Abstract
Prior work by us and others has demonstrated that the extracellular pH (pHe) of solid tumors is acidic, due to a combination of increased fermentative metabolism, resulting in lactic acid ...production and poor perfusion. This acidity promotes tumor progression and metastasis formation. Recently we have shown in melanoma and pancreatic cancer models that acidity inhibits antitumor immunity by preventing T-cell activation. Reversal of acidity with buffer therapy (200mM NaHCO3) synergized with checkpoint blockade (anti-CTLA4 and anti-PD1) and adoptive T-cell therapy has resulted in cures. While this is promising, concerns are high regarding the ingestion of such large amounts of sodium bicarbonate, which makes clinical translation a challenge. Hence, we hypothesize that alternative pharmacological interventions can neutralize the pHe of tumors and remove this immunosuppressive effect. To study this we first investigated a series of agents for their ability to inhibit metastasis in the PC3 prostate cancer model, which is exquisitely sensitive to inhibition with buffer therapy. In this study, male SCID mice were grouped in to 6 groups (n=5) and treated with tap water, 200 mM bicarbonate ad lib, 30 mg/kg daily (q.d.) intraperitoneal (i.p.) Acetazolamide (CA inhibitor), 1.2 mg/kg q.d.i.p. Furosemide (diuretic), 10 mg/kg q.d.i.p. DH348 (selective CAIX inhibitor) or 2.1 mg/kg q.d.i.p. FX-11 (LDHA inhibitor). Mice were intravenously injected with 5*10^6 PC3M-luc cells and ventral bioluminescence images were acquired at time 0 and weekly thereafter. Our results showed that FX-11, acetazolamide, DH348 and bicarbonate were able to effectively (p<0.004) suppress metastasis formation in this system, whereas furosemide was not. Based on these results, a subsequent study investigated the combination of bicarbonate, FX-11 or DH348 with immune checkpoint blockade in a Panc02 mouse model of pancreatic cancer. Animals were inoculated orthotopically with Panc02 cells and randomized into 8 groups (n=10). Once tumors reached 0.3 cc in size, mice were treated with either 15 mg/kg anti-PD-1 antibody or normal rat IgG controls twice weekly alone or in combination with bicarbonate; FX-11 or DH348 and tumor response was evaluated using US 3D-Mode imaging and volume analysis (FUJIFILM VisualSonics) and histopathology. Anti-PD-1 antibody was ineffective as a monotherapy in this system. Both bicarbonate and DH348 neutralized tumor acidity and reduced tumor growth as monotherapies. Notably, despite the fact that FX-11 was shown to inhibit LDH-A in pancreatic cancer models, it did not affect pH and had no effect on tumor growth as monotherapy. However, FX-11 significantly reduced tumor growth (p <0.01) and metastasis formation in combination with anti-PD-1 antibody, suggesting that inhibition of LDH-A might be effective in combination with checkpoint blockade.
Citation Format: Arig A. Ibrahim Hashim, Dominique Abrahams, Liping Xu, Barbra Centeno, Enakshi Sunassee, Rasha Abddelgader, Ludwig Dubois, Philippe Lambin, Robert A. Gatenby, Robert J. Gillies. Targeting tumor acidity with the LDHA inhibitor (FX11) and CAIX inhibitor (DH348) overcomes resistance to PD-1 blockade and inhibits metastasis in a pancreatic cancer model abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5932. doi:10.1158/1538-7445.AM2017-5932
ABSTRACT
Studying rotational variability of young stars is enabling us to investigate a multitude of properties of young star-disc systems. We utilize high cadence, multiwavelength optical time ...series data from the Hunting Outbursting Young Stars citizen science project to identify periodic variables in the Pelican Nebula (IC 5070). A double blind study using nine different period-finding algorithms was conducted and a sample of 59 periodic variables was identified. We find that a combination of four period finding algorithms can achieve a completeness of 85 per cent and a contamination of 30 per cent in identifying periods in inhomogeneous data sets. The best performing methods are periodograms that rely on fitting a sine curve. Utilizing Gaia EDR3 data, we have identified an unbiased sample of 40 periodic young stellar objects (YSOs), without using any colour or magnitude selections. With a 98.9 per cent probability, we can exclude a homogeneous YSO period distribution. Instead, we find a bi-modal distribution with peaks at 3 and 8 d. The sample has a disc fraction of 50 per cent, and its statistical properties are in agreement with other similarly aged YSOs populations. In particular, we confirm that the presence of the disc is linked to predominantly slow rotation and find a probability of 4.8 × 10−3 that the observed relation between period and presence of a disc has occurred by chance. In our sample of periodic variables, we also find pulsating giants, an eclipsing binary, and potential YSOs in the foreground of IC 5070.
Abstract Background and purpose Recently, we have shown that radiotherapy (RT) combined with the immunocytokine L19-IL2 can induce long-lasting antitumour effects, dependent on ED-B expression and ...infiltration of cytotoxic T cells. On the other hand, in certain tumours, IL2 treatment can trigger a natural killer cell (NK) immune response. The aim of this study is to investigate the therapeutic effect of our combination therapy in the ED-B positive F9 teratocarcinoma model, lacking MHCI expression and known to be dependent on NK immune responses. Material and methods In syngeneic F9 tumour bearing 129/FvHsd mice tumour growth delay was evaluated after local tumour irradiation (10 Gy) combined with systemic administration of L19-IL2. Immunological responses were investigated using flow cytometry. Results Tumour growth delay of L19-IL2 can be further improved by a single dose of RT administered before immunotherapy, but not during immunotherapy. Furthermore, treatment of L19-IL2 favours a NK response and lacks cytotoxic T cell tumour infiltrating immune cells, which may be explained by the absence of MHCI expression. Conclusion An additive effect can be detected when the NK dependent F9 tumour model is treated with radiotherapy and L19-IL2 and therefore this combination could be useful in the absence of tumoural MHCI expression.
A concern for researchers planning multisite studies is that scanner and T1-weighted sequence-related biases on regional volumes could overshadow true effects, especially for studies with a ...heterogeneous set of scanners and sequences. Current approaches attempt to harmonize data by standardizing hardware, pulse sequences, and protocols, or by calibrating across sites using phantom-based corrections to ensure the same raw image intensities. We propose to avoid harmonization and phantom-based correction entirely. We hypothesized that the bias of estimated regional volumes is scaled between sites due to the contrast and gradient distortion differences between scanners and sequences. Given this assumption, we provide a new statistical framework and derive a power equation to define inclusion criteria for a set of sites based on the variability of their scaling factors. We estimated the scaling factors of 20 scanners with heterogeneous hardware and sequence parameters by scanning a single set of 12 subjects at sites across the United States and Europe. Regional volumes and their scaling factors were estimated for each site using Freesurfer's segmentation algorithm and ordinary least squares, respectively. The scaling factors were validated by comparing the theoretical and simulated power curves, performing a leave-one-out calibration of regional volumes, and evaluating the absolute agreement of all regional volumes between sites before and after calibration. Using our derived power equation, we were able to define the conditions under which harmonization is not necessary to achieve 80% power. This approach can inform choice of processing pipelines and outcome metrics for multisite studies based on scaling factor variability across sites, enabling collaboration between clinical and research institutions.
•We hypothesize that biases of MRI regional volumes between scanners are scaled based on regional contrast and gradient distortions•Given this scaling property, we define a statistical model and provide a power equation•The variability between regional volumes were estimated from 12 subjects scanned in 20 nonstandardized scanners•Our statistical model and bias measurements allow researchers to optimize sample sizes rather than harmonize protocols for future multisite MRI studies
In the recently published meta-analysis of multiple sclerosis genome-wide association studies De Jager et al. identified three single nucleotide polymorphisms associated to MS: rs17824933 (CD6), ...rs1800693 (TNFRSF1A) and rs17445836 (61.5 kb from IRF8). To refine our understanding of these associations we sought to replicate these findings in a large more extensive independent sample set of 11 populations of European origin.
We calculated individual and combined associations using a meta-analysis method by Kazeem and Farral (2005). We confirmed the association of rs1800693 in TNFRSF1A (p 4.19 × 10-7, OR 1.12, 7,665 cases, 8,051 controls) and rs17445836 near IRF8 (p 5.35 × 10-10, OR 0.84, 6,895 cases, 7,580 controls and 596 case-parent trios) The SNP rs17824933 in CD6 also showed nominally significant evidence for association (p 2.19 × 10-5, OR 1.11, 8,047 cases, 9,174 controls, 604 case-parent trios).
Variants in TNFRSF1A and in the vicinity of IRF8 were confirmed to be associated in these independent cohorts, which supports the role of these loci in etiology of multiple sclerosis. The variant in CD6 reached genome-wide significance after combining the data with the original meta-analysis. Fine mapping is required to identify the predisposing variants in the loci and future functional studies will refine their molecular role in MS pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In vivo visualization of tumor hypoxia related markers, such as the endogenous transmembrane protein CA IX may lead to novel therapeutic and diagnostic applications in the management of solid tumors. ...In this study 4-(2-aminoethyl)benzene sulfonamide (AEBS, Ki = 33 nM for CA IX) has been conjugated with bis(aminoethanethiol) (BAT) and mercaptoacetyldiglycine (MAG2) tetradendate ligands and the conjugates radiolabelled with 99mTc, to obtain anionic and neutral 99mTc-labeled sulfonamide derivatives, respectively. The corresponding rhenium analogues were also prepared and showed good inhibitory activities against hCA IX (Ki = 59–66 nM). In addition, a second generation bis AEBS was conjugated with MAG2 and labeled with 99mTc, and the obtained diastereomers were also evaluated in targeting CA IX. Biodistribution studies in mice bearing HT-29 colorectal xenografts revealed a maximum tumor uptake of <0.5% ID/g at 0.5 h p.i for all the tracers. In vivo radiometabolite analysis indicated that at 1 h p.i. MAG2 tetradendate ligands were more stable in plasma (>50% intact) compared to the neutral complex (28% intact). This preliminary data suggest that negatively charged 99mTc-labeled sulfonamide derivatives with modest lipophilicity and longer circulation time could be promising markers to target CA IX.
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•The sulfonamide derivative AEBS was conjugated with a BAT and MAG2 ligand.•The new sulfonamide conjugates were successfully radiolabelled with 99mTc.•The corresponding rhenium analogs showed a good inhibitory constant against CA IX.•Biodistribution in mice bearing HT-29 tumor xenografts was studied.•All new tracers showed a limited retention in tumors (≤0.5% ID at 0.5–4 h p.i).
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