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Multiple studies have also demonstrated the role of DNMT inhibitors in differentiation therapy. Pinto et al. showed that azacitidine could induce primary AML cells from patients to differentiate into less or non-malignant cells [122, 123]. Prostate cancer derived-CSCs that were treated with decitabine showed decreased expression of stemness genes Octamer-binding transcription factor 4 (OCT40029 and Nanog homeobox (NANOG), leading to overall reduction in tumor growth [124]. In addition, low doses of SGI-110, a newer DNMT inhibitor, was recently reported to be capable of reprogramming ovarian CSCs to a more differentiated state [125]. Treatment with SGI-110 also decreased tumor-initiating ability and re-sensitized these cells to platinum, suggesting a potential use of DNMT inhibitors in combination with other chemotherapeutic agents in preventing recurrence of ovarian cancer [125]. Both azacitidine and decitabine have been approved by the FDA for treatment of myelodysplastic syndrome (MDS) [126]. Clinical trials for other indications such as AML and colorectal cancer are still ongoing. SGI-110 is also in phases of clinical trials for treatment of various cancers such as AML, MDS, liver cancer and platinum-resistant ovarian cancer.
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Thirteen of the SBS signatures we extracted (excluding those due to signature splitting) represent newly identified and probably real signatures, not present in COSMIC v.2. Some were rare (SBS31, SBS32, SBS35, SBS36, SBS42 and SBS44). Others were more common, but contributed relatively few mutations and/or were similar to previously discovered signatures (SBS38, SBS39 and SBS40). Notably, SBS40 is a flat signature similar to SBS5. It contributes to multiple types of cancer, but its similarity to SBS5 renders the extent of this contribution uncertain. For some of the newly identified signatures, there were plausible underlying aetiologies (Fig. 3, Extended Data Figs. 4, 5): for SBS31 and SBS35, platinum compound chemotherapy39; for SBS32, azathioprine therapy; for SBS36, inactivating germline or somatic mutations in MUTYH (which encodes a component of the base excision repair machinery)40,41; for SBS38, additional effects of exposure to ultraviolet (UV) light; for SBS42, occupational exposure to haloalkanes13; and for SBS44, defective DNA mismatch repair42.
Several base substitution signatures showed transcriptional strand bias, which may be attributable to transcription-coupled nucleotide excision repair acting on DNA damage and/or to an excess of DNA damage on untranscribed strands of genes44. Both mechanisms result in more mutations of damaged bases on untranscribed than on transcribed strands of genes. Assuming that either mechanism is responsible for the observed transcriptional strand biases, DNA damage to cytosine (SBS7a and SBS7b), guanine (SBS4, SBS8, SBS19, SBS23, SBS24, SBS31, SBS32, SBS35 and SBS42), thymine (SBS7c, SBS7d, SBS21, SBS26 and SBS33) and adenine (SBS5, SBS12, SBS16, SBS22 and SBS25) may underlie these mutational signatures (plots of strand bias are available at ). The likely DNA-damaging agents are known for SBS4 (tobacco mutagens), SBS7a, SBS7b, SBS7c and SBS7d (UV light), SBS22 (aristolochic acid), SBS24 (aflatoxin), SBS25 (chemotherapy), SBS31 and SBS35 (platinum compounds), SBS32 (azathioprine) and SBS42 (haloalkanes).
DBS3, DBS7, DBS8 and DBS10 showed hundreds to thousands of mutations in rare colorectal, stomach and oesophageal cancers, some of which showed evidence of defective DNA mismatch repair (DBS7 and DBS10) or polymerase epsilon exonuclease domain mutations (DBS3) that generate hypermutator phenotypes (Figs. 2, 3). DBS5 was found in cancers exposed to platinum chemotherapy, and is associated with SBS31 and SBS35.
SigProfiler is available both as a MATLAB framework and as a Python package. In both cases, SigProfiler is a fully functional, free and open-source tool distributed under the permissive 2-Clause BSD License. SigProfiler in MATLAB can be downloaded from: -sigprofiler. SigProfiler in Python can be downloaded from: SignatureAnalyzer code is available at -SignatureAnalyzer (github.com). The code used to generate the synthetic data and summarize SignatureAnalyzer and SigProfiler results is open source and freely available as the SynSig package: under the GNU General Public License v.3.0. The core computational pipelines used by the PCAWG Consortium for alignment, quality control and variant calling are available to the public at =pcawg under the GNU General Public License v.3.0, which allows for reuse and distribution.
Silence is the best secure chat program that eases and ensures secure SMS/MMS features. This is so you can use these two features even when you are not connected via the internet. Silence is monitored on a regular basis mainly with regards to security wherein the codes are locked and have been made unavailable to any other third party or government agency.
Other possible HPD-related genomic alterations were identified by Refae and coworkers [109]. The Authors evaluated the frequency of 17 SNPs in 4 genes (PD-1, PD-L1, IDO1 and VEGFR2), selected for their functional and clinical relevance, in a cohort of 98 patients, affected by different types of cancer and treated with anti-PD-1 or anti-PD-L1 monotherapy alone. In this cohort, 14% of patients experienced HPD during therapy. Multivariate analysis revealed that the polymorphisms rs2282055 G allele in the PD-L1 gene and rs1870377 A allele in the VEGFR2 gene are significantly and independently associated with a higher susceptibility to developing HPD. Based on the data available in the GTEX portal, the Authors hypothesized that rs2282055 PD-L1 polymorphisms may have a role in regulating the PD-L1 expression level that, in turn, may impact ICI therapy outcome, even though the real influence of PD-L1 expression on ICI treatment is still a matter of debate [110]. In the case of the VEGFR2 gene, which encodes a receptor that responds to the VEGF signal and regulates endothelial migration and proliferation [111], rs1870377 is reported to increase the affinity and activity of VEGF-A on VEGFR2 with the result of promoting angiogenesis, as reported in nonsmall cell lung cancer tissues [112]. Moreover, VEGFR2 can boost cancer proliferation and metastasis independently of proangiogenic stimuli [113]. Although these data are intriguing, they do not provide a biological explanation about how these polymorphisms and anti-PD-1/PD-L1 antibodies can work together in determining HPD. However, we can speculate that if ICIs are able to induce a stronger M2 phenotype in TAMs in some particular circumstances, as described in the previous section, one of the features of M2 macrophages is the ability to release VEGF that may more efficiently trigger the signaling pathways mediated by VEGFR2, exploiting the increased affinity of this receptor determined by the rs1870377 polymorphisms. Of note, this work highlighted the possible existence of a tight link between angiogenesis and HPD, and in this regard, it is worth mentioning the ability of ICI to induce the expression of pro-angiogenic molecules. For example, Wu et al. reported an increased serum level of angiopoietin-2 (ANGPT2), a molecule involved in blood vessel maturation with potential protumor activity [114], in patients with advanced melanoma who progressed after ICI treatment [115]. The biological activity of ANGPT2 is not only restricted to neoangiogenesis but can also impact the macrophage phenotype by promoting PD-L1 expression [115] and IL-10 secretion [116], which, in turn, are involved in the expansion of CD4+CD25highFoxp3+ Tregs in tumor-bearing mice [116]. These data suggest that ICI-induced angiogenesis might occur to create a stronger immunosuppressive microenvironment. Moreover, the augmented tumor growth kinetics presume higher energy consumption by tumor cells, and new vasculature formation may provide the nutrients required to sustain such rapid cell proliferation. Furthermore, HPD is often characterized by the appearance of metastatic foci, and more blood vessels vascularizing the tumor bed may represent an escape route for cancer cells, increasing the possibility for dissemination throughout the body.
Effect of chemotherapy on HPD. a Representative image of the crossover of the survival curves observed in clinical trials comparing ICIs versus chemotherapy. b Representative image of survival curves observed in clinical trials comparing chemotherapy+ICIs versus chemotherapy alone. c Overview of the main immunological effect of platinum compounds
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Extensive stage SCLC is generally not considered curable, and is managed palliatively with therapies aimed at prolonging life and reducing symptoms associated with disease. The most commonly used first-line systemic therapy in the United States and Europe is platinum (cisplatin or carboplatin) combined with etoposide. Table 1 summarizes a selection of randomized studies, reported between 1991 and 2017, in which platinum/etoposide was compared to an investigational arm. The response rates, median PFS and median OS for the platinum/etoposide arm in each study are shown in Table 1. 041b061a72