We previously reported a correlation between small doses of oxaliplatin penetrating onto the spinal cord and acute pain after chemotherapy. Here, we propose that MT2 within the spinal dorsal horns ...participates in the development of oxaliplatin-induced neuropathic pain and may be a pharmacological target for the prevention and treatment of chemotherapy-induced peripheral neuropathy (CIPN).
The rat model of CIPN was established by 5 consecutive injections of oxaliplatin (0.4 mg/100 g/day). Genetic restoration of neuron-specific metallothionein-2 was implemented 21 days before oxaliplatin treatment, and also, genetic inhibition by metallothionein-2 siRNA was performed. Mechanical allodynia and locomotor activity were assayed. Cell-specific expression of metallothionein-2, the mRNA levels of pro-inflammatory cytokines, nuclear translocation of NF-κB, the protein levels of expression of IκB-α, and interaction between IκB-α and P65 were evaluated in the spinal dorsal horns. Also, in vitro interaction of sequentially deleted IκB-α promoter with metallothionein-2 was used to assess the signal transduction mechanism.
We found that oxaliplatin induced downregulation of metallothionein-2 in rat spinal cord neurons. By contrast, genetic restoration of metallothionein-2 in the spinal dorsal horn neuron blocked and reversed neuropathic pain in oxaliplatin-treated rats of both sexes, whereas genetic inhibition of metallothionein-2 triggered neuropathic pain in normal rats. Overall locomotor activity was not impaired after the genetic alterations of metallothionein-2. At the molecular level, metallothionein-2 modulated oxaliplatin-induced neuroinflammation, activation of NF-κB, and inactive transcriptional expression of IκB-α promoter, and these processes could be blocked by genetic restoration of metallothionein-2 in the spinal dorsal horn neurons.
Metallothionein-2 is a potential target for the prevention and treatment of CIPN. A reduction of NF-κB activation and inflammatory responses by enhancing the transcription of IκB-α promoter is proposed in the mechanism.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Molecular profiling of tumors promises to advance the clinical management of cancer, but the benefits of integrating molecular data with traditional clinical variables have not been systematically ...studied. Here we retrospectively predict patient survival using diverse molecular data (somatic copy-number alteration, DNA methylation and mRNA, microRNA and protein expression) from 953 samples of four cancer types from The Cancer Genome Atlas project. We find that incorporating molecular data with clinical variables yields statistically significantly improved predictions (FDR < 0.05) for three cancers but those quantitative gains were limited (2.2-23.9%). Additional analyses revealed little predictive power across tumor types except for one case. In clinically relevant genes, we identified 10,281 somatic alterations across 12 cancer types in 2,928 of 3,277 patients (89.4%), many of which would not be revealed in single-tumor analyses. Our study provides a starting point and resources, including an open-access model evaluation platform, for building reliable prognostic and therapeutic strategies that incorporate molecular data.
The current classification systems of myelodysplastic syndromes (MDS), including the International Prognostic Scoring System (IPSS), do not fully reflect the molecular heterogeneity of the disease. ...Molecular characterization may predict clinical outcome and help stratify patients for targeted therapies. Epigenetic therapy using decitabine, a DNA hypomethylating agent, is clinically effective for the treatment of MDS. Therefore, we investigated the association between DNA methylation and clinical outcome in MDS.
We screened 24 patients with MDS for promoter CpG island methylation of 24 genes and identified aberrant hypermethylation at 10 genes. We then performed quantitative methylation analyses by bisulfite pyrosequencing of the identified genes in 317 patient samples from three independent studies and assessed relations between methylation and clinical outcome.
In an initial training cohort of 89 patients with MDS, methylation frequencies of individual genes ranged from 7% to 70% and were highly concordant. Therefore, we defined a methylation z score based on all genes for each patient. We found that patients with higher levels of methylation, compared with patients with lower levels, had a shorter median overall survival (12.3 v 17.5 months, respectively; P = .04) and shorter median progression-free survival (6.4 v 14.9 months, respectively; P = .009). This methylation prognostic model was independent of age, sex, and IPSS group. Applied to two validation cohorts (228 patients), this model was confirmed as an independent prognostic predictor for survival. Although methylation at baseline did not correlate with clinical response to decitabine, we observed a significant correlation between reduced methylation over time and clinical responses.
DNA methylation predicts overall and progression-free survival in MDS.
Fms-like tyrosine kinase-3 (FLT3) inhibitors have been used to overcome the dismal prognosis of acute myeloid leukemia (AML) with FLT3 mutations. Clinical results with FLT3 inhibitor monotherapy have ...shown that bone marrow responses are commonly less pronounced than peripheral blood responses. We investigated the role of p53 in bone marrow stromal cells in stromal cell-mediated resistance to FLT3 inhibition in FLT3 mutant AML. While the FLT3 inhibitor FI-700 induced apoptosis in FLT3 mutant AML cells, apoptosis induction was diminished under stromal coculture conditions. Protection appeared to be mediated, in part, by CXCL12 (SDF-1)/CXCR4 signaling. The protective effect of stromal cells was significantly reduced by pre-exposure to the HDM2 inhibitor Nutlin-3a. p53 activation by Nutlin-3a was not cytotoxic to stromal cells, but reduced CXCL12 mRNA levels and secretion of CXCL12 partially through p53-mediated HIF-1α down-regulation. Results show that p53 activation in stroma cells blunts stroma cell-mediated resistance to FLT3 inhibition, in part through down-regulation of CXCL12. This is the first report of Nutlin effect on the bone marrow environment. We suggest that combinations of HDM2 antagonists and FLT3 inhibitors may be effective in clinical trials targeting mutant FLT3 leukemias.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The clinical challenge posed by p53 abnormalities in hematological malignancies requires therapeutic strategies other than standard genotoxic chemotherapies. ONC201 is a first-in-class small molecule ...that activates p53-independent apoptosis, has a benign safety profile, and is in early clinical trials. We found that ONC201 caused p53-independent apoptosis and cell cycle arrest in cell lines and in mantle cell lymphoma (MCL) and acute myeloid leukemia (AML) samples from patients; these included samples from patients with genetic abnormalities associated with poor prognosis or cells that had developed resistance to the nongenotoxic agents ibrutinib and bortezomib. Moreover, ONC201 caused apoptosis in stem and progenitor AML cells and abrogated the engraftment of leukemic stem cells in mice while sparing normal bone marrow cells. ONC201 caused changes in gene expression similar to those caused by the unfolded protein response (UPR) and integrated stress responses (ISRs), which increase the translation of the transcription factor ATF4 through an increase in the phosphorylation of the translation initiation factor eIF2α. However, unlike the UPR and ISR, the increase in ATF4 abundance in ONC201-treated hematopoietic cells promoted apoptosis and did not depend on increased phosphorylation of eIF2α. ONC201 also inhibited mammalian target of rapamycin complex 1 (mTORC1) signaling, likely through ATF4-mediated induction of the mTORC1 inhibitor DDIT4. Overexpression of BCL-2 protected against ONC201-induced apoptosis, and the combination of ONC201 and the BCL-2 antagonist ABT-199 synergistically increased apoptosis. Thus, our results suggest that by inducing an atypical ISR and p53-independent apoptosis, ONC201 has clinical potential in hematological malignancies.
A shape-stable phase change material (PCM) compounded through polyethylene glycol (PEG) and triallyl isocyanurate (TAIC) was investigated, in which PEG was used as component of PCM and confined ...inside cross-linked TAIC. The microstructure of the PEG/TAIC composites was determined by Fourier Transform Infrared Spectroscopy (FT-IR) and X-ray Diffraction (XRD). The results indicated that there was no chemical interaction between PEG and TAIC and the composites remained the PEG crystalline. The size of the composite nanoparticles was about 150 nm. The thermal characteristic of the composites determined by Differential Scanning Calorimeter (DSC) indicated that the composites had excellent thermal stability and heat storage durability after 200 heating-cooling cycles. Moreover, the composites had typical solid-solid phase transition temperatures among the range of 31.16–57.14 °C and high latent heat enthalpy between 110.2 J/g and 136.9 J/g. The shape analysis suggested that the composites could be used under a high temperature 100 °C as thermal energy storage materials.
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•Shape-stabilized PEG/TAIC composites were prepared by in-situ reactive blend.•The melting temperatures and latent heat values of the PCMs were in the range of 31∼58 °C and 110∼137 J/g, respectively.•Latent heat of the PCMs almost have no change after 200 heating-cooling cycles.•PEG/TAIC composites were determined as promising candidates for heat storage application.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Induction with ibrutinib and rituximab provides an opportunity to minimise chemotherapy exposure, because upfront use of these targeted therapies could result in remission without chemotherapy and ...allow for consolidation with only four cycles of chemotherapy instead of the conventional eight. We aimed to determine the activity and safety of ibrutinib–rituximab induction followed by shortened chemoimmunotherapy (four cycles) with rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HCVAD) alternating with methotrexate–cytarabine in previously untreated patients with mantle cell lymphoma.
We did a single-centre, single-arm, phase 2 trial in previously untreated patients with mantle cell lymphoma. Eligible patients were aged 65 years or younger and had serum bilirubin of less than 1·5 mg/dL, creatinine clearance of 30 mL/min or more, Eastern Cooperative Oncology Group performance status of 2 or less, and cardiac ejection fraction 50% or more by echocardiogram. Patients received 12 cycles of ibrutinib–rituximab induction (part A; oral ibrutinib 560 mg daily and intravenous rituximab 375 mg/m2 weekly for the first 4 weeks and then on day 1 of cycles 3–12). As soon as patients had a complete response, four cycles of R-HCVAD alternating with methotrexate–cytarabine (part B) were administered. If they did not have a complete response or had a partial response, patients received two cycles of R-HCVAD alternating with methotrexate–cytarabine followed by reassessment, up to a total of eight cycles. Patients were taken off study if they had stable disease or progression during R-HCVAD. The primary outcome was the overall response rate after part A. The analyses were conducted on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT02427620.
131 patients were enrolled between June 12, 2015, and Dec 6, 2018. The median age was 56 years (IQR 49–60). 58 (50%) of 117 patients had high Ki-67 (≥30%). 129 (98%, 95% CI 95–100) of 131 patients had an overall response in part A. The most common grade 3–4 adverse events were lymphocytopenia (19 14% of 131), skin rash (16 12%), thrombocytopenia (12 9%), infections (11 8%), and fatigue (ten 8%) in part A and lymphocytopenia (96 73%), leukocytopenia (42 32%), thrombocytopenia (40 30%), and neutropenia (26 20%) in part B. There was one on-study death, which was not deemed to be treatment-related.
Induction with ibrutinib–rituximab in the frontline treatment of young patients with mantle cell lymphoma is active and safe. This approach allowed minimisation of the number of chemotherapy cycles, thereby reducing the adverse events associated with chemotherapy. Newer trials bringing the next-generation Bruton's tyrosine kinase inhibitors into the frontline setting might obviate the need for chemotherapy altogether in patients with mantle cell lymphoma.
Pharmacyclics, Janssen.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This study investigated the prevalence of antimicrobial resistant Enterococcus faecalis (E. faecalis) from ducks at slaughterhouses, analyzed antimicrobial resistance genes and virulence-associated ...genes of the isolates. Multilocus sequence typing (MLST) was performed to characterize their molecular characteristics. A total of 227 E. faecalis isolates (67.8%) were obtained from cecum (n = 114), cloaca (n = 50), skin (n = 59), and rinsed water (n = 4). These E. faecalis exhibited high level of resistance against tetracycline (95.6%), doxycycline (94.3%), linezolid (75.8%), erythromycin (72.2%), followed by norfloxacin (56.8%), vancomycin (38.3%), penicillin (36.1%), teicoplanin (30.8%). Lower level of resistance was found to high-level streptomycin (19.8%), imipenem (15.9%) and high-level gentamicin (5.7%). The vast majority of isolates (90.3%) were multidrug resistant (MDR). Moreover, the commonly observed resistance genes were optrA (90.7%) and ermB (90.3%), followed by aph(3’)-Ⅲ (86.8%), tetM (84.6%), acc(6’)-aph(2) (77.5%), blaZ (76.7%) and aac(6’)-Ie-aph(2”)-Ia (75.8%). The less frequently observed genes were vanC (19.8%), blaTEM (4.8%), vanM (2.6%), and vanA (0.4%). None of the strains carried aph(2”)-Ic and vanB genes. Furthermore, a high prevalence of ten virulence determinants was identified, and efaA (99.1%) was predominant, followed by eep (97.4%), srtA (96.9%), asa1 (95.6%), fsrB (92.1%), sprE (89.9%), aggA (63.9%), gelE (56.4%), esp (33.9%), and cylL (15.4%). Eleven isolates (4.9%) co-carried all of the tested virulence-associated genes. MLST analysis demonstrated that, E. faecalis isolates consisted of 12 known STs and 5 new STs, among which 6 of the identified STs were associated with nosocomial infection. Our data indicated that retail ducks serve as an important source of MDR E. faecalis with high pathogenicity potential, and suggested that transmission to humans could not be excluded.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We previously reported the feasibility of clofarabine and cytarabine combinations in AML. Questions remain as to (1) the therapeutic advantage of this combination and (2) the role of lower doses of ...clofarabine and cytarabine in older patients. We have conducted an adaptively randomized study of lower-dose clofarabine with or without low-dose cytarabine in previously untreated patients with AML aged 60 years and older. Patients received 30 mg/m2 clofarabine intravenously daily for 5 days with or without 20 mg/m2 cytarabine subcutaneously daily for 14 days as induction. Consolidation consisted of 3 days of clofarabine with or without 7 days of cytarabine. Seventy patients were enrolled. The median age was 71 years (range, 60-83 years). Sixteen patients received clofarabine and 54 the combination. Overall, 56% achieved complete remission (CR). CR rate was significantly higher with the combination (63% vs 31%; P = .025). Induction mortality was 19% with the combination versus 31% with clofarabine alone (P = .276). The combination showed better event-free survival (7.1 months vs 1.7 months; P = .04), but not overall survival (11.4 months vs 5.8 months; P = .1). Clofarabine plus low-dose cytarabine has a higher response rate than clofarabine alone with comparable toxicity. This trial is registered at www.clinicaltrials.gov as no. NCT00088218.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Treatment response is heterogeneous. However, the classical methods treat the treatment response as homogeneous and estimate the average treatment effects. The traditional methods are difficult to ...apply to precision oncology. Artificial intelligence (AI) is a powerful tool for precision oncology. It can accurately estimate the individualized treatment effects and learn optimal treatment choices. Therefore, the AI approach can substantially improve progress and treatment outcomes of patients. One AI approach, conditional generative adversarial nets for inference of individualized treatment effects (GANITE) has been developed. However, GANITE can only deal with binary treatment and does not provide a tool for optimal treatment selection. To overcome these limitations, we modify conditional generative adversarial networks (MCGANs) to allow estimation of individualized effects of any types of treatments including binary, categorical and continuous treatments. We propose to use sparse techniques for selection of biomarkers that predict the best treatment for each patient. Simulations show that MCGANs outperform seven other state-of-the-art methods: linear regression (LR), Bayesian linear ridge regression (BLR), k-Nearest Neighbor (KNN), random forest classification RF (C), random forest regression RF (R), logistic regression (LogR), and support vector machine (SVM). To illustrate their applications, the proposed MCGANs were applied to 256 patients with newly diagnosed acute myeloid leukemia (AML) who were treated with high dose ara-C (HDAC), Idarubicin (IDA) and both of these two treatments (HDAC+IDA) at M. D. Anderson Cancer Center. Our results showed that MCGAN can more accurately and robustly estimate the individualized treatment effects than other state-of-the art methods. Several biomarkers such as GSK3, BILIRUBIN, SMAC are identified and a total of 30 biomarkers can explain 36.8% of treatment effect variation.
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