Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is one of the most important intracellular pathways, which can be considered as a master regulator for cancer. ...Enormous efforts have been dedicated to the development of drugs targeting PI3K signaling, many of which are currently employed in clinical trials evaluation, and it is becoming increasingly clear that PI3K inhibitors are effective in inhibiting tumor progression. PI3K inhibitors are subdivided into dual PI3K/mTOR inhibitors, pan-PI3K inhibitors and isoform-specific inhibitors. In this review, we performed a critical review to summarize the role of the PI3K pathway in tumor development, recent PI3K inhibitors development based on clinical trials, and the mechanisms of resistance to PI3K inhibition.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The role of tumor-associated macrophages (TAMs) in tumor microenvironment remains controversial due to the two different polarized subsets of TAMs. Here, we performed a meta-analysis to evaluate the ...correlation between subpopulations of TAMs and clinical outcomes in patients with ovarian cancer.
A comprehensive search in PUBMED/Medline and EMBASE databases was performed. The association between TAMs and patient prognosis of ovarian cancer was estimated with hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) using a random-effect model. Additionally, sensitivity analysis and Begg's test were conducted.
Nine studies including 794 patients were enrolled in the meta-analysis. The results showed that higher M1/M2 ratio in tumor tissues was associated with a favorable overall survival (OS) (HR=0.449, 95% CI=0.283–0.712, P=0.001). Elevated intra-islet M1/M2 TAMs ratio showed a positive correlation for OS (HR=0.510, 95% CI=0.264–0.986, P=0.045). No significant relation was observed between OS and CD68+ TAMs (HR=0.99, 95% CI=0.88–1.11, P=0.859), CD163+ TAMs (HR=1.04, 95% CI=0.92–1.16, P=0.544) or CD163+/CD68+ TAMs ratio (HR=1.628, 95% CI=0.529–5.008, P=0.395). Worse progression-free survival (PFS) was associated with high density of CD163+ TAMs (HR=2.157, 95% CI=1.406–3.312, P=0.000) and higher ratio of CD163+/CD68+ TAMs (HR=3.223, 95% CI=1.805–5.755, P=0.000). Elevated M1/M2 TAMs ratio predicted better PFS of ovarian cancer (HR=0.490, 95% CI=0.270–0.890, P=0.019). Furthermore, high density of CD163+ and CD68+ TAMs was observed in ovarian cancer with advanced TNM stage.
In our study, it was revealed that CD163+ TAMs infiltration was associated with poor prognosis of ovarian cancer and high M1/M2 macrophages ratio in tumor tissues predicted better prognosis.
•Higher M1/M2 TAMs ratio in ovarian tumors was associated with a favorable OS and PFS.•High density of CD163+ TAMs might predict poor prognosis in patients with ovarian cancer.•M1 and M2 subsets presented distinct effects on ovarian cancer prognosis.•This suggests that M2 subtypes could be a potential therapeutic target of ovarian cancer.•High density of TAMs was related to advanced TNM stage of ovarian cancer.
Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence. Epigenetic dysregulation is often linked ...to human disease, notably cancer. With the development of various drugs targeting epigenetic regulators, epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials. In this review, we summarize the aberrant functions of enzymes in DNA methylation, histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.
Targeting the KRAS pathway is a promising but challenging approach for colorectal cancer therapy. Despite showing potent efficacy in BRAF-mutated melanoma, MEK inhibitors appeared to be tolerated by ...colorectal cancer cells due to their intrinsic compensatory signaling. Here, we performed genome-wide CRISPR/Cas9 screening in the presence of MEK inhibitor to identify genes that are synthetically lethal with MEK inhibition in CRC models harboring KRAS mutations. Several genes were identified as potential functional drivers, which were significantly enriched in the GRB7-mediated RTK pathway. Loss-of-function and gain-of-function assays validated that GRB7 potently rendered CRC cells primary resistance to MEK inhibitors through the RTK pathway. Mass spectrum analysis of GRB7 immunoprecipitates revealed that PLK1 was the predominant interacting kinase of GRB7. Inhibition of PLK1 suppressed downstream signaling of RTK, including FAK, STAT3, AKT, and 4EBP1. The combination of PLK1 and MEK inhibitors synergistically inhibited CRC cell proliferation and induced apoptosis in vitro and in vivo. In conclusion, we identified GRB7-PLK1 as a pivotal axis mediating RTKs, resulting in MEK inhibitor tolerance. PLK1 is therefore a promising target for synergizing MEK inhibitors in the clinical treatment of CRC patients harboring KRAS mutations.
Targeting immune cells or factors are effective for patients with solid tumors. Myeloid-derived suppressor cells (MDSCs) are known to have immunosuppressive functions, and the levels of MDSCs in ...patients with solid tumor are assumed to have prognostic values. This meta-analysis aimed at evaluating the relationship between MDSCs and the prognosis of patients with solid tumors. We searched articles in PUBMED and EMBASE comprehensively, updated to March 2016. Eight studies with 442 patients were included in the meta-analysis. We analyzed pooled hazard ratios (HRs) for overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS). The results showed that MDSCs were associated with poor OS (HR, 1.94; 95% confidence interval CI, 1.42-2.66; P < 0.0001) in patients with solid tumors. PFS/RFS (HR, 1.85; 95% CI, 1.16-2.97; P = 0.01) also indicated the association between MDSCs and prognosis. The HRs and 95% CIs for OS in Asian and non-Asian patients were 2.53 (95% CI 1.61-3.42, p < 0.00001) and 1.67 (95% CI 1.14-2.46, p < 0.0001), respectively. We further analyzed the data according to tumor types. The combined HRs and 95% CIs for OS were 1.26 (95% CI 1.10-1.44, p = 0.0003) for gastrointestinal (GI) cancer, 2.59 (95% CI 1.69-3.98, p < 0.0001) for hepatocellular carcinoma (HCC) and 1.86 (95% CI 1.26-2.75, p = 0.002) for other tumor types. In conclusion, MDSCs had a fine prognostic value for OS and PFS/RFS in patients with solid tumors. MDSCs could be used as biomarkers to evaluate prognosis in clinical practice.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To evaluate the performance of a deep learning (DL)-based radiomics strategy on contrast-enhanced computed tomography (CT) to predict microvascular invasion (MVI) status and clinical outcomes, ...recurrence-free survival (RFS) and overall survival (OS) in patients with early stage hepatocellular carcinoma (HCC) receiving surgical resection.
All 283 eligible patients were included retrospectively between January 2008 and December 2015, and assigned into the training cohort (n = 198) and the testing cohort (n = 85). We extracted radiomics features via handcrafted radiomics analysis manually and DL analysis of pretrained convolutional neural networks via transfer learning automatically. Support vector machine was adopted as the classifier. A clinical-radiological model for MVI status integrated significant clinical features and the radiological signature generated from the radiological model with the optimal area under the receiver operating characteristics curve (AUC) in the testing cohort. Otherwise, DL-based prognostic models were constructed in prediction of recurrence and mortality via Cox proportional hazard analysis.
The clinical-radiological model for MVI represented an AUC of 0.909, accuracy of 96.47%, sensitivity of 90.91%, specificity of 97.30%, positive predictive value of 83.33%, and negative predictive value of 98.63% in the testing cohort. The clinical-radiological models for identification of RFS and OS outperformed prediction performance of the clinical model or the DL signature alone. The DL-based integrated model for prognostication showed great predictive value with significant classification and discrimination abilities after validation.
The integrated DL-based radiomics models achieved accurate preoperative prediction of MVI status, and might facilitate predicting tumor recurrence and mortality in order to optimize clinical decisions for patients with early stage HCC.
T-cell-based immunotherapies, particularly immune checkpoint inhibitors, are promising treatments for various cancers. However, a large subset of patients develop primary or secondary resistance upon ...treatment. Although the detailed mechanisms remain unclear, immune escape via alterations in both cancer and tumor microenvironment has been identified as critical causes of immune resistance. Moreover, some long non-coding RNAs (lncRNAs), named as immune-related lncRNAs, have been recognized as regulators of immune cell-specific gene expression that mediate immune processes. These immune-related lncRNAs may play a vital role in immunotherapy resistance. Herein, we summarize current immune-related lncRNAs and their underlying roles in immune resistance to provide strategies for future research and therapeutic alternatives to overcome immunotherapy resistance.
A growing number of studies have examined associations between night shift work and the risks of common cancers among women, with varying conclusions. We did a meta-analysis to identify whether ...long-term night shift work increased the risks of common cancers in women. We enrolled 61 articles involving 114,628 cases and 3,909,152 participants from Europe, North America, Asia, and Australia. Risk estimates were performed with a random-effect model or a fixed-effect model. Subgroup analyses and meta-regression analyses about breast cancer were conducted to explore possible sources of heterogeneity. In addition, we carried out a dose-response analysis to quantitatively estimate the accumulative effect of night shift work on the risk of breast cancer. A positive relationship was revealed between long-term night shift work and the risks of breast OR = 1.316; 95% confidence interval (CI), 1.196-1.448, digestive system (OR = 1.177; 95% CI, 1.065-1.301), and skin cancer (OR = 1.408; 95% CI, 1.024-1.934). For every 5 years of night shift work, the risk of breast cancer in women was increased by 3.3% (OR = 1.033; 95% CI, 1.012-1.056). Concerning the group of nurses, long-term night shift work presented potential carcinogenic effect in breast cancer (OR = 1.577; 95% CI, 1.235-2.014), digestive system cancer (OR = 1.350; 95% CI, 1.030-1.770), and lung cancer (OR = 1.280; 95% CI, 1.070-1.531). This systematic review confirmed the positive association between night shift work and the risks of several common cancers in women. We identified that cancer risk of women increased with accumulating years of night shift work, which might help establish and implement effective measures to protect female night shifters.
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Immune checkpoint inhibitors (ICIs), as one of the innovative types of immunotherapies, including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte ...antigen 4 (CTLA-4) inhibitors, have obtained unprecedented benefit in multiple malignancies. However, the immune response activation in the body organs could arise immune-related adverse events (irAEs). Checkpoint inhibitor colitis (CIC) is the most widely reported irAEs. However, some obscure problems, such as the mechanism concerning gut microbiota, the confusing differential diagnosis with inflammatory bowel disease (IBD), the optimal steroid schedule, the reintroduction of ICIs, and the controversial prognosis features, influence the deep understanding and precise diagnosis and management of CIC. Herein, we based on these problems and comprehensively summarized the relevant studies of CIC in patients with NSCLC, further discussing the future research direction of this specific pattern of irAEs.
Background
It is a clinical problem to identify histological component in enlarged cervical lymph nodes, particularly in differentiation between lymph node metastasis and lymphoma involvement.
...Purpose
To construct two kinds of deep learning (DL)‐based computer‐aided diagnosis (CAD) systems including DL‐convolutional neural networks (DL‐CNN) and DL‐machine learning for pathological diagnosis of cervical lymph nodes by positron emission tomography (PET)/computed tomography (CT) images.
Methods
We collected CT, PET, and PET/CT images series from 165 patients with enlarged cervical lymph nodes receiving examinations from January 2014 to June 2018. Six CNNs pretrained on ImageNet as DL architectures were used for two kinds of DL‐based CAD models, including DL‐CNN and DL‐machine learning models. The DL‐CNN models were constructed via transfer learning for classification of lymphomatous and metastatic lymph nodes. The DL‐machine learning models were developed by DL‐based features extractors and support vector machine (SVM) classifier. As for DL‐SVM models, we also evaluate the effect of handcrafted radiomics features in combination of DL‐based features.
Results
The DL‐CNN model with ResNet50 architecture on PET/CT images had the best diagnostic performance among all six algorithms with an area under the receiver operating characteristic curve (AUC) of 0.845 and accuracy of 78.13% in the testing cohort. The DL‐SVM model on ResNet50 extractor showed great performance for the testing cohort with an AUC of 0.901, accuracy of 86.96%, sensitivity of 76.09%, and specificity of 94.20%. The combination of DL‐based and handcrafted features yielded the improvement of diagnostic performance.
Conclusions
Our DL‐based CAD systems on PET/CT images were developed for classifying metastatic and lymphomatous involvement with favorable diagnostic performance in enlarged cervical lymph nodes. Further clinical practice of our systems may improve quality of the following therapeutic interventions and optimize patients’ outcomes.
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