Impact of obese patients in ovarian cancer surgery on postoperative wound complications: A meta-analysis.

The effect of obesity on wound-related outcomes in post-ovarian cancer patients is not clear. A number of studies on the association of fat with post-operation injury in ovarian carcinoma have produced contradictory findings. This study aims to conduct a study of the available data to assess the association of obese individuals with significant surgery results in ovarian cancer. We looked up Cochrane Library, Embase, and PubMed for qualifying research on ovarian cancer operations to determine the primary evidence for evaluating the association of obesity with post-surgical wound injury in ovarian cancer. The odds ratio (OR) was analysed with a fixed effect model if the variability of the study was small; otherwise, the analysis of the data was done with a random effect model. Out of 1259 related trials which were reviewed for eligibility, 6 publications were chosen from 2009 to 2019, 3076 patients who had had an operation for ovarian cancer. Obesity has been linked to an increased rate of wound-related complications in ovarian cancer operations compared to those without obesity (OR, 0.50; 95% CI, 0.37, 0.69 p < 0.0001). Non-obesity was significantly less likely to occur with respect to operation time compared to those with obesity (MD, -48.00; 95% CI, -55.33, -40.68 p < 0.00001). There were no statistically significant differences in the rate of haemorrhage after the operation (OR, 0.26; 95% CI, 0.04, 1.57, p = 0.14). Because of the limited number of trials in this meta-analysis, caution should be exercised in their treatment. More high-quality research with a large sample is required in order to confirm the findings.

[Mechanism of Qiwei Guibao Granules in treatment of premature ovarian failure based on proteomics].

In this study, the underlying mechanism of Qiwei Guibao Granules(QWGB) in the treatment of premature ovarian fai-lure(POF) was explored by the proteomics technique. Firstly, the POF model was induced in mice by intragastric administration of Tripterygium wilfordii glycosides solution at 50 mg·kg~(-1) for 14 days. Ten days prior to the end of the modeling, the estrous cycle of mice was observed every day to evaluate the success of modeling. From the 1st day after modeling, the POF model mice were treated with QWGB by gavage every day and the treatment lasted four weeks. On the 2nd day after the end of the experiment, blood was collected from the eyeballs and the serum was separated by centrifugation. The ovaries and uterus were collected and the adipose tissues were carefully stripped. The organ indexes of the ovaries and uterus of each group were calculated. The serum estrogen(E_2) level of mice in each group was detected by ELISA. Protein samples were extracted from ovarian tissues of mice, and the differential proteins before and after QWGB intervention and before and after modeling were analyzed by quantitative proteomics using tandem mass tags(TMT). As revealed by the analysis of differential proteins, QWGB could regulate 26 differentially expressed proteins related to the POF model induced by T. wilfordii glycosides, including S100A4, STAR, adrenodoxin oxidoreductase, XAF1, and PBXIP1. GO enrichment results showed that the 26 differential proteins were mainly enriched in biological processes and cellular components. The results of KEGG enrichment showed that those differential proteins were involved in signaling pathways such as completion and coalescence cascades, focal adhesion, arginine biosynthesis, and terpenoid backbone biosynthesis. The complement and coalescence cascades signaling pathway was presumably the target pathway of QWGB in the treatment of POF. In this study, the proteomics technique was used to screen the differential proteins of QWGB in the treatment of POF in mice induced by T. wilfordii glycosides, and they were mainly involved in immune regulation, apoptosis regulation, complement and coagulation cascade reactions, cholesterol metabolism, and steroid hormone production, which may be the main mechanisms of QWGB in the treatment of POF.

Tripartite motif-containing 68-stabilized modulator of apoptosis-1 retards the proliferation and metastasis of lung cancer.

Non-small cell lung cancer (NSCLC) is a major global health threat with high incidence and mortality. Modulator of apoptosis-1 (MOAP1), also named MAP-1, belongs to the PNMA gene family and plays a key role in regulating apoptosis and tumor growth. However, its influences on NSCLC are largely unclear, and thus were explored in our present study, particularly the underlying mechanisms. Here, we initially find that MOAP1 expression is significantly decreased in NSCLC patients compared with the normal ones, and negatively correlated with the TNM and pathologic stages among patients. Additionally, MOAP1 low expression predicts a poorer prognosis than that of the NSCLC patients expressing higher MOAP1. Our in vitro studies confirm much lower MOAP1 expression in NSCLC cell lines. Of note, promoting MOAP1 expression strongly reduces the proliferation and induces apoptosis in NSCLC cells, accompanied with cell cycle arrest distributed in G0/G1 phase. Moreover, we find that MOAP1 has a negative correlation with Th2 cells' infiltration, but a positive correlation with the infiltration levels of eosinophils. Epithelial mesenchymal transition (EMT) process is also greatly restrained in NSCLC cells with MOAP1 over-expression, as proved by the reduced migration and invasion of cells. We further identify a positive correlation between MOAP1 and tripartite motif-containing 68 (TRIM68) in patients with NSCLC. Further analysis shows that TRIM68 directly interacts with MOAP1 and stabilizes MOAP1. Importantly, TRIM68 can activate MOAP1 by inducing the K63-linked polyubiquitination of MOAP1. Finally, animal studies verify that promoting MOAP1 efficiently suppresses tumor growth and lung metastasis in the nude mice. Collectively, our results reveal a novel mechanism through which MOAP1 stabilized by TRIM68 inhibits NSCLC development and targeting MOAP1 for its up-regulation may be a promising therapeutic strategy for NSCLC treatment.

The use of modified TI-RADS using contrast-enhanced ultrasound features for classification purposes in the differential diagnosis of benign and malignant thyroid nodules: A prospective and multi-center study.

Objectives: To evaluate the diagnostic efficacy of a modified thyroid imaging reporting and data system (TI-RADS) in combination with contrast-enhanced ultrasound (CEUS) for differentiating between benign and malignant thyroid nodules and to assess inter-observer concordance between different observers. Methods: This study included 3353 patients who underwent thyroid ultrasound (US) and CEUS in ten multi-centers between September 2018 and March 2020. Based on a modified TI-RADS classification using the CEUS enhancement pattern of thyroid lesions, ten radiologists analyzed all US and CEUS examinations independently and assigned a TI-RADS category to each thyroid nodule. Pathology was the reference standard for determining the diagnostic performance (accuracy (ACC), sensitivity (SEN), specificity (SPN), positive predictive value (PPV), and negative predictive value (NPV)) of the modified TI-RADS for predicting malignant thyroid nodules. The risk of malignancy was stratified for each TI-RADS category-based on the total number of benign and malignant lesions in that category. ROC curve was used to determine the cut-off value and the area under the curve (AUC). Cohen's Kappa statistic was applied to assess the inter-observer agreement of each sonological feature and TI-RADS category for thyroid nodules. Results: The calculated malignancy risk in the modified TI-RADS categories 5, 4b, 4a, 3 and 2 nodules was 95.4%, 86.0%, 12.0%, 4.1% and 0%, respectively. The malignancy risk for the five categories was in agreement with the suggested malignancy risk. The ROC curve showed that the AUC under the ROC curve was 0.936, and the cutoff value of the modified TI-RADS classification was >TI-RADS 4a, whose SEN, ACC, PPV, NPV and SPN were 93.6%, 91.9%, 90.4%, 93.7% and 88.5% respectively. The Kappa value for taller than wide, microcalcification, marked hypoechoic, solid composition, irregular margins and enhancement pattern of CEUS was 0.94, 0.93, 0.75, 0.89, 0.86 and 0.81, respectively. There was also good agreement between the observers with regards to the modified TI-RADS classification, the Kappa value was 0.80. Conclusions: The actual risk of malignancy according to the modified TI-RADS concurred with the suggested risk of malignancy. Inter-observer agreement for the modified TI-RADS category was good, thus suggesting that this classification was very suitable for clinical application.

An MRI-based joint model of radiomics and spatial distribution differentiates autoimmune encephalitis from low-grade diffuse astrocytoma.

Background: The differential diagnosis between autoimmune encephalitis and low-grade diffuse astrocytoma remains challenging. We aim to develop a quantitative model integrating radiomics and spatial distribution features derived from MRI for discriminating these two conditions. Methods: In our study, we included 188 patients with confirmed autoimmune encephalitis (n = 81) and WHO grade II diffuse astrocytoma (n = 107). Patients with autoimmune encephalitis (AE, n = 59) and WHO grade II diffuse astrocytoma (AS, n = 79) were divided into training and test sets, using stratified sampling according to MRI scanners. We further included an independent validation set (22 patients with AE and 28 patients with AS). Hyperintensity fluid-attenuated inversion recovery (FLAIR) lesions were segmented for each subject. Ten radiomics and eight spatial distribution features were selected via the least absolute shrinkage and selection operator (LASSO), and joint models were constructed by logistic regression for disease classification. Model performance was measured in the test set using the area under the receiver operating characteristic (ROC) curve (AUC). The discrimination performance of the joint model was compared with neuroradiologists. Results: The joint model achieved better performance (AUC 0.957/0.908, accuracy 0.914/0.840 for test and independent validation sets, respectively) than the radiomics and spatial distribution models. The joint model achieved lower performance than a senior neuroradiologist (AUC 0.917/0.875) but higher performance than a junior neuroradiologist (AUC 0.692/0.745) in the test and independent validation sets. Conclusion: The joint model of radiomics and spatial distribution from a single FLAIR could effectively classify AE and AS, providing clinical decision support for the differential diagnosis between the two conditions.

Natural medicines of targeted rheumatoid arthritis and its action mechanism.

Rheumatoid arthritis (RA) is an autoimmune disease involving joints, with clinical manifestations of joint inflammation, bone damage and cartilage destruction, joint dysfunction and deformity, and extra-articular organ damage. As an important source of new drug molecules, natural medicines have many advantages, such as a wide range of biological effects and small toxic and side effects. They have become a hot spot for the vast number of researchers to study various diseases and develop therapeutic drugs. In recent years, the research of natural medicines in the treatment of RA has made remarkable achievements. These natural medicines mainly include flavonoids, polyphenols, alkaloids, glycosides and terpenes. Among them, resveratrol, icariin, epigallocatechin-3-gallate, ginsenoside, sinomenine, paeoniflorin, triptolide and paeoniflorin are star natural medicines for the treatment of RA. Its mechanism of treating RA mainly involves these aspects: anti-inflammation, anti-oxidation, immune regulation, pro-apoptosis, inhibition of angiogenesis, inhibition of osteoclastogenesis, inhibition of fibroblast-like synovial cell proliferation, migration and invasion. This review summarizes natural medicines with potential therapeutic effects on RA and briefly discusses their mechanisms of action against RA.

The Emerging Roles of Human Gut Microbiota in Gastrointestinal Cancer.

The gut microbiota is composed of a large number of microorganisms with a complex structure. It participates in the decomposition, digestion, and absorption of nutrients; promotes the development of the immune system; inhibits the colonization of pathogens; and thus modulates human health. In particular, the relationship between gut microbiota and gastrointestinal tumor progression has attracted widespread concern. It was found that the gut microbiota can influence gastrointestinal tumor progression in independent ways. Here, we focused on the distribution of gut microbiota in gastrointestinal tumors and further elaborated on the impact of gut microbiota metabolites, especially short-chain fatty acids, on colorectal cancer progression. Additionally, the effects of gut microbiota on gastrointestinal tumor therapy are outlined. Finally, we put forward the possible problems in gut microbiota and the gastrointestinal oncology field and the efforts we need to make.

Genome-wide gain-of-function screening identifies EZH2 mediating resistance to PI3Kα inhibitors in oesophageal squamous cell carcinoma.

Phosphoinositide-3 kinase alpha (PI3Kα) has been confirmed to be a potential therapeutic target for esophageal squamous cell carcinoma (ESCC), while the potency of PI3Kα inhibitors is often attenuated by concurrent oncogenic signalling pathways. We performed genome-wide gain-of-function screening with a CRISPR-SAM library and identified enhancer of zeste homolog 2 (EZH2) rendering ESCC cells resistant to the PI3Kα inhibitor CYH33. Enhanced expression of EZH2 frequently occurs in ESCC and is related to poor prognosis. Overexpression of full-length EZH2 but not methyltransferase-deficient EZH2 conferred resistance to CYH33, while downregulating EZH2 expression restored sensitivity. EZH2 expression was negatively related to the activity of CYH33 against the proliferation of ESCC cell lines and patient-derived cells. Transcriptomic analysis revealed that EZH2 abrogated CYH33-mediated cell cycle regulation. EZH2 epigenetically suppressed the transcription of CDKN1A, promoting RB phosphorylation and cell cycle progression. Concurrently targeting EZH2 significantly potentiated CYH33 to inhibit the growth of ESCC cells and patient-derived xenografts accompanied by enhanced cell cycle arrest. Taken together, our study demonstrated that an EZH2-p21-RB axis remodeled cell cycle regulation and rendered resistance to PI3Kα inhibitors in ESCC. Simultaneously targeting PI3Kα and EZH2 may provide an effective strategy for ESCC therapy with high expression of EZH2.

Emerging role of m6A methylation modification in ovarian cancer.

m6A (N6-methyladenosine) methylation, a well-known modification in tumour epigenetics, dynamically and reversibly fine tunes the entire process of RNA metabolism. Aberrant levels of m6A and its regulators, which can predict the survival and outcomes of cancer patients, are involved in tumorigenesis, metastasis and resistance. Ovarian cancer (OC) ranks first among gynaecological tumours in the causes of death. At first diagnosis, patients with OC are usually at advanced stages owing to a lack of early biomarkers and effective targets. After treatment, patients with OC often develop drug resistance. This article reviews the recent experimental advances in understanding the role of m6A modification in OC, raising the possibility to treat m6A modification and its regulators as promising diagnostic markers and therapeutic targets for OC.

Differential diagnosis between small breast phyllodes tumors and fibroadenomas using artificial intelligence and ultrasound data.

BACKGROUND: It is challenging to differentiate between phyllodes tumors (PTs) and fibroadenomas (FAs). Artificial intelligence (AI) can provide quantitative information regarding the morphology and textural features of lesions. This study attempted to use AI to evaluate the ultrasonic images of PTs and FAs and to explore the diagnostic performance of AI features in the differential diagnosis of PTs and FAs. METHODS: A total of 40 PTs and 290 FAs <5 cm in maximum diameter found in female patients were retrospectively analyzed. All tumors were segmented by doctors, and the features of the lesions were collated, including circularity, height-to-width ratio, margin spicules, margin coarseness (MC), margin indistinctness, margin lobulation (ML), internal calcification, angle between the long axis of the lesion and skin, energy, grey entropy, and grey mean. The differences between PTs and FAs were analyzed, and the diagnostic performance of AI features in the differential diagnosis of PTs and FAs was evaluated. RESULTS: Statistically significant differences (P<0.05) were found in the height-to-width ratio, ML, energy, and grey entropy between the PTs and FAs. Receiver operating characteristic (ROC) curve analysis of single features showed that the area under the curve [(AUC) 0.759] of grey entropy was the largest among the four features with statistically significant differences, and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 0.925, 0.459, 0.978, and 0.190, respectively. When considering the combinations of the features, the combination of height-to-width ratio, margin indistinctness, ML, energy, grey entropy, and internal calcification was the most optimal of the combinations of features with an AUC of 0.868, and a sensitivity, specificity, PPV, and NPV of 0.734, 0.900, 0.982, and 0.316, respectively. CONCLUSIONS: Quantitative analysis of AI can identify subtle differences in the morphology and textural features between small PTs and FAs. Comprehensive consideration of multiple features is important for the differential diagnosis of PTs and FAs.

LncRNA LINC01305 promotes cervical cancer progression through KHSRP and exosome-mediated transfer.

Cervical cancer (CC) is one of the deadliest female malignancies worldwide. Long non-coding RNAs (lncRNAs) are essential regulators for cancer progression. This study aimed to elucidate the role of lncRNA LINC01305 in the progression of CC. We found where LINC01305 was expressed in CC tissues and its correlation with the survival rate of CC patients. Functional experiments were performed to elucidate the effect of LINC01305 on CC. The results showed that LINC01305 was increased in CC tumor tissues and was correlated with a lower survival rate. The overexpression and knockdown of LINC01305 enhanced and inhibited the progression of CC, respectively. Additionally, the upregulation of LINC01305 promoted tumor growth in xenograft mice. Moreover, the effect of LINC01305 on CC was mediated through interacting with the RNA-binding protein, KHSRP. Furthermore, LINC01305 was mainly distributed in exosomes and was transferred to recipient cells to enhance CC progression. Lastly, LINC01305 may participate in the regulation of the stemness of CC. Taken together, the results suggest that LINC01305 promotes the progression of CC through KHSRP and that LINC01305 is released through exosomes and is involved in the stemness of CC. This study sheds light on the molecular mechanism underlying the progression of CC.

Antitumor Activity of Lipid-DNA Aptamer Modified T Lymphocytes in Carcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with no current effective therapeutics. One of the main reasons for the low efficacy of PDAC immunotherapy is the limited CD8+ T cell infiltration, without neo antigen present in PDAC. Aptamers represent single-stranded oligonucleotides which bind to specific targets with high specificity. We developed DNA conjugates and prepared diacyl phospholipid-aptamer XQ-2d which has potential for the targeted therapy and diagnosis of PDAC. In this study, flow cytometry and fluorescence microscopy were employed to assess whether the Lipo-XQ-2d probe could anchor on activated T cells to constitute ligands specifically recognizing PDAC PL45 cells. Flow cytometry was employed to determine cytotoxicity in activated T cells. Results showed that the Lipo-XQ-2d probe could be inserted into T cells, and was specifically bound to both T cells and PL45 cells. In addition, the Lipo-XQ-2d probe redirected T cells to kill PL45 cells in vitro and was not toxic to cells. In conclusion, lipid-DNA-aptamer-modified T-lymphocytes might effectively kill PDAC in vitro, supporting the clinical application of T cell adoptive immunotherapy.

Application of ultrasound artificial intelligence in the differential diagnosis between benign and malignant breast lesions of BI-RADS 4A.

BACKGROUND: The classification of Breast Imaging Reporting and Data System 4A (BI-RADS 4A) lesions is mostly based on the personal experience of doctors and lacks specific and clear classification standards. The development of artificial intelligence (AI) provides a new method for BI-RADS categorisation. We analysed the ultrasonic morphological and texture characteristics of BI-RADS 4A benign and malignant lesions using AI, and these ultrasonic characteristics of BI-RADS 4A benign and malignant lesions were compared to examine the value of AI in the differential diagnosis of BI-RADS 4A benign and malignant lesions. METHODS: A total of 206 lesions of BI-RADS 4A examined using ultrasonography were analysed retrospectively, including 174 benign lesions and 32 malignant lesions. All of the lesions were contoured manually, and the ultrasonic morphological and texture features of the lesions, such as circularity, height-to-width ratio, margin spicules, margin coarseness, margin indistinctness, margin lobulation, energy, entropy, grey mean, internal calcification and angle between the long axis of the lesion and skin, were calculated using grey level gradient co-occurrence matrix analysis. Differences between benign and malignant lesions of BI-RADS 4A were analysed. RESULTS: Significant differences in margin lobulation, entropy, internal calcification and ALS were noted between the benign group and malignant group (P = 0.013, 0.045, 0.045, and 0.002, respectively). The malignant group had more margin lobulations and lower entropy compared with the benign group, and the benign group had more internal calcifications and a greater angle between the long axis of the lesion and skin compared with the malignant group. No significant differences in circularity, height-to-width ratio, margin spicules, margin coarseness, margin indistinctness, energy, and grey mean were noted between benign and malignant lesions. CONCLUSIONS: Compared with the naked eye, AI can reveal more subtle differences between benign and malignant BI-RADS 4A lesions. These results remind us carefully observation of the margin and the internal echo is of great significance. With the help of morphological and texture information provided by AI, doctors can make a more accurate judgment on such atypical benign and malignant lesions.

A measurement method of knee joint space width by ultrasound: a large multicenter study.

BACKGROUND: Although plain radiology is the primary method for assessing joint space width (JSW), it has poor sensitivity to change over time in regards to determining longitudinal progression. We, therefore, developed a new ultrasound (US) measurement method of knee JSW and aimed to provide a monitoring method for the change of JSW in the future. METHODS: A multicenter study was promoted by the Professional Committee of Musculoskeletal Ultrasound, the Ultrasound Society, and the Chinese Medical Doctor Association. US study of knee specimens determined the landmarks for ultrasonic measurement of knee JSW. The US of 1,272 participants from 27 centers was performed to discuss the feasibility and possible influencing factors of knee JSW. The landmarks for US measurement of knee JS, the inflection point of medial femoral epicondyle and the proximal end of the tibia, were determined. RESULTS: The mean knee JSW1 (medial knee JSW) was 8.57±1.95 mm in females and 9.52±2.31 mm in males. The mean knee JSW2 (the near medial knee JSW) was 9.07±2.24 mm in females and 10.17±2.35 mm in males. The JSW values of males were significantly higher than those of females, with a statistical difference. JSW values were negatively correlated with age and body mass index (BMI) to different degrees and positively correlated with height. CONCLUSIONS: The novel US measurement method can be used to measure knee JSW.

Development and External Validation of Radiomics Approach for Nuclear Grading in Clear Cell Renal Cell Carcinoma.

BACKGROUND AND PURPOSE: Nuclear grades of clear cell renal cell carcinoma (ccRCC) are usually confirmed by invasive methods. Radiomics is a quantitative tool that uses non-invasive medical imaging for tumor diagnosis and prognosis. In this study, a radiomics approach was proposed to analyze the association between preoperative computed tomography (CT) images and nuclear grades of ccRCC. METHODS: Our dataset included 320 ccRCC patients from two centers and was divided into a training set (n = 124), an internal test set (n = 123), and an external test set (n = 73). A radiomic feature set was extracted from unenhanced, corticomedullary phase, and nephrographic phase CT images. The maximizing independent classification information criteria function and recursive feature elimination with cross-validation were used to select effective features. Random forests were used to build a final model for predicting nuclear grades, and area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of radiomic features and models. RESULTS: The radiomic features from the three CT phases could effectively distinguished the four nuclear grades. A combined model, merging radiomic features and clinical characteristics, obtained good predictive performances in the internal test set (AUC 0.77, 0.75, 0.79, and 0.85 for the four grades, respectively), and performance was further confirmed in the external test set, with AUCs of 0.75, 0.68, and 0.73 (no fourth-level data). CONCLUSION: The combination of CT radiomic features and clinical characteristics could discriminate the nuclear grades in ccRCC, which may help in assisting treatment decision making.

Design, synthesis, and biological activity evaluation of (-)-6-O-desmethylantofine analogues as potent anti-cancer agents.

Phenanthroindolizidine alkaloids that possess profound anti-proliferative activity and unique mode of action have recently attracted much attention as potential anti-cancer drug candidates. To intensively study the structure-activity-relationship, we designed, synthesized, and evaluated a series of derivatives of 6-desmethylantofine at C-6 position. Most of the derivatives exhibited potent anti-proliferative activity in BEL-7402 and HL60cells. Compound R-12, the cyanomethyl ether of 6-desmethylantofine, exhibited significant anti-cancer activity and inhibited the proliferation of a panel of 30 cancer cell lines including 2 multi-drug-resistant cell lines with an average IC50 value of 18.7 nM, which suggests that R-12 is a promising new anti-cancer agent. Our studies suggest that R-12 displayed potent inhibitory effect on cell growth and colony formation, which is associated with delaying S phase progression by inhibiting DNA synthesis in human hepatoma cancer BEL-7402, SMMC-7721 and ZIP-177 cells.

Bioactive Compounds Isolated from Marine-Derived Microbes in China: 2009-2018.

This review outlines the research that was carried out regarding the isolation of bioactive compounds from marine-derived bacteria and fungi by China-based research groups from 2009-2018, with 897 publications being surveyed. Endophytic organisms featured heavily, with endophytes from mangroves, marine invertebrates, and marine algae making up more than 60% of the microbial strains investigated. There was also a strong focus on fungi as a source of active compounds, with 80% of publications focusing on this area. The rapid increase in the number of publications in the field is perhaps most notable, which have increased more than sevenfold over the past decade, and suggests that China-based researchers will play a major role in marine microbial natural products drug discovery in years to come.

Simultaneous inhibition of PI3Kα and CDK4/6 synergistically suppresses KRAS-mutated non-small cell lung cancer.

OBJECTIVE: Activating KRAS mutations are the most common drivers in the development of non-small cell lung cancer (NSCLC). However, unsuccess of treatment by direct inhibition of KRAS has been proven. Deregulation of PI3K signaling plays an important role in tumorigenesis and drug resistance in NSCLC. The activity of PI3Kα-selective inhibition against KRAS-mutated NSCLC remains largely unknown. METHODS: Cell proliferation was detected by sulforhodamine B assay. Cell cycle distribution and apoptosis were measured by flow cytometry. Cell signaling was assessed by Western blot and immunohistochemistry. RNA interference was used to down-regulate the expression of cyclin D1. Human NSCLC xenografts were employed to detect therapeutic efficacy in vivo. RESULTS: CYH33 possessed variable activity against a panel of KRAS-mutated NSCLC cell lines. Although CYH33 blocked AKT phosphorylation in all tested cells, Rb phosphorylation decreased in CYH33-sensitive, but not in CYH33-resistant cells, which was consistent with G1 phase arrest in sensitive cells. Combined treatment with the CDK4/6 inhibitor, PD0332991, and CYH33 displayed synergistic activity against the proliferation of both CYH33-sensitive and CYH33-resistant cells, which was accompanied by enhanced G1-phase arrest. Moreover, down-regulation of cyclin D1 sensitized NSCLC cells to CYH33. Reciprocally, CYH33 abrogated the PD0332991-induced up-regulation of cyclin D1 and phosphorylation of AKT in A549 cells. Co-treatment with these two drugs demonstrated synergistic activity against A549 and H23 xenografts, with enhanced inhibition of Rb phosphorylation. CONCLUSIONS: Simultaneous inhibition of PI3Kα and CDK4/6 displayed synergistic activity against KRAS-mutated NSCLC. These data provide a mechanistic rationale for the combination of a PI3Kα inhibitor and a CDK4/6 inhibitor for the treatment of KRAS-mutated NSCLC.

Impact of thyroid nodule sizes on the diagnostic performance of Korean thyroid imaging reporting and data system and contrast-enhanced ultrasound.

OBJECTIVE: This study aimed to evaluate the impact of thyroid nodule sizes on the diagnostic performance of Korean thyroid imaging reporting and data system (TIRADS) and contrast-enhanced ultrasound (CEUS). METHODS: In total, 308 consecutive patients with 382 thyroid nodules underwent US-guided FNA or surgery were included in this retrospective study. The nodule size was classified into 3 categories: ≤10 mm (group A), 10-20 mm (group B), and ≥20 mm (group C). We compared the risk of malignancy in each subgroup, categorized according to the TIRADS and CEUS patterns. RESULTS: In group A, the differences in diagnostic value between TIRADS and CEUS were significant (AUC: 0.804 vs 0.733, P = 0.028, sensitivity: 81.8% vs 72.7%, P = 0.013, specificity: 88.9% vs 79.4%, P = 0.011). In group B, the AUC (0.897), sensitivity (88.1%) and specificity (91.9%) of CEUS were highest. In group C, the specificity of CEUS was significantly higher compared with TIRADS classification (90.8% vs 82.9%, P = 0.023), while the sensitivity and AUC showed no significant difference between the two models (84.2% vs 81.5%, P > 0.406, 0.848 vs 0.820, P = 0.545). CONCLUSIONS: Nodule size influences the diagnostic accuracy of the two methods. TIRADS have best value in nodules ≤10 mm, while CEUS perform best for differentiating lesions >10 mm, especially in lesions ≥20 mm.