Effective Prevention and Treatment of Acute Leukemias in Mice by Activation of Thermogenic Adipose Tissues.

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are common hematological malignancies in adults. Despite considerable research advances, the development of standard therapies, supportive care, and prognosis for the majority of AML and ALL patients remains poor and the development of new effective therapy is urgently needed. Here, it is reported that activation of thermogenic adipose tissues (TATs) by cold exposure or ß3-adrenergic receptor agonists markedly alleviated the development and progression of AML and ALL in mouse leukemia models. TAT activation (TATA) monotherapy substantially reduces leukemic cells in bone marrow and peripheral blood, and suppresses leukemic cell invasion, including hepatomegaly and splenomegaly. Notably, TATA therapy prolongs the survivals of AML- and ALL-bearing mice. Surgical removal of thermogenic brown adipose tissue (BAT) or genetic deletion of uncoupling protein 1 (UCP1) largely abolishes the TATA-mediated anti-leukemia effects. Metabolomic pathway analysis demonstrates that glycolytic metabolism, which is essential for anabolic leukemic cell growth, is severely impaired in TATA-treated leukemic cells. Moreover, a combination of TATA therapy with chemotherapy produces enhanced anti-leukemic effects and reduces chemotoxicity. These data provide a new TATA-based therapeutic paradigm for the effective treatment of AML, ALL, and likely other types of hematological malignancies.

Desflurane improves electrical activity of neurons and alleviates oxygen-glucose deprivation-induced neuronal injury by activating the Kcna1-dependent Kv1.1 channel.

Several volatile anesthetics have presented neuroprotective functions in ischemic injury. This study investigates the effect of desflurane (Des) on neurons following oxygen-glucose deprivation (OGD) challenge and explores the underpinning mechanism. Mouse neurons HT22 were subjected to OGD, which significantly reduced cell viability, increased lactate dehydrogenase release, and promoted cell apoptosis. In addition, the OGD condition increased oxidative stress in HT22 cells, as manifested by increased ROS and MDA contents, decreased SOD activity and GSH/GSSG ratio, and reduced nuclear protein level of Nrf2. Notably, the oxidative stress and neuronal apoptosis were substantially blocked by Des treatment. Bioinformatics suggested potassium voltage-gated channel subfamily A member 1 (Kcna1) as a target of Des. Indeed, the Kcna1 expression in HT22 cells was decreased by OGD but restored by Des treatment. Artificial knockdown of Kcna1 negated the neuroprotective effects of Des. By upregulating Kcna1, Des activated the Kv1.1 channel, therefore enhancing K+ currents and inducing neuronal repolarization. Pharmacological inhibition of the Kv1.1 channel reversed the protective effects of Des against OGD-induced injury. Collectively, this study demonstrates that Des improves electrical activity of neurons and alleviates OGD-induced neuronal injury by activating the Kcna1-dependent Kv1.1 channel.

Development of a combined model incorporating clinical characteristics and magnetic resonance imaging features to enhance the predictive value of a prognostic model for locally advanced cervical cancer.

Objective: This study aimed to develop non-invasive predictive tools based on clinical characteristics and magnetic resonance imaging (MRI) features to predict survival in patients with locally advanced cervical cancer (LACC), thereby facilitating clinical decision-making. Methods: We conducted a retrospective analysis of clinical and MRI data from LACC patients who underwent radical radiotherapy at our center between September 2012 and May 2020. Prognostic predictors were identified using single-factor and multifactor Cox analyses. Clinical and MRI models were established based on relevant features, and combined models were created by incorporating MRI factors into the clinical model. The predictive performance of the models was evaluated using the area under the curve (AUC), consistency index (C-index), and decision curve analysis (DCA). Results: The study included 175 LACC patients. Multivariate Cox analysis revealed that patients with FIGO IIA-IIB stage, ECOG score 0-1, CYFRA 21-1<7.7 ng/ml, ADC ≥ 0.79 mm^2/s, and Kep ≥ 4.23 minutes had a more favorable survival prognosis. The clinical models, incorporating ECOG, FIGO staging, and CYFRA21-1, outperformed individual prognostic factors in predicting 5-year overall survival (AUC: 0.803) and 5-year progression-free survival (AUC: 0.807). The addition of MRI factors to the clinical model (AUC: 0.803 for 5-year overall survival) increased the AUC of the combined model to 0.858 (P=0.011). Similarly, the combined model demonstrated a superior predictive ability for 5-year progression-free survival, with an AUC of 0.849, compared to the clinical model (AUC: 0.807) and the MRI model (AUC: 0.673). Furthermore, the C-index of the clinical models for overall survival and progression-free survival were 0.763 and 0.800, respectively. Upon incorporating MRI factors, the C-index of the combined model increased to 0.826 for overall survival and 0.843 for progression-free survival. The DCA further supported the superior prognostic performance of the combined model. Conclusion: Our findings indicate that ECOG, FIGO staging, and CYFRA21-1 in clinical characteristics, as well as ADC and Kep values in MRI features, are independent prognostic factors for LACC patients undergoing radical radiotherapy. The combined models provide enhanced predictive ability in assessing the risk of patient mortality and disease progression.

Incorporation of PET Metabolic Parameters With Clinical Features Into a Predictive Model for Radiotherapy-Related Esophageal Fistula in Esophageal Squamous Cell Carcinoma.

Purpose: To determine whether the addition of metabolic parameters from fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scans to clinical factors could improve risk prediction models for radiotherapy-related esophageal fistula (EF) in esophageal squamous cell carcinoma (ESCC). Methods and Materials: Anonymized data from 185 ESCC patients (20 radiotherapy-related EF-positive cases) were collected, including pre-therapy PET/CT scans and EF status. In total, 29 clinical features and 15 metabolic parameters from PET/CT were included in the analysis, and a least absolute shrinkage and selection operator logistic regression model was used to construct a risk score (RS) system. The predictive capabilities of the models were compared using receiver operating characteristic (ROC) curves. Results: In univariate analysis, metabolic tumor volume (MTV)_40% was a risk factor for radiotherapy (RT)-related EF, with an odds ratio (OR) of 1.036 [95% confidence interval (CI): 1.009-1.063, p = 0.007]. However, it was excluded from the predictive model using multivariate logistic regression. Predictive models were built based on the clinical features in the training cohort. The model included diabetes, tumor length and thickness, adjuvant chemotherapy, eosinophil count, and monocyte-to-lymphocyte ratio. The RS was defined as follows: 0.2832 - (7.1369 × diabetes) + (1.4304 × tumor length) + (2.1409 × tumor thickness) - [8.3967 × adjuvant chemotherapy (ACT)] - (28.7671 × eosinophils) + (8.2213 × MLR). The cutoff of RS was set at -1.415, with an area under the curve (AUC) of 0.977 (95% CI: 0.9536-1), a specificity of 0.929, and a sensitivity of 1. Analysis in the testing cohort showed a lower AUC of 0.795 (95% CI: 0.577-1), a specificity of 0.925, and a sensitivity of 0.714. Delong's test for two correlated ROC curves showed no significant difference between the training and testing sets (p = 0.109). Conclusions: MTV_40% was a risk factor for RT-related EF in univariate analysis and was screened out using multivariate logistic regression. A model with clinical features can predict RT-related EF.

Determination of veterinary drug/pesticide residues in livestock and poultry excrement using selective accelerated solvent extraction and magnetic material purification combined with ultra-high-performance liquid chromatography-tandem mass spectrometry.

An ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method based on selective accelerated solvent extraction and magnetic material purification was established to analyze the residues of various veterinary antibiotics and agricultural fungicides and insecticides in livestock and poultry excrement. Methanol-acetonitrile (4:1, V/V) was used as the extraction solvent and static extraction was conducted three times in 5 min. Preliminary purification was achieved by adding 0.5 g acidic alumina-florisil (1:1, W/W) to the extraction cell while the extraction was conducted. This preliminarily-purified extract was further purified using magnetic material, then analyzed using UPLC-MS/MS. Under optimal conditions, 33 types of antibiotics, including 3 amphenicols, 8 macrolides, 17 sulfonamides and 5 nitroimidazoles, as well as 37 types of pesticides, including 27 insecticides and 10 fungicides, were detected. Recoveries ranged from 60.3% to 110.0% at three spiked concentrations (10 µg/kg, 20 µg/kg and 50 µg/kg), the detection limits ranged from 0.2 to 3.5 µg/kg and the quantitative limits ranged from 0.5 to 11.5 µg/kg. This newly-established method was tested using 30 livestock and poultry excrement samples and confirmed its use for determining veterinary drugs and pesticides in practical samples.

FSTL1 suppresses tumor cell proliferation, invasion and survival in non-small cell lung cancer.

Follistatin like-1 (FSTL1) is a secreted glycoprotein involved in a series of physiological and pathological processes. However, its contribution to the development of cancer, especially the pathogenesis of NSCLC, remains to be elucidated. We explored the expression, function, and molecular mechanism of FSTL1 in NSCLC. In this study, we detected the expression of FSTL1 in a panel of NSCLC cell lines and lung normal epithelial cell line by qRT-PCR and western blot analysis and found that FSTL1 was downregulated in NSCLC cells compared with normal control. Knockdown of FSTL1 with different shRNA sequences result in increased cell proliferation and cell migration, invasion and reduced cell apoptosis in A549 cell line with high FSTL1 endogenous level. FSTL1 overexpression in H446 cell line with low FSTL1 endogenous level suppressed cell proliferation and migration, invasion and increased cell apoptosis. Knockdown and overexpression of FSTL1 caused altered cell cycle. Reduced cell apoptosis was revealed in FSTL1 knockdown cells accompanied by increased FAS expression and decreased FASL, cleaved caspase­3 and ­7 expression. By contrast, overexpression of FSTL1 caused reduced FAS level and increased activated caspase­3 and ­7 expression, which may lead to increased cell apoptosis. Moreover, the changed migration and invasion ability in FSTL1 sufficient or deficient cells may be caused by alterations in MMP2, MMP3 and MMP9 expression. Altogether, our results revealed the critical tumor-suppression function of FSTL1 in NSCLC progression, suggesting that FSTL1 might be an important factor in NSCLC progression.

FZUImageReg: A toolbox for medical image registration and dose fusion in cervical cancer radiotherapy.

The combination external-beam radiotherapy and high-dose-rate brachytherapy is a standard form of treatment for patients with locally advanced uterine cervical cancer. Personalized radiotherapy in cervical cancer requires efficient and accurate dose planning and assessment across these types of treatment. To achieve radiation dose assessment, accurate mapping of the dose distribution from HDR-BT onto EBRT is extremely important. However, few systems can achieve robust dose fusion and determine the accumulated dose distribution during the entire course of treatment. We have therefore developed a toolbox (FZUImageReg), which is a user-friendly dose fusion system based on hybrid image registration for radiation dose assessment in cervical cancer radiotherapy. The main part of the software consists of a collection of medical image registration algorithms and a modular design with a user-friendly interface, which allows users to quickly configure, test, monitor, and compare different registration methods for a specific application. Owing to the large deformation, the direct application of conventional state-of-the-art image registration methods is not sufficient for the accurate alignment of EBRT and HDR-BT images. To solve this problem, a multi-phase non-rigid registration method using local landmark-based free-form deformation is proposed for locally large deformation between EBRT and HDR-BT images, followed by intensity-based free-form deformation. With the transformation, the software also provides a dose mapping function according to the deformation field. The total dose distribution during the entire course of treatment can then be presented. Experimental results clearly show that the proposed system can achieve accurate registration between EBRT and HDR-BT images and provide radiation dose warping and fusion results for dose assessment in cervical cancer radiotherapy in terms of high accuracy and efficiency.

Early changes of volume and spatial location in target and normal tissues caused by IMRT for cervical cancer.

AIMS: To investigate the early changes of volume and spatial location in target and normal tissues caused by intensity-modulated radiotherapy (IMRT) for cervical cancer. METHODS: Forty patients with cervical cancer were included in this study and treated by IMRT. Computed tomography (CT) was performed before radiotherapy and when the patient had received 27 Gy in 15 fractions. After image registration, the volume of interest (VOI) for the targets and organs at risk was delineated by clinicians on the CT images. Changes of volume, spatial location and Dice similarity were calculated for all VOIs. RESULTS: There were significant changes in gross tumor volume (GTV) in the primary tumor (GTV-T) with t = 8.304 (p<0.01) and visible pelvic lymph nodes (GTV-N) with t = 4.996 (p<0.01) caused by IMRT. The mean volume differences for GTV-T and GTV-N were 38.64% ± 19.50% (range 3.16%-86.49%) and 42.49% ± 25.68% (range 2.79%-87.42%), respectively. Among the organs at risk, the bladder had the greatest volume change with 55.13% ± 33.40% (range 3.25%-116.01%). The Dice similarity for GTV-T and GTV-N was 0.50 ± 0.18 (range 0.10-0.85) and 0.31 ± 0.20 (range 0.00-0.71), respectively. The rectum had the least Dice similarity among the normal tissues, with a mean value of 0.57 ± 0.14 (range 0.18-0.76). CONCLUSIONS: There were significant changes in volume and spatial location of the target and normal tissues after 27 Gy IMRT. In order to maintain the radiation dose to the targets and minimize the radiation to normal tissues, it is necessary to modify the radiotherapy planning.

Diffusion-weighted magnetic resonance imaging in predicting the radiosensitivity of cervical cancer.

This study investigates the application value of diffusion-weighted magnetic resonance imaging in predicting cervical cancer radiosensitivity. Twenty-five patients who were newly diagnosed as cervical cancer and accepted simple radiotherapy were included in this study. Before external irradiation, 20 GY and at the end of irradiation, routine 1.5 T MRI and diffusion-weighted magnetic resonance imaging scanning were carried. Apparent diffusion coefficient (ADC) value of primary tumor was measured. Its correlation with tumor regression rate was analyzed. ADC values of before irradiation, 20 GY and at the end of irradiation was (0.93 ± 0.14) × 10(-3) mm(2)/s, (1.25 ± 0.17) × 10(-3) mm(2)/s and (1.55 ± 0.13) × 10(-3) mm(2)/s, respectively. There were statistical significant differences (P< 0.01). D-value of ADC values between before and 20 GY external irradiation was (0.33 ± 0.16) mm(2)/s. The tumor volume before and at the end of external irradiation were (37.48 ± 26.83) cm(3) and (4.41 ± 3.72) cm(3) respectively, with tumor regression rate of before and after external irradiation of (0.86 ± 0.11). ADC values of before irradiation, 20 GY and at the end of irradiation did not correlate with tumor regression rate. D-value of ADC values between before and 20 GY external irradiation positively correlated with tumor regression rate (r = 0.423, P = 0.035). ADC value of cervical cancer increased after radiotherapy and early changes of ADC value was positively correlated with tumor regression rate, thus, ADC value could be used as a potential prediction factor for cervical cancer radiosensitivity.

Factors associated with overall survival in 1706 patients with nasopharyngeal carcinoma: significance of intensive neoadjuvant chemotherapy and radiation break.

BACKGROUND AND PURPOSE: To exam factors associated with overall survival (OS) in patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: This study is a retrospective study of a total of 1706 consecutive NPC patients from a single institution between January 1995 and December 1998. One thousand eighty-one patients were treated with radiotherapy (RT) alone and 625 with an intensive course of neoadjuvant chemotherapy followed by RT. Patient, tumor and treatment factors were analyzed for their significance on 5-year overall survival (OS). RESULTS: Younger age, female gender, absence of anemia pre-RT, early tumor stage, interruption of RT, and neoadjuvant chemotherapy were significantly associated with survival under multivariate analysis (all P<0.05). The 5-year OS rates were 100%, 75.9% (95%CI 71.6-80.2%), 66.5% (95%CI 62.8-70.2%), and 49.3% (95%CI 45.0-53.6%) for stage I, II, III, and IV (P<0.05); 68.9% (95%CI 66.2-71.5%) and 63.7% (95%CI 61.5-65.8%), for patients treated with or without neoadjuvant chemotherapy (P=0.0051), and 51.7% (95%CI 45.0-58.4%) and 69.5% (95%CI 67.2-71.7%) for patients with or without treatment break (P<0.0001), respectively. CONCLUSION: Intensive neoadjuvant chemotherapy and absence of radiation break seem to be favorable factors associated with long-term survival in patients with NPC.