hypertension treatment was adjusted on the basis of ambulatory BP), we simultaneously monitored BP and physical activity (wrist actigraphy) for 48 hours to accurately derive individualized mean awake and asleep BP. During a median 5.9-year follow-up, 404 participants developed CKD. Mean asleep systolic BP was the most significant predictor of CKD in a Cox proportional hazard model adjusted for age, diabetes, serum creatinine concentration, urinary albumin concentration, previous cardiovascular event, and hypertension treatment time (on awakening versus at bedtime; per 1-SD elevation: hazard ratio, 1.44; 95% confidence interval, 1.31 to 1.56; P &lt;0.001). The predictive values of mean clinic BP and mean awake or 48-hour ambulatory BP was not significant when corrected by mean asleep BP. Analyses of BP changes during follow-up revealed 27% reduction in the risk of CKD per 1-SD decrease in mean asleep systolic BP, independent of changes in mean clinic BP or awake ambulatory BP. In conclusion, sleep-time BP is a highly significant independent prognostic marker for CKD. Furthermore, progressive treatment–induced decrease of asleep BP, a potential therapeutic target requiring ambulatory BP evaluation, might be a significant method for reducing CKD risk.
Thousands march in support of science
Authors: Janice Hopkins Tanne
Journal: BMJ (2017)

Thousands of people took part in the March for Science in more than 600 cities around the world on Saturday 22 April, when Earth Day was also celebrated.

At the main event in Washington, DC, celebrity science spokesman Bill Nye, co-chair of the march and head of the Planetary Society, pointed out that the US Constitution calls on Congress “to promote the progress of science and useful arts.”1 “Yet today,” he said, “we have a great many lawmakers, not just here but around the world, deliberately ignoring and actively suppressing science. Their inclination is misguided …
OS02.1 Multicenter pilot study of radio-chemotherapy as first-line treatment for adults with medulloblastoma - the NOA-07 trial
Authors: D. Beier, M. Proescholdt, C. Reinert, E. Hattingen, C. Seidel, L. Dirven, R. Lürding, S. Pfister, T. Pietsch, P. Hau
Journal: Neuro-Oncology (2017)

Background: Medulloblastoma in adult patients has a low incidence, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. In contrast to children, no prospective data on the feasibility of radio-chemotherapy in adults exists. The German Neuro-Oncology Working Group (NOA) performed a prospective multicenter single-arm Phase II trial to evaluate the feasibility and toxicity of radio-chemotherapy in this population. Methods: The NOA-07 trial combined cranio-spinal irradiation with vincristine, followed by a maximum of eight cycles of cisplatin, lomustine and vincristine. Adverse events, imaging and progression patterns, combined histological and genetic markers, health-related quality of life (HRQoL) and cognition were evaluated prospectively. The primary endpoints were the rate of toxicity-related treatment terminations after four cycles of chemotherapy, and the toxicity profile. Findings: Thirty patients were evaluable. Fifty percent of patients showed classic, and 50% desmoplastic-nodular histology. Sixty-eight percent of patients were genetically classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13.6% in wingless (WNT), and 17.7% in Non-WNT/Non-SHH (Group 4). Four cycles of chemotherapy were feasible in the majority of patients (n=21; 70.0%). Leukopenia was the major toxicity, with 79 events of CTC grade 3 and 4 in 17 patients. Polyneuropathy and ototoxicity were the only grade 3 or 4 non-haematological toxicities during the active treatment phase and occurred 12 times in eight patients and one time in one patient, respectively. Events were also calculated per cycle and showed an increase of toxicity over treatment time. Feasibility appeared to be age-dependent, leading to application of four cycles of chemotherapy in 72.7% of patients below age 45 and 62.5% of patients 45 or above. Testing for all eight adjuvant cycles revealed that 45.5% of all patients younger than 45 years completed eight cycles, whereas only 12.5% of patients over 45 years received all cycles. Severe adverse events were significantly more frequent in patients older than 45 years of age (p = 0.040). We observed no treatment-related deaths. During the active treatment period, HRQoL showed clinically relevant improvements in several domains. Verbal fluency also improved. The 3-year EFS rate was 66.6% at the time of databank lock. Interpretation: This is a prospective trial in a homogenous population of adults with medulloblastoma. Radio-chemotherapy was safe and tolerable throughout the active treatment phase and generated improvements of HRQoL and cognition. However, toxicity was more severe than in comparable paediatric trials. Thus, we propose frequent patient surveillance using this regimen. We conclude that NOA-07 sets the standard for future randomized trials in adults with medulloblastoma.
Preparation of 5-fluorouracil-loaded chitosan nanoparticles and study of the sustained release in vitro and in vivo
Authors: Li Sun, Yunna Chen, Yali Zhou, Dongdong Guo, Yufan Fan, Fangyan Guo, Yufeng Zheng, Weidong Chen
Journal: Asian Journal of Pharmaceutical Sciences (2017)

The sustained-release properties of the biodegradable nano-drug delivery systems were used to improve the residence time of the chemotherapeutic agent in the body. These drug delivery systems were widely used to deliver chemotherapeutic drugs. The 5-fluorouracil loaded chitosan nanoparticles prepared in this paper have the above advantage. Here, we found that when the mass ratio of 5-fluorouracil and chitosan was 1:1, the maximum drug loading of nanoparticles was 20.13 ± 0.007%, the encapsulation efficiency was 44.28 ± 1.69%, the particle size was 283.9 ± 5.25 nm and the zeta potential was 45.3 ± 3.23 mV. The prepared nanoparticles had both burst-release and sustained-release phases in vitro release studies. In addition, the inhibitory effect of the prepared nanoparticles on gastric cancer SGC-7901 cells was similar to that of 5-fluorouracil injection, and the blank vector had no obvious inhibitory effect on SGC-7901 cells. In the pharmacokinetic study of rats in vivo, we found that AUC (0-t), MRT (0-t) and t1/2z of nanoparticles were significantly increased in vivo compared with 5-fluorouracil solution, indicating that the prepared nanoparticles can play a role in sustained-release.
Feasibility of Ultra-High-Throughput Functional Screening of Melanoma Biopsies for Discovery of Novel Cancer Drug Combinations
Authors: Adam A. Friedman, Yun Xia, Lorenzo Trippa, Long Phi Le, Vivien Igras, Dennie T. Frederick, Jennifer A. Wargo, Kenneth K. Tanabe, Donald P. Lawrence, Donna S. Neuberg, Keith T. Flaherty, David E. Fisher
Journal: Clinical Cancer Research (2017)

Purpose: Successful development of targeted therapy combinations for cancer patients depends on first discovering such combinations in predictive preclinical models. Stable cell lines and mouse xenograft models can have genetic and phenotypic drift and may take too long to generate to be useful as a personalized medicine tool.Experimental Design: To overcome these limitations, we have used a platform of ultra-high-throughput functional screening of primary biopsies preserving both cancer and stroma cell populations from melanoma patients to nominate such novel combinations from a library of thousands of drug combinations in a patient-specific manner within days of biopsy. In parallel, patient-derived xenograft (PDX) mouse models were created and novel combinations tested for their ability to shrink matched PDXs.Results: The screening method identifies specific drug combinations in tumor cells with patterns that are distinct from those obtained from stable cell lines. Screening results were highly specific to individual patients. For patients with matched PDX models, we confirmed that individualized novel targeted therapy combinations could inhibit tumor growth. In particular, a combination of multi-kinase and PI3K/Akt inhibitors was effective in some BRAF-wild-type melanomas, and the addition of cediranib to the BRAF inhibitor PLX4720 was effective in a PDX model with BRAF mutation.Conclusions: This proof-of-concept study demonstrates the feasibility of using primary biopsies directly for combinatorial drug discovery, complementing stable cell lines and xenografts, but with much greater speed and efficiency. This process could potentially be used in a clinical setting to rapidly identify therapeutic strategies for individual patients. Clin Cancer Res; 23(16); 4680-92. ©2017 AACR.
Non-invasive monitoring of tumor growth and progression over time using flat panel-volume computed tomography
Authors: Jeannine Missbach-Guentner, Christian Dullin, Sarah Kimmina, Silvia Obenauer, Marta Zientkowska, Melanie Domeyer-Missbach, Walter Stuehmer, Lorenz Truemper, Eckhardt Grabbe, Frauke Alves
Journal: Cancer Research (2006)

1003  A major limitation in the evaluation of clinically relevant murine tumor models is the inability to detect and monitor tumor progression in detail over the course of disease. This study was designed to investigate the utility of flat panel detector based cone beam volume computed tomography (fpVCT) in detecting and monitoring non-invasively tumor spread and growth rates as well as vascularization and structural changes within tumor tissue over time in mice. Human breast cancer MDA-MB-231 cells were either injected intracardially or were implanted orthotopically into female SCID mice. C57/BL6 mice were injected subcutaneously or intravenously with syngeneic B16F1 melanoma cells. Scans of anesthetized mice were performed within 8 seconds at various time points using fpVCT (GE Global Research Niskayuna, NY, USA) in combination with Iodine-containing contrast medium A modified Feldkamp algorithm was used for image reconstruction resulting in an isotropic high-resolution volume data set. Axial images as well as multiplanar reconstruction and volume rendering images were obtained and analyzed. In general, tumor growth rates could be clearly and accurate determined over time by volumetric calculations using fpVCT data sets. The system also allows the presentation of density and density ratios within the primary tumors and thus delineating necrotic tissue, tumor tissue and blood vessels. Micrometastases caused by intravenous application of melanoma cells were sufficiently revealed by fpVCT. Pulmonary tumor nodules of about 500 μm in diameter could be detected reproducibly as metastases by fpVCT. FpVCT also demonstrated the development and growth of distinct radiolucent metastatic osteolytic lesions in bones after intracardial implantation of breast tumor cells. These osteolytic cavities within upper and lower legs of mice could be visualized three dimensionally allowing volumetric measurements. The results were subsequently validated by standard caliper measurements and histological analysis. In conclusion, non-invasive imaging by fpVCT allows an accurate real time assessment of tumor growth rates and shows exactly quantitative structural changes within primary tumors in longitudinal studies by visualizing reduction of proliferating tumor tissue caused by induced necrosis. The system is also useful for early detection of pulmonary metastases and shows excellent sensitivity in detecting skeletal lesions. Therefore, fpVCT is a useful non-invasive tool to evaluate preclinically the effect of novel tumor therapies on tumor growth and progression over the course of disease.
Delayed, oral pharmacological inhibition of calpains attenuates adverse post-infarction remodelling
Authors: Marcos Poncelas, Javier Inserte, David Aluja, Victor Hernando, Ursula Vilardosa, David Garcia-Dorado
Journal: Cardiovascular Research (2017)

Calpains activate during myocardial ischemia-reperfusion and contribute to reperfusion injury. Studies in transgenic animals with altered calpain/calpastatin system subjected to permanent ischemia suggest that calpains are also involved in post-infarction remodelling and heart failure.To determine whether delayed oral administration of the calpain inhibitor SNJ-1945 reduces adverse myocardial remodelling and dysfunction following transient coronary occlusion.Male Sprague-Dawley rats were subjected to 30 min of ischemia followed by 21 days of reperfusion and received the calpain inhibitor SNJ-1945 intraperitoneally at the onset of reperfusion (Acute group), orally starting after 24 h of reperfusion and for 14 days (Chronic group), or the combination of both treatments. Calpain-1 and calpain-2 protein content increased and correlated with higher calpain activity in control hearts. Administration of SNJ-1945 attenuated calpain activation, and reduced scar expansion, ventricular dilation and dysfunction in both acute and chronic groups. Acute treatment reduced infarct size in hearts reperfused for 24 h and inflammation measured after 3 days. Delayed, chronic oral administration of SNJ-1945 attenuated inflammation, cardiomyocyte hypertrophy and collagen infiltration in the non-infarcted myocardium at 21 days in correlation with increased levels of IĸB and reduced NF-ĸB activation. In cultured fibroblasts, SNJ-1945 attenuated TGF-β1-induced fibroblast activation.Our data demonstrate for the first time that long-term calpain inhibition is possible with delayed oral treatment, attenuates adverse post-infarction remodelling, likely through prevention of NF-ĸB activation, and may be a promising therapeutic intervention to prevent adverse remodelling and heart failure in patients with acute myocardial infarction.
Identification of CD44 As a RAS-MEK-Regulated Invasion Receptor That Is Overexpressed in Neoplastic Mast Cells and Triggers Disease Expansion in Advanced Systemic Mastocytosis
Authors: Niklas Mueller, Daniel Wicklein, Gregor Eisenwort, Juliana Schwaab, Mohamad Jawhar, Alexandra Boehm, Harald Herrmann, Gabriele Stefanzl, Gregor Hoermann, Wolfgang R. Sperr, Michel Arock, Andreas Reiter, Udo Schumacher, Peter Valent
Journal: Blood (2016)
P01.20 Treatment of recurrent glioblastoma with the cytokine inhibitor, ibudilast in combination with temozolomide
Authors: K. L. McDonald, W. Ha, M. Khasraw
Journal: Neuro-Oncology (2017)

BACKGROUND: Recurrence in patients with glioblastoma (GBM) is inevitable, even in patients with O-6-Methylguanine-DNA Methyl Transferase (MGMT) methylation. We identified increased expression of the inflammatory cytokine, Macrophage Inhibitory Factor (MIF) and its receptor CD74 in patients with recurrent tumours. High levels of MIF and CD74 were associated with poor overall survival in GBM patients. This study aims to determine efficacy of Ibudliast (AV411; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine) to block MIF expression and decrease tumour burden. Ibudilast is an anti-inflammatory drug that was developed for the treatment of bronchial asthma. METHODS: The patient derived cell lines (PDCLs) RN1 (MGMT unmethylated), BAH1 (MGMT methylated), and HW1 (MGMT methylated) were treated in vitro with different concentrations of ibudilast in combination with temozolomide (TMZ). Patient derived xenograft (PDX) models of GBM were developed and treated with the combination of ibudilast and TMZ. Overall survival was calculated. Results: Regardless of MGMT status, significant synergism between ibudilast and TMZ was observed in the PDCLs. Efficacy was associated with significantly decreased expression of its targets, MIF and CD74. Downstream proteins such as Src and Akt were also significantly inhibited. The combination induced apoptosis. RN1 and HW1 tumors were established intracranially in Balb/c nude mice. Significant increases in survival times of the mice were recorded when treated with the combination. CONCLUSION: Ibudilast in combination with TMZ resulted in significant blockage of MIF expression, increased apoptosis and longer survival in vivo. A human pilot study for recurrent GBM patients is underway.