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1.
Int Urogynecol J ; 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35013757

RESUMO

INTRODUCTION AND HYPOTHESIS: The aim of this study was to investigate the relationship between compression effect exerted by the sling on the urethra using translabial ultrasound and the prognosis of sling surgery in women for stress urinary incontinence (SUI). METHODS: We retrospectively reviewed 151 women with SUI who had undergone either a TVT-Abbrevo (n = 81) or TVT-O (n = 70) procedure. Preoperative and 12-month postoperative assessments including sonographic data, urinary symptoms and signs were compared. Objective and subjective success rates were assessed at 12 months postoperatively. RESULTS: Overall, 140 patients (92.7%) were objectively cured and 138 patients (91.4%) were subjectively cured of SUI 12 months after the operation with no significant differences between groups (p > 0.05). After both the TVT-Abbrevo and TVT-O procedures, the shortest distance between the tape and the urethral cavity line (TU) on straining (objective cure 4.1 mm vs. 4.5 mm, subjective cure 4.1 mm vs. 4.4 mm), the changes of the angle (∆) between the two arms of the sling (objective cure 15.8° vs. 20.8°, subjective cure 16.5° vs. 21.3°) and the gap between the sling and symphysis pubis (objective cure 9.9 mm vs. 12.1 mm, subjective cure 9.8 mm vs. 12.4 mm) were significantly smaller in the success group (p < 0.05). Analysis of ultrasound measurements in women reporting success and those reporting failure of the procedure showed the ∆TU (objective cure 1.6 mm vs. 0.9 mm, subjective cure 1.6 mm vs. 1.0 mm) and the angle on straining (objective cure 93.4° vs. 89.2°, subjective cure 94.3° vs. 88.9°) to be significantly bigger (p < 0.05). However, none of the assessed sonographic variables showed any significant differences between the TVT-Abbrevo and TVT-O groups. CONCLUSIONS: The change in distance between the tape and urethral cavity line in the center of the urethra in the mid-sagittal plane after straining is an effective indicator of the compression effect exerted by the sling on the urethra after a mid-urethral sling (MUS) procedure and may contribute to both objective and subjective cure rates postoperatively.

2.
BMC Endocr Disord ; 22(1): 12, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34986823

RESUMO

BACKGROUND: Whether Hashimoto's thyroiditis (HT) affects the lymph node metastasis of papillary thyroid carcinoma (PTC) remains uncertain. The diagnostic criteria for HT differed in previous studies. Our study focused on analysing the influence of HT on PTC lymph node metastasis (LNM) with stringent diagnostic criteria for HT. METHODS: A total of 444 patients diagnosed with PTC from 2019 to 2020 were enrolled and divided into two groups: HT group and non-HT group. Diagnostic criteria of HT were as follows: thyroid peroxidase antibody (+) and postoperative histopathology of Hashimoto's disease. RESULTS: There was no significant difference in the LNM rate between HT group and non-HT group. Patients in the HT group had fewer numbers of metastatic LNs and lower metastatic LNs ratio in central region. In the HT group, age < 55 and tumor size ≥10 mm were independent risk factors for central LNM. CONCLUSION: The autoimmune response of HT seems to reduce the central lymph node metastasis of HT PTCs. Age < 55 and tumor size ≥10 mm were independent risk factors of central lymph node metastasis in HT PTCs.

3.
Toxicol Appl Pharmacol ; 435: 115834, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34933054

RESUMO

Kinesin family member 23 (KIF23) has been described as one of the main genes that are associated with malignant transformation in numerous cancers. However, the exact significance of KIF23 in breast cancer has not been well-addressed. The present study was dedicated to the comprehensive investigation of KIF23 in breast cancer. Initial expression analysis through The Cancer Genome Atlas (TCGA) demonstrated high KIF23 levels in breast cancer compared with normal controls. These in silico data showing high levels of KIF23 in breast cancer were verified by assessing clinical specimens using real-time quantitative PCR and immunoblot assays. Moreover, a high KIF23 level was correlated with adverse clinical outcomes in breast cancer patients. Cellular functional experiments showed that the down-regulation of KIF23 affected the malignant behaviors of breast cancer cells in vitro, whereas the forced expression of KIF23 stimulated them. Mechanistic studies revealed that KIF23 restraint down-regulated the levels of phosphorylated glycogen synthetase kinase-3ß (GSK-3ß), ß-catenin, cyclin D1 and c-myc in breast cancer cells, showing an inhibitory effect on the Wnt/ß-catenin pathway. The suppression of GSK-3ß was able to reverse KIF23-silencing-induced inactivation of the Wnt/ß-catenin pathway. Inhibition of the Wnt/ß-catenin pathway abolished KIF23 overexpression-mediated protumor effects in breast cancer. A xenograft assay confirmed the in vivo antitumor function of KIF23 inhibition. In conclusion, these findings suggest that KIF23 may exert a protumor function in breast cancer by stimulating the Wnt/ß-catenin pathway. This work suggests that KIF23 has potential values for targeted therapy and prognosis in breast cancer.

4.
Int J Mol Med ; 49(2)2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34935058

RESUMO

Ferroptosis has been previously implicated in the pathological progression of cardiomyopathy. Herceptin (trastuzumab), which targets HER2, is commonly applied for the treatment of HER2+ breast cancer. However, its clinical use is limited by its cardiotoxicity. Therefore, the present study aimed to investigate if targeting ferroptosis could protect against Herceptin­induced heart failure in an in vitro model of H9c2 cells after treatment of Herceptin, Herceptin + ferroptosis inhibitor ferrostatin­1 (Fer­1) or Herceptin + Deferoxamine. H9c2 cell viability was measured by MTT assay. Reactive oxygen species (ROS) levels were detected by measuring the fluorescence of DCFH­DA­A and MitoSOX™ Red. Glutathione (GSH)/oxidized glutathione (GSSG) ratio was measured using the GSH/GSSG Ratio Detection Assay kit. Mitochondrial membrane potential and ATP content were evaluated by JC­1 staining and bioluminescent assay kits, respectively. Protein expressions of glutathione peroxidase 4, recombinant solute carrier family 7 member 11, mitochondrial optic atrophy1­1/2, mitofusin, Acyl­CoA synthetase long chain family member 4, cytochrome c, voltage­dependent anion­selective channel, dynamin­related protein, mitochondrial fission 1 protein and mitochondrial ferritin were evaluated by western blotting. It was found that Herceptin reduced H9c2 cell viability whilst increasing intracellular and mitochondrial ROS levels in a dose­ and time­dependent manner. Furthermore, Herceptin decreased glutathione peroxidase (GPX) protein expression and the GSH/ GSSG ratio in H9c2 cells in a dose­ and time­dependent manner. The Fer­1 abolished this Herceptin­induced reduction in cell viability, GSH/GSSG ratio, mitochondrial membrane potential and ATP content. Fer­1 also reversed the suppressive effects of Herceptin on the protein expression levels of GPX4, recombinant solute carrier family 7 member 11, mitochondrial optic atrophy1­1/2 and mitofusin in H9c2 cells. Subsequently, Fer­1 was found to reverse the Herceptin­induced increase in mitochondrial ROS and iron levels in H9c2 cells, as well as the increased protein expression levels of Acyl­CoA synthetase long chain family member 4, cytochrome c, voltage­dependent anion­selective channel, dynamin­related protein, mitochondrial fission 1 protein and mitochondrial ferritin in H9c2 cells. However, compared with deferoxamine, an iron chelator, the effects of Fer­1 were less effective. Collectively, these findings provided insights into the pathogenic mechanism that underlie Herceptin­induced cardiomyopathy, which potentially provides a novel therapeutic target for the prevention of cardiotoxicity in HER2+ breast cancer treatment.

6.
IEEE Trans Med Imaging ; PP2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34855590

RESUMO

Accurate and robust segmentation of lung cancers from CT, even those located close to mediastinum, is needed to more accurately plan and deliver radiotherapy and to measure treatment response. Therefore, we developed a new cross-modality educed distillation (CMEDL) approach, using unpaired CT and MRI scans, whereby an informative teacher MRI network guides a student CT network to extract features that signal the difference between foreground and background. Our contribution eliminates two requirements of distillation methods: (i) paired image sets by using an image to image (I2I) translation and (ii) pre-training of the teacher network with a large training set by using concurrent training of all networks. Our framework uses an end-to-end trained unpaired I2I translation, teacher, and student segmentation networks. Architectural flexibility of our framework is demonstrated using 3 segmentation and 2 I2I networks. Networks were trained with 377 CT and 82 T2w MRI from different sets of patients, with independent validation (N=209 tumors) and testing (N=609 tumors) datasets. Network design, methods to combine MRI with CT information, distillation learning under informative (MRI to CT), weak (CT to MRI) and equal teacher (MRI to MRI), and ablation tests were performed. Accuracy was measured using Dice similarity (DSC), surface Dice (sDSC), and Hausdorff distance at the 95th percentile (HD95). The CMEDL approach was significantly (p < 0.001) more accurate (DSC of 0.77 vs. 0.73) than non-CMEDL methods with an informative teacher for CT lung tumor, with a weak teacher (DSC of 0.84 vs. 0.81) for MRI lung tumor, and with equal teacher (DSC of 0.90 vs. 0.88) for MRI multi-organ segmentation. CMEDL also reduced inter-rater lung tumor segmentation variabilities.

7.
Shanghai Kou Qiang Yi Xue ; 30(5): 548-550, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34888612

RESUMO

PURPOSE: To compare the effect of dexmedetomidine (Dex) and esmolol on controlled hypotension in patients with orthognathic surgery. METHODS: From January 2017 to December 2019, a total of 109 patients were treated with Dex (group D) and esmolol (group E) during orthognathic surgery (Le Fort I osteotomy of maxilla and sagittal split of mandibular ramus) in our hospital. Heart rate(HR) and mean arterial pressure(MAP) during controlled hypotension (the difference between the highest and lowest values and the percentage of basic values), intraoperative blood loss, allogeneic blood transfusion, operation time and dosage of propofol and remifentanil were compared between the two groups. The data were statistically analyzed using SPSS 22.0 software package. RESULTS: Compared with group E, HR and MAP, dose of propofol and remifentanil in group D were significantly lower than those in group E (P<0.05). There was no significant difference among other indexes. CONCLUSIONS: Compared with esmolol, the effect of Dex on controlled hypotension during orthognathic surgery is more stable and the dosage of propofol and remifentanil is decreased.

8.
Phys Med Biol ; 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34874302

RESUMO

ObjectiveDelineating swallowing and chewing structures aids in radiotherapy (RT) treatment planning to limit dysphagia, trismus, and speech dysfunction. We aim to develop an accurate and efficient method to automate this process.ApproachCT scans of 242 head and neck (H&N) cancer patients acquired from 2004-2009 at our institution were used to develop auto-segmentation models for the masseters, medial pterygoids, larynx, and pharyngeal constrictor muscle using DeepLabV3+. A cascaded architecture was used, wherein models were trained sequentially to spatially constrain each structure group based on prior segmentations. Additionally, an ensemble of models, combining contextual information from axial, coronal, and sagittal views was used to improve segmentation accuracy. Prospective evaluation was conducted by measuring the amount of manual editing required in 91 H&N CT scans acquired February-May 2021.Main resultsMedians and inter-quartile ranges of Dice Similarity Coefficients (DSC) computed on the retrospective testing set (N=24) were 0.87 (0.85-0.89) for the masseters, 0.80 (0.79- 0.81) for the medial pterygoids, 0.81 (0.79-0.84) for the larynx, and 0.69 (0.67-0.71) for the constrictor. Auto-segmentations, when compared to inter-observer variability in 10 randomly selected scans, showed better agreement (DSC) with each observer as compared to inter-observer DSC. Prospective analysis showed most manual modifications needed for clinical use were minor, suggesting auto-contouring could increase clinical efficiency. Trained segmentation models are available for research use upon request via https://github.com/cerr/CERR/wiki/Auto-Segmentation-models.SignificanceWe developed deep learning-based auto-segmentation models for swallowing and chewing structures in CT and demonstrated its potential for use in treatment planning to limit complications post-RT. To the best of our knowledge, this is the only prospectively-validated deep learning-based model for segmenting chewing and swallowing structures in CT. Additionally, the segmentation models have been made open-source to facilitate reproducibility and multi-institutional research.

9.
Phys Imaging Radiat Oncol ; 19: 96-101, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34746452

RESUMO

Background and Purpose: Reducing trismus in radiotherapy for head and neck cancer (HNC) is important. Automated deep learning (DL) segmentation and automated planning was used to introduce new and rarely segmented masticatory structures to study if trismus risk could be decreased. Materials and Methods: Auto-segmentation was based on purpose-built DL, and automated planning used our in-house system, ECHO. Treatment plans for ten HNC patients, treated with 2 Gy × 35 fractions, were optimized (ECHO0). Six manually segmented OARs were replaced with DL auto-segmentations and the plans re-optimized (ECHO1). In a third set of plans, mean doses for auto-segmented ipsilateral masseter and medial pterygoid (MIMean, MPIMean), derived from a trismus risk model, were implemented as dose-volume objectives (ECHO2). Clinical dose-volume criteria were compared between the two scenarios (ECHO0 vs. ECHO1; ECHO1 vs. ECHO2; Wilcoxon signed-rank test; significance: p < 0.01). Results: Small systematic differences were observed between the doses to the six auto-segmented OARs and their manual counterparts (median: ECHO1 = 6.2 (range: 0.4, 21) Gy vs. ECHO0 = 6.6 (range: 0.3, 22) Gy; p = 0.007), and the ECHO1 plans provided improved normal tissue sparing across a larger dose-volume range. Only in the ECHO2 plans, all patients fulfilled both MIMean and MPIMean criteria. The population median MIMean and MPIMean were considerably lower than those suggested by the trismus model (ECHO0: MIMean = 13 Gy vs. ≤42 Gy; MPIMean = 29 Gy vs. ≤68 Gy). Conclusions: Automated treatment planning can efficiently incorporate new structures from DL auto-segmentation, which results in trismus risk sparing without deteriorating treatment plan quality. Auto-planning and deep learning auto-segmentation together provide a powerful platform to further improve treatment planning.

10.
Oncogene ; 40(46): 6417-6429, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34601505

RESUMO

Tumor cells must rewire cellular metabolism to satisfy the demands of unbridled growth and proliferation. How these metabolic processes are integrated to fuel cancer cell growth remains largely unknown. Deciphering the regulatory mechanisms is vital to develop targeted strategies for tumor-selective therapies. We herein performed an unbiased and functional siRNA screen against 96 deubiquitinases, which play indispensable roles in cancer and are emerging as therapeutic targets, and identified USP29 as a top candidate essential for metabolic reprogramming that support biosynthesis and survival in tumor cells. Integrated metabolic flux analysis and molecular investigation reveal that USP29 directly deubiquitinates and stabilizes MYC and HIF1α, two master regulators of metabolic reprogramming, enabling adaptive response of tumor cells in both normoxia and hypoxia. Systemic knockout of Usp29 depleted MYC and HIF1α in MYC-driven neuroblastoma and B cell lymphoma, inhibited critical metabolic targets and significantly prolonged survival of tumor-bearing mice. Strikingly, mice homozygous null for the Usp29 gene are viable, fertile, and display no gross phenotypic abnormalities. Altogether, these results demonstrate that USP29 selectively coordinates MYC and HIF1α to integrate metabolic processes critical for cancer cell growth, and therapeutic targeting of USP29, a potentially targetable enzyme, could create a unique vulnerability given deregulation of MYC and HIF1α frequently occurs in human cancers.

11.
Eur Radiol ; 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34657970

RESUMO

OBJECTIVES: From the viewpoint of ultrasound (US) physicians, an ideal thyroid US computer-assisted diagnostic (CAD) system for thyroid cancer should perform well in suspicious thyroid nodules with atypical risk features and be able to output explainable results. This study aims to develop an explainable US CAD model for suspicious thyroid nodules. METHODS: A total of 2992 solid or almost-solid thyroid nodules were analyzed retrospectively. All nodules had pathological results (1070 malignancies and 1992 benignities) confirmed by ultrasound-guided fine-needle aspiration cytology and histopathology after thyroidectomy. A deep learning model (ResNet50) and a multiple risk features learning ensemble model (XGBoost) were used to train the US images of 2794 thyroid nodules. Then, an integrated AI model was generated by combining both models. The diagnostic accuracies of the three AI models (ResNet50, XGBoost, and the integrated model) were predicted in a testing set including 198 thyroid nodules and compared to the diagnostic efficacy of five ultrasonographers. RESULTS: The accuracy of the integrated model was 76.77%, while the mean accuracy of the ultrasonographers was 68.38%. Of the risk features, microcalcifications showed the highest contribution to the diagnosis of malignant nodules. CONCLUSIONS: The integrated AI model in our study can improve the diagnostic accuracy of suspicious thyroid nodules and output the known risk features simultaneously, thus aiding in training young ultrasonographers by linking the explainable results to their clinical experience and advancing the acceptance of AI diagnosis for thyroid cancer in clinical practice. KEY POINTS: • We developed an artificial intelligence (AI) diagnosis model based on both deep learning and multiple risk feature ensemble learning methods. • The AI diagnosis model showed higher diagnostic accuracy for suspicious thyroid nodules than ultrasonographers. • The AI diagnosis model showed partial explainability by outputting the known risk features, thus aiding young ultrasonic doctors in increasing the diagnostic level for thyroid cancer.

12.
Exp Ther Med ; 22(3): 1040, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34373726

RESUMO

The aim of the present study was to investigate the changes in cardiac function and myocardial damage in rats with cirrhosis. In addition, a secondary aim was to explore any potential changes in the expression levels of ß1-adrenergic (ß1) and muscarinic acetylcholine (M2) receptors . A cirrhotic cardiomyopathy (CCM) rat model was established by CCL4-oil solution for subcutaneous injection into the neck. Pathological changes in the liver and myocardial tissues were detecting by H&E staining and Masson trichrome staining. Furthermore, changes in the levels of myocardial enzymes lactate dehydrogenase (LDH), creatine kinase isoenzyme (CK-MB) and troponin in serum were measured by ELISA. The myocardial samples were homogenized and centrifuged. Subsequently, the supernatant was collected for detecting the expression of interleukins in myocardial tissue. Changes in the levels of inflammatory factors, IL-1, IL-2 and IL-6 both in the serum and myocardial tissue were determined by ELISA. Changes in echocardiographic measurements were evaluated using high-frequency ultrasound and the expression levels of ß1 and M2 receptors in myocardial tissues were determined by western blotting. The normal lobular structure in liver tissues was found to be disappeared 8 weeks after modeling, which was replaced by pseudolobules in the rats in the CCM group. In addition, the myocardial cells were observed to be swollen and disorderly arranged. Compared with those in the control group, the left ventricular end-systolic and end-diastolic dimensions, interventricular septal dimension and LAD in rats in the CCM8 group were found to be significantly increased. The levels of myocardial enzymes LDH, CK-MB and cardiac troponin in the serum were also revealed to be significantly increased in the CCM8 group. Additionally, the levels of IL-1 and IL-6 in both serum and myocardial tissues were significantly increased in rats in the CCM8 group. However, the levels of IL-2 in both serum and myocardial tissues were decreased, which were observed alongside reductions in myocardial ß1 and M2 receptor protein expression in the myocardial tissues. Taken together, these results indicate that inflammatory factors may be involved in mediating damage to the myocardium in rats with cirrhosis. During cirrhosis-induced cardiac dysfunction, there may exist a mechanism for downregulation of autonomic nerve system.

13.
Med Phys ; 48(9): 4784-4798, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34245602

RESUMO

PURPOSE: Radiotherapy presents unique challenges and clinical requirements for longitudinal tumor and organ-at-risk (OAR) prediction during treatment. The challenges include tumor inflammation/edema and radiation-induced changes in organ geometry, whereas the clinical requirements demand flexibility in input/output sequence timepoints to update the predictions on rolling basis and the grounding of all predictions in relationship to the pre-treatment imaging information for response and toxicity assessment in adaptive radiotherapy. METHODS: To deal with the aforementioned challenges and to comply with the clinical requirements, we present a novel 3D sequence-to-sequence model based on Convolution Long Short-Term Memory (ConvLSTM) that makes use of series of deformation vector fields (DVFs) between individual timepoints and reference pre-treatment/planning CTs to predict future anatomical deformations and changes in gross tumor volume as well as critical OARs. High-quality DVF training data are created by employing hyper-parameter optimization on the subset of the training data with DICE coefficient and mutual information metric. We validated our model on two radiotherapy datasets: a publicly available head-and-neck dataset (28 patients with manually contoured pre-, mid-, and post-treatment CTs), and an internal non-small cell lung cancer dataset (63 patients with manually contoured planning CT and 6 weekly CBCTs). RESULTS: The use of DVF representation and skip connections overcomes the blurring issue of ConvLSTM prediction with the traditional image representation. The mean and standard deviation of DICE for predictions of lung GTV at weeks 4, 5, and 6 were 0.83 ± 0.09, 0.82 ± 0.08, and 0.81 ± 0.10, respectively, and for post-treatment ipsilateral and contralateral parotids, were 0.81 ± 0.06 and 0.85 ± 0.02. CONCLUSION: We presented a novel DVF-based Seq2Seq model for medical images, leveraging the complete 3D imaging information of a relatively large longitudinal clinical dataset, to carry out longitudinal GTV/OAR predictions for anatomical changes in HN and lung radiotherapy patients, which has potential to improve RT outcomes.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Radioterapia de Intensidade Modulada , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/radioterapia , Órgãos em Risco , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador
14.
Cell Cycle ; 20(16): 1603-1616, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34313525

RESUMO

Piwi-interacting RNAs (piRNAs/piRs) are small non-coding RNAs that play important roles in stablizing genome through silencing transposable genetic elements. The piR-651 was reported to be dysregulated in several human solid cancer tissues, such as gastric and lung cancers. However, the role of piRNA-651 in carcinogenesis of breast cancer has not been defined. We found that piR-651 was highly expressed in breast cancer tissues and cell lines. Overexpression of piR-651 facilitated cell proliferation and invasion, restrained cell apoptosis and the percentage of arrested cells in G0/G1 phase, accompanied by upregulated expression of oncogenes (MDM2, CDK4 and Cyclin D1), whereas piR-651 downregulation showed the opposite effects. Additionally, piR-651 could promote phosphatase and tensin homolog (PTEN) methylation and its downregulated expression by recruiting DNA methyltransferase 1 (DNMT1) to the PTEN promoter region through complex formation with PIWIL2. PTEN overexpression reversed the effects of upregulated piR-651 on cell functions. This study reveals that piR-651 promotes proliferation and migration and induces apoptosis of breast cancer cells by facilitating DNMT1-mediated PTEN promoter methylation, which may provide a potential therapeutic mechanism for breast cancer.

15.
Biofactors ; 47(5): 754-767, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34058791

RESUMO

Kinesin family member 18B (KIF18B) is a new tumor-associated protein that contributes to the carcinogenesis of multiple malignancies. However, the detailed relevance of KIF18B in breast cancer has not been fully elucidated. This work aimed was to evaluate a possible relationship between KIF18B and breast cancer progression. Our findings show KIF18B is increased in breast cancer and demonstrate that high KIF18B level predicts a reduced survival rate. Cellular functional studies revealed that knockdown of KIF18B markedly reduces the proliferation, invasion, and epithelial-mesenchymal transition of breast cancer cells and enhances their chemosensitivity toward doxorubicin. Further studies showed that KIF18B modulates the level of phospho-Akt, phospho-glycogen synthase kinase-3ß, and ß-catenin. Notably, suppression of Akt abolished KIF18B-overexpression-induced increases in activation of Wnt/ß-catenin pathway. In addition, re-expression of ß-catenin reversed KIF18B-silencing-induced cancer-promoting effect. In vivo animal experiments elucidated that knockdown of KIF18B significantly weakened the tumorigenicity of breast cancer cells. Taken together, data of this study illustrate that KIF18B exerts a potential cancer-promoting function in breast cancer via enhancement of Wnt/ß-catenin pathway through modulation of the Akt/GSK-3ß axis.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33886467

RESUMO

Ultrasound sound-speed tomography (USST) has shown great prospects for breast cancer diagnosis due to its advantages of nonradiation, low cost, 3-D breast images, and quantitative indicators. However, the reconstruction quality of USST is highly dependent on the first-arrival picking of the transmission wave. Traditional first-arrival picking methods have low accuracy and noise robustness. To improve the accuracy and robustness, we introduced a self-attention mechanism into the bidirectional long short-term memory (BLSTM) network and proposed the self-attention BLSTM (SAT-BLSTM) network. The proposed method predicts the probability of the first-arrival time and selects the time with maximum probability. A numerical simulation and prototype experiment were conducted. In the numerical simulation, the proposed SAT-BLSTM showed the best results. For signal-to-noise ratios (SNRs) of 50, 30, and 15 dB, the mean absolute errors (MAEs) were 48, 49, and 76 ns, respectively. The BLSTM had the second-best results, with MAEs of 55, 56, and 85 ns, respectively. The MAEs of the Akaike information criterion (AIC) method were 57, 296, and 489 ns, respectively. In the prototype experiment, the MAEs of the SAT-BLSTM, the BLSTM, and the AIC were 94, 111, and 410 ns, respectively.


Assuntos
Aprendizado Profundo , Humanos , Razão Sinal-Ruído , Som , Tomografia Computadorizada por Raios X , Ultrassonografia
17.
Med Phys ; 48(7): 3702-3713, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33905558

RESUMO

PURPOSE: Despite the widespread availability of in-treatment room cone beam computed tomography (CBCT) imaging, due to the lack of reliable segmentation methods, CBCT is only used for gross set up corrections in lung radiotherapies. Accurate and reliable auto-segmentation tools could potentiate volumetric response assessment and geometry-guided adaptive radiation therapies. Therefore, we developed a new deep learning CBCT lung tumor segmentation method. METHODS: The key idea of our approach called cross-modality educed distillation (CMEDL) is to use magnetic resonance imaging (MRI) to guide a CBCT segmentation network training to extract more informative features during training. We accomplish this by training an end-to-end network comprised of unpaired domain adaptation (UDA) and cross-domain segmentation distillation networks (SDNs) using unpaired CBCT and MRI datasets. UDA approach uses CBCT and MRI that are not aligned and may arise from different sets of patients. The UDA network synthesizes pseudo MRI from CBCT images. The SDN consists of teacher MRI and student CBCT segmentation networks. Feature distillation regularizes the student network to extract CBCT features that match the statistical distribution of MRI features extracted by the teacher network and obtain better differentiation of tumor from background. The UDA network was implemented with a cycleGAN improved with contextual losses separately on Unet and dense fully convolutional segmentation networks (DenseFCN). Performance comparisons were done against CBCT only using 2D and 3D networks. We also compared against an alternative framework that used UDA with MR segmentation network, whereby segmentation was done on the synthesized pseudo MRI representation. All networks were trained with 216 weekly CBCTs and 82 T2-weighted turbo spin echo MRI acquired from different patient cohorts. Validation was done on 20 weekly CBCTs from patients not used in training. Independent testing was done on 38 weekly CBCTs from patients not used in training or validation. Segmentation accuracy was measured using surface Dice similarity coefficient (SDSC) and Hausdroff distance at 95th percentile (HD95) metrics. RESULTS: The CMEDL approach significantly improved (p < 0.001) the accuracy of both Unet (SDSC of 0.83 ± 0.08; HD95 of 7.69 ± 7.86 mm) and DenseFCN (SDSC of 0.75 ± 0.13; HD95 of 11.42 ± 9.87 mm) over CBCT only 2DUnet (SDSC of 0.69 ± 0.11; HD95 of 21.70 ± 16.34 mm), 3D Unet (SDSC of 0.72 ± 0.20; HD95 15.01 ± 12.98 mm), and DenseFCN (SDSC of 0.66 ± 0.15; HD95 of 22.15 ± 17.19 mm) networks. The alternate framework using UDA with the MRI network was also more accurate than the CBCT only methods but less accurate the CMEDL approach. CONCLUSIONS: Our results demonstrate feasibility of the introduced CMEDL approach to produce reasonably accurate lung cancer segmentation from CBCT images. Further validation on larger datasets is necessary for clinical translation.


Assuntos
Aprendizado Profundo , Neoplasias Pulmonares , Tomografia Computadorizada de Feixe Cônico , Humanos , Processamento de Imagem Assistida por Computador , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/radioterapia , Imageamento por Ressonância Magnética
19.
Haematologica ; 106(7): 1816-1827, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31919076

RESUMO

T-cell acute lymphoblastic leukemias (T-ALLs) are aggressive and heterogeneous hematologic tumors resulting from the malignant transformation of T-cell progenitors. The major challenges in the treatments of T-ALL are dose-limiting toxicities of chemotherapeutics and drug resistance. Despite important progress in deciphering the genomic landscape of T-ALL, translation of these findings into effective targeted therapies remains largely unsuccessful. New targeted agents with significant antileukemic efficacy and less toxicity are in urgent need. We herein report that the expression of WEE1, a nuclear tyrosine kinase involved in cell cycle G2-M checkpoint signaling, is significantly elevated in T-ALL. Mechanistically, oncogenic MYC directly binds to the WEE1 promoter and activates its transcription. T-ALL cells particularly rely on the elevated WEE1 for cell viability. Pharmacological inhibition of WEE1 elicits global metabolic reprogramming which results in a marked suppression of aerobic glycolysis in T-ALL cells, leading to an increased dependency on glutaminolysis for cell survival. As such, dual targeting of WEE1 and glutaminase (GLS1) induces synergistic lethality in multiple T-ALL cell lines and shows great efficacy in T-ALL patient-derived xenografts. These findings provide mechanistic insights in the regulation of WEE1 kinase in T-ALL and suggest an additional vulnerability during WEE1 inhibitor treatments. In aggregate, we highlight a promising combination strategy of dual inhibition of cell cycle kinase and metabolic enzymes for T-ALL therapeutics.


Assuntos
Glutamina , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Apoptose , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Humanos , Proteínas Nucleares/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Tirosina Quinases/genética
20.
Carcinogenesis ; 42(3): 448-460, 2021 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-33206174

RESUMO

Deregulation of v-myc avian myelocytomatosis viral oncogene homolog (MYC) occurs in a broad range of human cancers and often predicts poor prognosis and resistance to therapy. However, directly targeting oncogenic MYC remains unsuccessful, and indirectly inhibiting MYC emerges as a promising approach. Checkpoint kinase 1 (CHK1) is a protein kinase that coordinates the G2/M cell cycle checkpoint and protects cancer cells from excessive replicative stress. Using c-MYC-mediated T-cell acute lymphoblastic leukemia (T-acute lymphoblastic leukemia) and N-MYC-driven neuroblastoma as model systems, we reveal that both c-MYC and N-MYC directly bind to the CHK1 locus and activate its transcription. CHIR-124, a selective CHK1 inhibitor, impairs cell viability and induces remarkable synergistic lethality with mTOR inhibitor rapamycin in MYC-overexpressing cells. Mechanistically, rapamycin inactivates carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), the essential enzyme for the first three steps of de novo pyrimidine synthesis, and deteriorates CHIR-124-induced replicative stress. We further demonstrate that dual treatments impede T-acute lymphoblastic leukemia and neuroblastoma progression in vivo. These results suggest simultaneous targeting of CHK1 and mTOR as a novel and powerful co-treatment modality for MYC-mediated tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Neuroblastoma/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/genética , Quinase 1 do Ponto de Checagem/metabolismo , Conjuntos de Dados como Assunto , Progressão da Doença , Sinergismo Farmacológico , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/genética , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Quinuclidinas/farmacologia , Quinuclidinas/uso terapêutico , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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