Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers ...remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA mis-splicing in human breast cancers correlates with innate and adaptive immune signatures, especially in MYC-amplified tumors that are typically immune cold. These findings indicate that dsRNA-sensing pathways respond to global aberrations of RNA splicing in cancer and provoke the hypothesis that STTs may provide unexplored strategies to activate anti-tumor immune pathways.
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•Spliceosome-targeted therapies (STTs) induce widespread mis-spliced mRNA in cancer•Mis-spliced, intron-retained mRNAs are an unexplored source of endogenous dsRNA•STTs trigger antiviral signaling and extrinsic apoptosis in TNBCs via dsRNA sensors•RNA mis-splicing in human breast cancers correlates with immune signatures
Spliceosome-targeted therapies generate intron-retained, double-stranded RNAs that activate downstream antiviral signaling and extrinsic apoptosis in breast cancer.
This expansion cohort of a multicenter, dose-escalation, phase I study (NCT00557856) evaluated safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamic effects of the ...anti-activin receptor-like kinase-1 (ALK-1) monoclonal antibody PF-03446962 in advanced hepatocellular carcinoma (HCC).
Patients with HCC and disease progression after prior antiangiogenic therapy or intolerance to treatment received PF-03446962 7 mg/kg intravenously biweekly, as recommended in the dose-escalation part of the study.
Twenty-four patients received PF-03446962. The most frequent treatment-related adverse events (AEs) were thrombocytopenia (33.3%), asthenia (29.2), and chills (16.7%). Two patients experienced treatment-related telangiectasia, suggesting an in vivo knockout of ALK-1 function through ALK-1 pathway inhibition. Overall, treatment-related grade 3–4 AEs were reported in eight patients (33.3%). Treatment-related grade 3–4 thrombocytopenia was noted in four patients. No complete or partial responses were reported. Twelve (50%) patients achieved stable disease, which lasted ≥12 weeks in seven (29.2%) patients. The median time to progression was 3 months. Biomarker analyses showed higher mean tumor expression of c-tumor mesenchymal–epithelial transition factor and higher mean serum levels of bone morphogenetic protein-9 in patients with disease control (DC) for ≥12 weeks versus patients with disease progression. Conversely, lower mean serum transforming growth factor-β and vascular endothelial growth factor receptor-3 levels were detected in patients with DC versus patients with progression.
The observed safety, tolerability, pharmacokinetic profile, and clinical activity support further evaluation of PF-03446962 in patients with HCC and other solid malignancies, as single agent or in combination with other antiangiogenic, chemotherapeutic, or immunotherapeutic agents.
NCT00557856.
Intestinal inflammation is associated with an increased risk of developing colorectal cancer and may result from dysregulated responses to commensal bacteria or exposure to bacterial pathogens. ...Dietary modulation of intestinal inflammation may protect against development of colon cancer. However, the precise diet-derived components and underlying mechanisms remain elusive.
(
) induces acute intestinal inflammation and has been used to study the role of inflammation in the susceptibility to colon cancer. Here we examine the effects of indole-3-carbinol (I3C), a dietary compound with anticarcinogenic properties, on intestinal immune and inflammatory responses to
infection and adhesion to colonic cells in vitro. C57BL/6J mice were fed a diet with/without 1 μmol/g I3C and infected with
. Compared to infected mice fed with a control diet, consumption of a 1 μmol I3C/g diet significantly reduced fecal excretion of
,
colonization of the colon, and reduced colon crypt hyperplasia. Furthermore, expression of
-induced inflammatory markers such as IL-17A, IL-6, and IL1β were attenuated in infected mice fed with the I3C diet, compared to mice fed a control diet. The expression of cytotoxic T cell markers CD8 and FasL mRNA were increased in I3C-fed infected mice. In-vitro, I3C inhibited
growth and adhesion to Caco-2 cells. I3C alleviates
-induced murine colitis through multiple mechanisms including inhibition of
growth and adhesion to colonic cells in vitro and enhancement of cytotoxic T cell activity.
The humidity sensing performance of Polyaniline/Water soluble graphene oxide PWGO composites have been presented in this work. Various mass ratios of Water soluble graphene oxide WGO were ...mechanically mixed with Polyaniline PANI prepared by in-situ polymerization process to form PANI / WGO composites. For the purpose of humidity sensing studies, the samples were structurally characterized by FTIR, Raman, XRD, SEM and TEM techniques and comparatively analyzed. The film of the samples prepared by deposition on ordinary glass substrate using cost effective spin coating technique were tested for their humidity sensing performance in the relative humidity (RH) range of 11–97%. Of the four composites studied, the PWGO-4 composite recorded a good response time of 8 s and a recovery time of 9 s and a very low humidity hysteresis. The mechanism for sensing has been explained on the basis of three sequential steps: chemisorption, physisorption and condensation process. The humidity sensing stability of the composites were tested over a period of 2 months.
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•Polyaniline/Water soluble Graphene oxide (PANI/WGO) nano composite – prepared by mechanical mixing method.•Characterizations of the samples by FTIR, Raman, XRD, SEM and TEM techniques, for the pupose of humidity sensing.•Humidity sensing response of PANI/WGO composite experimentally examined.•The sensing mechanism discussed on the basis of chemisorptions, physisorption and condensation process.
Indole-3-carbinol (I3C) and its dimer diindolylmethane (DIM) are bioactive metabolites of a glucosinolate, glucobrassicin, found in cruciferous vegetables. Both I3C and DIM have been reported to ...possess pro-apoptotic, anti-proliferative and anti-carcinogenic properties via modulation of immune pathways. However, results from these studies remain inconclusive since they lack thorough evaluation of these bioactives' physiological versus pharmacological effects. In the present study, we investigated I3C and DIM's dose-dependent effects on cytokines production in human T lymphocytes Jurkat cell line (Clone E6-1). The results showed that I3C and DIM pretreatment, at higher concentrations of 50 and 10 μM, respectively, significantly increased PMA/ionomycin-induced interleukin-2 (IL-2), interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) production, measured by real time polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA). As a plausible mechanism underlying such pronounced cytokine release, we found robust increase in downstream nuclear factor κB (NF-κB) and nuclear factor of activated T-cells 1 (NFAT1) signaling with I3C pretreatment, whereas DIM pretreatment only significantly induced NF-κB activation, but not NFAT1. We hypothesize that I3C/DIM pretreatment primes the T cells to become hyperresponsive upon PMA/ionomycin stimulation which in turn differentially induces two major downstream Ca
-dependent inflammatory pathways, NF-κB and NFAT1. Our data show novel insights into the mechanisms underlying induction of pro-inflammatory cytokine release by pharmacological concentrations of I3C and DIM, an effect negligible under physiological conditions.
Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter γ-aminobutyric acid (GABA) in the human brain. ...Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA-edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within-site, while site-level differences accounted for comparatively more variance (20%) than vendor-level differences (8%). For MM-suppressed GABA data, the variance was distributed equally between site- (50%) and participant-level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community.
•GABA-edited MEGA-PRESS data from 272 adults were collected from 24 sites.•GABA+ data showed good agreement across vendors and sites.•Variability in MM-suppressed GABA data was attributed in part to B0 field offsets.•Multi-site studies using GABA editing are feasible using a standardized protocol.•These results provide valuable benchmarks for the MRS community.
Enteropathogenic and enterohemorrhagic
are important enteric pathogens that induce hemorrhagic colitis or even fatal hemolytic uremic syndrome. Emerging evidence shows that some bio-actives derived ...from fruits and vegetables may serve as alternatives to antibiotics for overcoming multidrug resistant
infections. In this study, the
(Cr) infection model was utilized to mimic
-induced acute intestinal inflammation, and the effects of a cruciferous vegetable-derived cancer protective compound, indole-3-carbinol (I3C), on the immune responses of Cr-susceptible C3H/HeN mice were investigated. Dietary I3C significantly inhibited the loss of body weight and the increase in spleen size in Cr infected mice. In addition, I3C treatment reduced the inflammatory response to Cr infection by maintaining anti-inflammatory cytokine IL-22 mRNA levels while reducing expression of other pro-inflammatory cytokines including IL17A, IL6, IL1β, TNF-α, and IFN-γ. Moreover, the serum cytokine levels of IL17, TNF-α, IL12p70, and G-CSF also were down-regulated by I3C in Cr-infected mice. Additionally, dietary I3C specifically enhanced the Cr-specific IgG response to Cr infection. In general, dietary I3C reduced the Cr-induced pro-inflammatory response in susceptible C3H/HeN mice and alleviated the physiological changes and tissue damage induced by Cr infection but not Cr colonization.
Chemotherapy-induced nausea and vomiting (CINV) are distressing symptoms. This randomized study evaluated the antiemetic efficacies of standard antiemetic regimen with/without olanzapine.
Eligible ...patients were chemotherapy-naive Chinese breast cancer patients who were planned for (neo)adjuvant doxorubicin/cyclophosphamide. Antiemetic regimen for all studied population included aprepitant, ondansetron and dexamethasone; patients were randomized to Olanzapine (with olanzapine) or Standard arms (without olanzapine). Patients filled in self-reported diaries and completed visual analogue scales for nausea, as well as Functional Living Index-Emesis questionnaires. Blood profiles including fasting glucose and lipids were monitored.
120 patients were randomized. In Cycle 1 doxorubicin/cyclophosphamide, the Olanzapine arm had significantly higher rates of “Complete Response” than the Standard arm: 65.0% vs 38.3% in the overall period (p = 0.0035), 70.0% vs 51.7% in the acute period (p = 0.0397) and 92.9% vs 74.2% in the delayed period (p = 0.0254). Olanzapine arm also had significantly higher rates of “No significant nausea” and “No nausea” during all 3 time-frames and better QOL. Similar findings were also revealed throughout multiple cycles. Pre-study abnormalities in glucose and lipids occurred in 39.7% and 34.2% of the studied population respectively; there were no differences in these parameters between the two arms at end-of-study assessment.
The addition of olanzapine to standard aprepitant-based antiemetic regimen provides clinically meaningful improvement in controlling CINV. This was associated with a positive impact on QOL and tolerable toxicity profiles among Chinese breast cancer patients receiving doxorubicin/cyclophosphamide chemotherapy. Further studies on metabolic profiles of breast cancer patients are warranted.
•Olanzapine is reported to reduce nausea and vomiting after highly emetogenic chemotherapy.•Reported studies are limited by heterogeneous populations receiving diverse cytotoxic regimes.•This study enrolled Chinese breast cancer patients undergoing doxorubicin/cyclophosphamide.•Adding olanzapine to aprepitant/ondansetron/dexamethasone is superior in controlling nausea and vomiting.•Baseline investigations shows a surprisingly high rate of glucose and lipids abnormalities.
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