Objective
To evaluate the diagnostic performance of machine-learning based quantitative texture analysis of CT images to differentiate small (≤ 4 cm) angiomyolipoma without visible fat (AMLwvf) from ...renal cell carcinoma (RCC).
Methods
This single-institutional retrospective study included 58 patients with pathologically proven small renal mass (17 in AMLwvf and 41 in RCC groups). Texture features were extracted from the largest possible tumorous regions of interest (ROIs) by manual segmentation in preoperative three-phase CT images. Interobserver reliability and the Mann-Whitney U test were applied to select features preliminarily. Then support vector machine with recursive feature elimination (SVM-RFE) and synthetic minority oversampling technique (SMOTE) were adopted to establish discriminative classifiers, and the performance of classifiers was assessed.
Results
Of the 42 extracted features, 16 candidate features showed significant intergroup differences (
P
< 0.05) and had good interobserver agreement. An optimal feature subset including 11 features was further selected by the SVM-RFE method. The SVM-RFE+SMOTE classifier achieved the best performance in discriminating between small AMLwvf and RCC, with the highest accuracy, sensitivity, specificity and AUC of 93.9 %, 87.8 %, 100 % and 0.955, respectively.
Conclusion
Machine learning analysis of CT texture features can facilitate the accurate differentiation of small AMLwvf from RCC.
Key Points
•
Although conventional CT is useful for diagnosis of SRMs, it has limitations.
•
Machine-learning based CT texture analysis facilitate differentiation of small AMLwvf from RCC.
•
The highest accuracy of SVM-RFE+SMOTE classifier reached 93.9 %.
•
Texture analysis combined with machine-learning methods might spare unnecessary surgery for AMLwvf
.
This Special Issue of
(two original articles, five reviews), presented by international experts in tumor hypoxia, focuses on the role of hypoxia, or low oxygen levels, in the development and ...progression of cancer ....
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Plumbagin (PLB) has shown anti-cancer activity but the mechanism is unclear. This study has found that PLB has a potent pro-apoptotic and pro-autophagic effect on A549 and H23 cells. PLB ...arrests cells in G2/M phase, and increases the intracellular level of reactive oxygen species in both cell lines. PLB dose-dependently induces autophagy through inhibition of PI3K/Akt/mTOR pathway as indicated by reduced phosphorylation of Akt and mTOR. Inhibition or induction of autophagy enhances PLB-induced apoptosis. There is crosstalk between PLB-induced apoptosis and autophagy. These findings indicate that PLB initiates both apoptosis and autophagy in NSCLC cells through coordinated pathways.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Naturally occurring polyphenols are believed to have beneficial effects in the prevention and treatment of a myriad of disorders due to their anti-inflammatory, antioxidant, antineoplastic, ...cytotoxic, and immunomodulatory activities documented in a large body of literature. In the era of molecular medicine and targeted therapy, there is a growing interest in characterizing the molecular mechanisms by which polyphenol compounds interact with multiple protein targets and signaling pathways that regulate key cellular processes under both normal and pathological conditions. Numerous studies suggest that natural polyphenols have chemopreventive and/or chemotherapeutic properties against different types of cancer by acting through different molecular mechanisms. The present review summarizes recent preclinical studies on the applications of bioactive polyphenols in lung cancer therapy, with an emphasis on the molecular mechanisms that underlie the therapeutic effects of major polyphenols on lung cancer. We also discuss the potential of the polyphenol-based combination therapy as an attractive therapeutic strategy against lung cancer.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose: As combination chemotherapy of antiangiogenic agents with conventional chemotherapeutic drugs continues to evolve, an understanding
of the pharmacokinetic and pharmacodynamic variables ...associated with optimal treatment is needed. Thus, the effect of the
multitargeted tyrosine kinase inhibitor sunitinib on tumor distribution of temozolomide was investigated to evaluate conditions
for optimal combination chemotherapy.
Experimental Design: In mice bearing SF188V+ human glioma xenografts, measurements of temozolomide pharmacokinetic properties and sunitinib pharmacodynamic
activities were evaluated, the latter including determinants for vascular normalization, including CD31, collagen IV, and
α-SMA.
Results: Sunitinib given in a daily dose of either 10 or 40 mg/kg orally over 14 days increased temozolomide tumor distribution, as
indicated by the tumor-to-plasma AUC ratio compared with control; however, only the 10 mg/kg group reached statistical significance
( P < 0.05). From the pharmacodynamic analysis, a “vascular normalization index” incorporating the microvessel density (MVD)
and protein expression of α-SMA and collagen IV was proposed as an indication of the number of tumor vessels with relatively
good quality, which was found to be significantly correlated with the unbound temozolomide AUC in tumor interstitial fluid
( P = 0.05). Furthermore, both sunitinib-treated groups maintained the molecular balance between angiopoietins Ang-1 and Ang-2,
suggesting a critical role of angiopoietins in vascular normalization.
Conclusions: Several important factors relevant to the antiangiogenic agent–induced tumor vascular normalization have been identified
and incorporated into a vascular normalization index that may serve to correlate the angiogenic phenotype to the distribution
of cytotoxic drugs in solid tumors.
For nearly five decades, cisplatin has played an important role as a standard chemotherapeutic agent and been prescribed to 10-20% of all cancer patients. Although nephrotoxicity associated with ...platinum-based agents is well recognized, treatment of cisplatin-induced acute kidney injury is mainly supportive and no specific mechanism-based prophylactic approach is available to date. Here, we postulated that systemically delivered rapamycin perfluorocarbon nanoparticles (PFC NP) could reach the injured kidneys at sufficient and sustained concentrations to mitigate cisplatin-induced acute kidney injury and preserve renal function. Using fluorescence microscopic imaging and fluorine magnetic resonance imaging/spectroscopy, we illustrated that rapamycin-loaded PFC NP permeated and were retained in injured kidneys. Histologic evaluation and blood urea nitrogen (BUN) confirmed that renal structure and function were preserved 48 h after cisplatin injury. Similarly, weight loss was slowed down. Using western blotting and immunofluorescence staining, mechanistic studies revealed that rapamycin PFC NP significantly enhanced autophagy in the kidney, reduced the expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), as well as decreased the expression of the apoptotic protein Bax, all of which contributed to the suppression of apoptosis that was confirmed with TUNEL staining. In summary, the delivery of an approved agent such as rapamycin in a PFC NP format enhances local delivery and offers a novel mechanism-based prophylactic therapy for cisplatin-induced acute kidney injury.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Studies on the effective and safe therapeutic dosage of delta-9-tetrahydrocannabinol (THC) for the treatment of Alzheimer's disease (AD) have been sparse due to the concern about THC's psychotropic ...activity. The present study focused on demonstrating the beneficial effect of low-dose THC treatment in preclinical AD models. The effect of THC on amyloid-β (Aβ) production was examined in N2a/AβPPswe cells. An in vivo study was conducted in aged APP/PS1 transgenic mice that received an intraperitoneal injection of THC at 0.02 and 0.2 mg/kg every other day for three months. The in vitro study showed that THC inhibited Aβ aggregation within a safe dose range. Results of the radial arm water maze (RAWM) test demonstrated that treatment with 0.02 and 0.2 mg/kg of THC for three months significantly improved the spatial learning performance of aged APP/PS1 mice in a dose-dependent manner. Results of protein analyses revealed that low-dose THC treatment significantly decreased the expression of Aβ oligomers, phospho-tau and total tau, and increased the expression of Aβ monomers and phospho-GSK-3β (Ser9) in the THC-treated brain tissues. In conclusion, treatment with THC at 0.2 and 0.02 mg/kg improved the spatial learning of aged APP/PS1 mice, suggesting low-dose THC is a safe and effective treatment for AD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
AHNAK, also known as desmoyokin, is a giant protein with the molecular size of approximately 700 kDa and exerts diverse functions in different types of cancer.
In the present study, we demonstrated ...that AHNAK mRNA levels were down-regulated in 7 out of 8 human breast cancer cell lines, especially in triple - negative breast cancer (TNBC) cell lines. Moreover, in patients with TNBC, the expression of AHNAK gene was inversely correlated with the tumor status (P = 0.015), lymph node status (P < 0.001), lymph node (LN) infiltration (P < 0.001) and TNM stage (P < 0.001). Moreover, down-regulated AHNAK expression was considered an independent prognostic factor associated with the poor survival of patients with TNBC. Overexpression of AHNAK in two TNBC cell lines, MDA-MB-231 and BT549, suppressed the in vitro TNBC cell proliferation and colony formation, and inhibited the in vivo TNBC xenograft growth and lung metastasis. The tumor suppressing effect of AHNAK in TNBC was associated with the AKT/MAPK signaling pathway and Wnt/β-catenin pathway. Consistent results were observed when AHNAK was knockdown in BT20 and MDA-MB-435 cells.
Taken together, our results suggest that AHNAK acts as a tumor suppressor that negatively regulates TNBC cell proliferation, TNBC xenograft growth and metastasis via different signaling pathways.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
HIV-1 Tat Interactive Protein 2 (HTATIP2) is a tumor suppressor, of which reduced or absent expression is associated with increased susceptibility to tumorigenesis and enhanced tumor invasion and ...metastasis. However, whether the absent expression of HTATIP2 is a tumor-promoting factor that acts through improving tumor adaptation to hypoxia is unclear. Here, we established a stable HTATIP2-knockdown A549 human lung adenocarcinoma cell line (A549shHTATIP2) using lentiviral-delivered HTATIP2-targeting short hairpin RNA (shRNA), employed a double subcutaneous xenograft model and incorporated photoacoustic imaging and metabolomics approaches to elucidate the impact of the absent HTATIP2 expression on tumor response to hypoxic stress. Results from the in vivo study showed that A549shHTATIP2 tumors exhibited accelerated growth but decreased intratumoral oxygenation and angiogenesis and reduced sensitivity to sorafenib treatment as compared with their parental counterparts. Moreover, results of the immunoblot and real-time PCR analyses revealed that the HIF2α protein and mRNA levels in vehicle-treated A549shHTATIP2 tumors were significantly increased (p < 0.01 compared with the parental control tumors). Despite the strong HIF2α-c-Myc protein interaction indicated by our co-immunoprecipitation data, the increase in the c-Myc protein and mRNA levels was not significant in the A549shHTATIP2 tumors. Nonetheless, MCL-1 and β-catenin protein levels in A549shHTATIP2 tumors were significantly increased (p < 0.05 compared with the parental control tumors), suggesting an enhanced β-catenin/c-Myc/MCL-1 pathway in the absence of HTATIP2 expression. The finding of significantly decreased E-cadherin (p < 0.01 compared with vehicle-treated A549shHTATIP2 tumors) and increased vimentin (p < 0.05 compared with sorafenib-treated A549 tumors) protein levels in A549shHTATIP2 tumors implicates that the absence of HTATIP2 expression increases the susceptibility of A549 tumors to sorafenib-activated epithelial-mesenchymal transition (EMT) process. Comparison of the metabolomic profiles between A549 and A549shHTATIP2 tumors demonstrated that the absence of HTATIP2 expression resulted in increased tumor metabolic plasticity that enabled tumor cells to exploit alternative metabolic pathways for survival and proliferation rather than relying on glutamine and fatty acids as a carbon source to replenish TCA cycle intermediates. Our data suggest a mechanism by which the absent HTATIP2 expression modulates tumor adaptation to hypoxia and promotes an aggressive tumor phenotype by enhancing the HIF2α-regulated β-catenin/c-Myc/MCL-1 signaling, increasing the susceptibility of tumors to sorafenib treatment-activated EMT process, and improving tumor metabolic plasticity.
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Radiation proctitis is a common complication after radiotherapy for cervical cancer. Unlike simple radiation damage to other organs, radiation proctitis is a complex disease closely related to the ...microbiota. However, analysis of the gut microbiota is time-consuming and expensive. This study aims to mine rectal information using radiomics and incorporate it into a nomogram model for cheap and fast prediction of severe radiation proctitis prediction in postoperative cervical cancer patients.
The severity of the patient's radiation proctitis was graded according to the RTOG/EORTC criteria. The toxicity grade of radiation proctitis over or equal to grade 2 was set as the model's target. A total of 178 patients with cervical cancer were divided into a training set (
= 124) and a validation set (
= 54). Multivariate logistic regression was used to build the radiomic and non-raidomic models.
The radiomics model AUC=0.6855(0.5174-0.8535) showed better performance and more net benefit in the validation set than the non-radiomic model AUC=0.6641(0.4904-0.8378). In particular, we applied SHapley Additive exPlanation (SHAP) method for the first time to a radiomics-based logistic regression model to further interpret the radiomic features from case-based and feature-based perspectives. The integrated radiomic model enables the first accurate quantitative assessment of the probability of radiation proctitis in postoperative cervical cancer patients, addressing the limitations of the current qualitative assessment of the plan through dose-volume parameters only.
We successfully developed and validated an integrated radiomic model containing rectal information. SHAP analysis of the model suggests that radiomic features have a supporting role in the quantitative assessment of the probability of radiation proctitis in postoperative cervical cancer patients.
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