Metronomic chemotherapy in cancer treatment: new wine in an old bottle.

Over the past two decades, metronomic chemotherapy has gained considerable attention and has demonstrated remarkable success in the treatment of cancer. Through chronic administration and low-dose regimens, metronomic chemotherapy is associated with fewer adverse events but still effectively induces disease control. The identification of its antiangiogenic properties, direct impact on cancer cells, immunomodulatory effects on the tumour microenvironment, and metabolic reprogramming ability has established the intrinsic multitargeted nature of this therapeutic approach. Recently, the utilization of metronomic chemotherapy has evolved from salvage treatment for metastatic disease to adjuvant maintenance therapy for high-risk cancer patients, which has been prompted by the success of several substantial phase III trials. In this review, we delve into the mechanisms underlying the antitumour effects of metronomic chemotherapy and provide insights into potential combinations with other therapies for the treatment of various malignancies. Additionally, we discuss health-economic advantages and candidates for the utilization of this treatment option.

Spatiotemporal Dynamics of Neuroinflammation Relate to Behavioral Recovery in Rats with Spinal Cord Injury.

PURPOSE: The degree and dynamic progression of neuroinflammation after traumatic spinal cord injuries (SCI) are crucial determinants of the severity of injury and potential for recovery. We used Positron Emission Tomography (PET) to monitor neuroinflammation longitudinally, correlating it with Chemical Exchange Saturation Transfer (CEST) Magnetic Resonance Imaging (MRI) and behavior in contusion-injured rats. These studies help validate CEST metrics and confirm how imaging may be used to evaluate the efficacy of therapies and understand their mechanisms of action. PROCEDURES: 12 SCI and 4 sham surgery rats were subjected to CEST MRI and PET-Translocator Protein (TSPO) scans for 8 weeks following injury. Z-spectra from the SCI were analyzed using a 5-Lorentzian pool model for fitting. Weekly motor and somatosensory behavior were correlated with imaging metrics, which were validated through post-mortem histological and immuo-staining using ionized calcium-binding adaptor protein-1 (iba-1, microglia) and glial fibrillary acidic protein (GFAP, astrocytes). RESULTS: PET-TSPO showed widespread inflammation and post-mortem histology confirmed the presence of activated microglia. Changes in CEST and nuclear Overhauser Effect (NOE) peaks at 3.5 ppm and -1.6 ppm respectively were largest within the first week after injury and more pronounced in rostral versus caudal segments. These temporal indices of neuroinflammation corresponded to the recovery of locomotor behaviors and somatic sensation in rats with moderate contusion injury. The results confirm that CEST MRI metrics are sensitive indices of states of neuroinflammation within injured spinal cords. CONCLUSIONS: The detection of dynamic spatiotemporal features of neuroinflammation progression underscores the importance of considering their timings and locations for neuroprotective and anti-inflammatory therapies. The availability of noninvasive MRI indices of neuroinflammation may facilitate clinical trials aimed at treatments that promote recovery after SCI.

Transcriptional regulation of Glis2 in hepatic fibrosis.

The role of Gli-similar 2 (Glis2) in hepatic fibrosis (HF) is controversial. In this study, we focused on the functional and molecular mechanisms involved in the Glis2-mediated activation of hepatic stellate cells (HSCs)-a milestone event leading to HF. The expression levels of Glis2 mRNA and protein were significantly decreased in the liver tissues of patients with severe HF and in mouse fibrotic liver tissues as well as HSCs activated by TGFß1. Functional studies indicated that upregulated Glis2 significantly inhibited HSC activation and alleviated BDL-induced HF in mice. Downregulation of Glis2 was found to correlate significantly with DNA methylation of the Glis2 promoter mediated by methyltransferase 1 (DNMT1), which restricted the binding of hepatic nuclear factor 1-α (HNF1-α), a liver-specific transcription factor, to Glis2 promoters. In addition, the enrichment of DNMT1 in the Glis2 promoter region was mediated by metastasis-associated lung adenocarcinoma transcriptor-1 (MALAT1) lncRNA, leading to transcriptional silencing of Glis2 and activation of HSCs. In conclusion, our findings reveal that the upregulation of Glis2 can maintain the resting state of HSCs. The decreased expression of Glis2 under pathological conditions may lead to the occurrence and development of HF with the expression silencing of DNA methylation mediated by MALAT1 and DNMT1.

Longitudinal multiparametric MRI of traumatic spinal cord injury in animal models.

Multi-parametric MRI (mpMRI) technology enables non-invasive and quantitative assessments of the structural, molecular, and functional characteristics of various neurological diseases. Despite the recognized importance of studying spinal cord pathology, mpMRI applications in spinal cord research have been somewhat limited, partly due to technical challenges associated with spine imaging. However, advances in imaging techniques and improved image quality now allow longitudinal investigations of a comprehensive range of spinal cord pathological features by exploiting different endogenous MRI contrasts. This review summarizes the use of mpMRI techniques including blood oxygenation level-dependent (BOLD) functional MRI (fMRI), diffusion tensor imaging (DTI), quantitative magnetization transfer (qMT), and chemical exchange saturation transfer (CEST) MRI in monitoring different aspects of spinal cord pathology. These aspects include cyst formation and axonal disruption, demyelination and remyelination, changes in the excitability of spinal grey matter and the integrity of intrinsic functional circuits, and non-specific molecular changes associated with secondary injury and neuroinflammation. These approaches are illustrated with reference to a nonhuman primate (NHP) model of traumatic cervical spinal cord injuries (SCI). We highlight the benefits of using NHP SCI models to guide future studies of human spinal cord pathology, and demonstrate how mpMRI can capture distinctive features of spinal cord pathology that were previously inaccessible. Furthermore, the development of mechanism-based MRI biomarkers from mpMRI studies can provide clinically useful imaging indices for understanding the mechanisms by which injured spinal cords progress and repair. These biomarkers can assist in the diagnosis, prognosis, and evaluation of therapies for SCI patients, potentially leading to improved outcomes.

SNHG15 enhances cisplatin resistance in lung adenocarcinoma by affecting the DNA repair capacity of cancer cells.

BACKGROUND: Lung adenocarcinoma (LUAD) is a prevalent malignancy. SNHG15 has been demonstrated to be oncogenic in many kinds of cancers, however the mechanism of SNHG15 in LUAD cisplatin (DDP) resistance remains unclear. In this study, we demonstrated the effect of SNHG15 on DDP resistance in LUAD and its related mechanism. METHODS: Bioinformatics analysis was adopted to assess SNHG15 expression in LUAD tissues and predict the downstream genes of SNHG15. The binding relationship between SNHG15 and downstream regulatory genes was proved through RNA immunoprecipitation, chromatin immunoprecipitation and dual-luciferase reporter assays. Cell counting kit-8 assay was adopted to evaluate LUAD cell viability, and gene expression was determined by Western blot and quantitative real-time polymerase chain reaction. We then performed comet assay to assess DNA damage. Cell apoptosis was detected by Tunnel assay. Xenograft animal models were created to test the function of SNHG15 in vivo. RESULTS: SNHG15 was up-regulated in LUAD cells. Moreover, SNHG15 was also highly expressed in drug-resistant LUAD cells. Down-regulated SNHG15 strengthened the sensitivity of LUAD cells to DDP and induced DNA damage. SNHG15 could elevate ECE2 expression through binding with E2F1, and it could induce DDP resistance by modulating the E2F1/ECE2 axis. In vivo experiments verified that the SNHG15 could enhance DDP resistance in LUAD tissue. CONCLUSION: The results suggested that SNHG15 could up-regulate ECE2 expression by recruiting E2F1, thereby enhancing the DDP resistance of LUAD.

Role of noncoding RNAs in liver fibrosis.

Liver fibrosis is a wound-healing response following chronic liver injury caused by hepatitis virus infection, obesity, or excessive alcohol. It is a dynamic and reversible process characterized by the activation of hepatic stellate cells and excess accumulation of extracellular matrix. Advanced fibrosis could lead to cirrhosis and even liver cancer, which has become a significant health burden worldwide. Many studies have revealed that noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs and circular RNAs, are involved in the pathogenesis and development of liver fibrosis by regulating signaling pathways including transforming growth factor-ß pathway, phosphatidylinositol 3-kinase/protein kinase B pathway, and Wnt/ß-catenin pathway. NcRNAs in serum or exosomes have been reported to tentatively applied in the diagnosis and staging of liver fibrosis and combined with elastography to improve the accuracy of diagnosis. NcRNAs mimics, ncRNAs in mesenchymal stem cell-derived exosomes, and lipid nanoparticles-encapsulated ncRNAs have become promising therapeutic approaches for the treatment of liver fibrosis. In this review, we update the latest knowledge on ncRNAs in the pathogenesis and progression of liver fibrosis, and discuss the potentials and challenges to use these ncRNAs for diagnosis, staging and treatment of liver fibrosis. All these will help us to develop a comprehensive understanding of the role of ncRNAs in liver fibrosis.

T4 reduces cisplatin resistance by inhibiting AEG-1 gene expression in lung cancer cells.

Lung cancer is the most malignant form of cancer and has the highest morbidity and mortality worldwide. Due to drug resistance, the current chemotherapy for lung cancer is not effective and has poor therapeutic effects. Tripchlorolide (T4), a natural extract from the plant Tripterygium wilfordii, has powerful immunosuppressive and antitumour effects and may become a potential therapeutic agent for lung cancer. Therefore, this study aimed to investigate the effect of T4 on reducing chemoresistance in lung cancer cells and to explore the mechanism. 1. A549 and A549/DDP cells were separately transfected with AEG-1 overexpression and AEG-1 knockdown plasmids. A549/DDP cells were divided into the A549/DDP empty group, T4 group, and T4 + AEG-1 overexpression group. A CCK-8 assay was used to evaluate the proliferation of cells in each group. RT-qPCR and Western blotting were used to detect the expression of AEG-1 and MDR-1. Expression of AEG-1 in A549 and A549/DDP cells was positively correlated with cisplatin resistance. When the AEG-1 protein was overexpressed in A549 cells, the lethal effect of cisplatin on A549 cells was attenuated (all P < 0.05). After the AEG-1 protein was knocked down in A549/DDP cells, cisplatin was applied. The lethal effect was significantly increased compared to that in the corresponding control cells (all P < 0.05). AEG-1 protein expression gradually decreased with increasing T4 concentration in A549 and A549/DDP cells. Resistance to cisplatin was reduced after the addition of T4 to A549/DDP cells (P < 0.05), and this effect was enhanced after transfection with the AEG-1 knockdown plasmid. T4 plays an important role in increasing the sensitivity of lung cancer cells to cisplatin.

A novel prognostic index for sporadic Burkitt lymphoma in adult patients: a real-word multicenter study.

BACKGROUND: Adult sporadic Burkitt lymphoma (BL) is a rare but highly aggressive subtype of lymphoma which lacks its own unique prognostic model. Systemic inflammatory biomarkers have been confirmed as prognostic markers in several types of malignancy. Our objective was to explore the predictive value of pretreatment inflammatory biomarkers and establish a novel, clinically applicable prognostic index for adult patients with sporadic BL. METHODS: We surveyed retrospectively 336 adult patients with newly diagnosed sporadic BL at 8 Chinese medical centers and divided into training cohort (n = 229) and validation cohort (n = 107). The pretreatment inflammatory biomarkers were calculated for optimal cut-off value. The association between serum biomarkers and overall survival (OS) was analyzed by Kaplan-Meier curves and Cox proportional models. The risk stratification was defined based on normal LDH level, Ann Arbor stage of I and completely resected abdominal lesion or single extra-abdominal mass < 10 cm. RESULTS AND CONCLUSIONS: Univariate and multivariate analyses revealed that platelets< 254 × 109/L, albumin< 40 g/L, lactate dehydrogenase≥334 U/L independently predicted unfavorable OS. We used these data as the basis for the prognostic index, in which patients were stratified into Group 1 (no or one risk factor), Group 2 (two risk factors), or Group 3 (three risk factors), which were associated with 5-year OS rates of 88.1, 72.4, and 45%, respectively. In the subgroup analysis for high-risk patients, our prognostic model results showed that high-risk patients with no more than one adverse factor presented a 5-year survival rate of 85.9%, but patients with three adverse factors had a 5-year survival rate of 43.0%. Harrell's concordance index (C-index) of the risk group score was 0.768. Therefore, the new prognostic model could be used to develop risk-adapted treatment approaches for adult sporadic BL.

Circular RNA circ_GLIS2 suppresses hepatocellular carcinoma growth and metastasis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is one of the leading causes of tumour-related death. Here, we investigated the molecular mechanism of HCC by studying the function of circ_GLIS2. METHODS: Human HCC specimens and cell lines were used. Sanger sequencing, actinomycin D and RNase R treatment were performed to validate circular RNA features of circ_GLIS2. qRT-PCR, western blotting, immunostaining, and IHC were employed to examine levels of circ_GLIS2, GLIS2 mRNA, and EMT-related markers. CCK-8, colony formation, flow cytometry, wound healing assay, and transwell assays were performed to evaluate cancer cell proliferation, apoptosis, migration, and invasion. RIP and RNA pull-down assay were used to validate EIF4A3/GLIS2 mRNA interaction. MSP was performed to measure the methylation status of GLIS2 promoter. Nude mouse xenograft model was used to examine tumour growth and metastasis in vivo. RESULTS: Circ_GLIS2 and linear GLIS2 mRNA were reduced in human HCC tissues and cells. Their low levels correlated with a poor survival rate of HCC patients. Overexpression of circ_GLIS2 and GLIS2 suppressed HCC cell proliferation, migration, and invasion but promoted cell apoptosis. GLIS2 promoter region was hypermethylated in HCC cells. EIF4A3 was directly bound with GLIS2 mRNA and promoted circ_GLIS2/GLIS2 expression. Moreover, overexpression of circ_GLIS2 restrained HCC tumour growth and metastasis in vivo. CONCLUSION: Circ_GLIS2 suppresses HCC growth and metastasis by inhibiting cell proliferation, migration, and invasion, but promoting cell apoptosis. These findings provide molecular insights into the mechanism of HCC and indicate that circ_GLIS2 could serve as a diagnosis marker or therapeutic target for HCC.

Six-month follow-up of functional status in discharged patients with coronavirus disease 2019.

BACKGROUND: The long-term functional outcome of discharged patients with coronavirus disease 2019 (COVID-19) remains unresolved. We aimed to describe a 6-month follow-up of functional status of COVID-19 survivors. METHODS: We reviewed the data of COVID-19 patients who had been consecutively admitted to the Tumor Center of Union Hospital (Wuhan, China) between 15 February and 14 March 2020. We quantified a 6-month functional outcome reflecting symptoms and disability in COVID-19 survivors using a post-COVID-19 functional status scale ranging from 0 to 4 (PCFS). We examined the risk factors for the incomplete functional status defined as a PCFS > 0 at a 6-month follow-up after discharge. RESULTS: We included a total of 95 COVID-19 survivors with a median age of 62 (IQR 53-69) who had a complete functional status (PCFS grade 0) at baseline in this retrospective observational study. At 6-month follow-up, 67 (70.5%) patients had a complete functional outcome (grade 0), 9 (9.5%) had a negligible limited function (grade 1), 12 (12.6%) had a mild limited function (grade 2), 7 (7.4%) had moderate limited function (grade 3). Univariable logistic regression analysis showed a significant association between the onset symptoms of muscle or joint pain and an increased risk of incomplete function (unadjusted OR 4.06, 95% CI 1.33-12.37). This association remained after adjustment for age and admission delay (adjusted OR 3.39, 95% CI 1.06-10.81, p = 0.039). CONCLUSIONS: A small proportion of discharged COVID-19 patients may have an incomplete functional outcome at a 6-month follow-up; intervention strategies are required.

Sensitivity and specificity of CEST and NOE MRI in injured spinal cord in monkeys.

PURPOSE: The sensitivity and accuracy of chemical exchange saturation transfer (CEST) and nuclear Overhauser enhancement (NOE) effects for assessing injury-associated changes in cervical spinal cords were evaluated in squirrel monkeys. Multiple interacting pools of protons, including one identified by an NOE at -1.6 ppm relative to water (NOE(-1.6)), were derived and quantified from fitting proton Z-spectra. The effects of down-sampled data acquisitions and corrections for non-specific factors including T1, semi-solid magnetization transfer, and direct saturation of free water (DS), were investigated. The overall goal is to develop a protocol for rapid data acquisition for assessing the molecular signatures of the injured spinal cord and its surrounding regions. METHODS: MRI scans were recorded of anesthetized squirrel monkeys at 9.4 T, before and after a unilateral dorsal column sectioning of the cervical spinal cord. Z-spectral images at 51 different RF offsets were acquired. The amplitudes of CEST and NOE effects from multiple proton pools were quantified using a six-pool Lorenzian fitting of each Z-spectrum (MTRmfit). In addition, down-sampled data using reduced selections of RF offsets were analyzed and compared. An apparent exchange-dependent relaxation (AREXmfit) method was also used to correct for non-specific factors in quantifying regional spectra around lesion sites. RESULTS: The parametric maps from multi-pool fitting using the complete sampling data (P51e) detected unilateral changes at and around the injury. The maps derived from selected twofold down-sampled data with appropriate interpolation (P26sI51) revealed quite similar spatial distributions of different pools as those obtained using P51e at each resonance shift. Across 10 subjects, both data acquisition schemes detected significant decreases in NOE(-3.5) and NOE(-1.6) and increases in DS(0.0) and CEST(3.5) at the lesion site relative to measures of the normal tissues before injury. AREXmfit of cysts and other abnormal tissues at and around the lesion site also exhibited significant changes, especially at 3.5, -1.6 and -3.5 ppm RF offsets. CONCLUSION: These results confirm that a reduced set of RF offsets and down sampling are adequate for CEST imaging of injured spinal cord and allow shorter imaging times and/or permit additional signal averaging. AREXmfit correction improved the accuracy of CEST and NOE measures. The results provide a rapid (~13 mins), sensitive, and accurate protocol for deriving multiple NOE and CEST effects simultaneously in spinal cord imaging at high field.

Evaluation of foliar fungus-mediated interactions with below and aboveground enemies of the invasive plant Ageratina adenophora.

Plant-fungal associations are frequently key drivers of plant invasion success. Foliar fungi can benefit their invasive hosts by enhancing growth promotion, disease resistance and environmental stress tolerance. However, the roles of foliar fungi may vary when a given invasive plant faces different stresses. In this study, we designed three independent experiments to evaluate the effects of a foliar fungus, Colletotrichum sp., on the growth performance of the invasive plant Ageratina adenophora under different soil conditions, as well as the responses of A. adenophora to the foliar fungal pathogen Diaporthe helianthi and to herbivory. We found that the soil type was the most influential factor for the growth of A. adenophora. The role of the foliar fungus Colletotrichum sp. varied in the different soil types but generally adversely affected leaf development in A. adenophora. Colletotrichum sp. may be a weak latent foliar pathogen that can enhance the pathogenicity of D. helianthi on leaves of A. adenophora and marginally reduce signs of herbivory by natural insects in the wild on A. adenophora seedlings. In general, the benefits of the foliar fungus Colletotrichum to the fitness of A. adenophora are not significant in the context of this experimental design. However, our data highlight the need to consider both aboveground and belowground biota in different soil habitats when evaluating the effects of foliar fungi.

Prognostic Value of the Modified Systemic Inflammation Score in Patients With Extranodal Natural Killer/T-Cell Lymphoma.

BACKGROUND: Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare and extremely malignant tumor. The systemic inflammation score (SIS), which is based on the pretreatment level of lymphocyte-to-monocyte ratio (LMR) and serum albumin (Alb), has been shown to be of prognostic value in a number of cancers. We integrate several other pretreatment serum inflammatory indicators, including the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), serum C-reactive protein (CRP) and albumin (Alb) level, to establish a modified systemic inflammatory scoring system to predict clinical outcomes of ENKTL. METHODS: A total of 184 patients with newly diagnosed ENKTL was retrospectively investigated. Systemic inflammatory indexes, including NLR, LMR, CRP, and Alb level were reviewed. Receiver operating characteristic (ROC) curve analysis was carried out to obtain the optimal cut-off value. The associations between cutoff values and overall survival (OS) were analyzed by Kaplan-Meier curves and Cox proportional models. RESULTS: The median age of patients was 44.0 years, ranging from 15 to 82 years. There were 129 (70.1%) male patient. About 57.1% of patients had stage III or IV disease. The optimal cut-off values of NLR and LMR in predicting OS were 3.1 and 2.4, respectively. The clinical standard of CRP and Alb levels at 10 and 40 mg/L, respectively, were chosen as the optimal cut-off values. By multivariate analysis, hemophilic syndrome (hazard ratio [HR]: 10.540, 95% confidence interval [CI]: 3.440-32.291, P < 0.001), advanced Ann Arbor stages (III-IV) (HR: 4.606, 95% CI: 1.661-12.774, P = 0.003), paranasal sinus invasion (HR: 2.323, 95% CI: 1.069-5.047, P = 0.033), NLR ≥ 3.1 (HR: 3.019, 95% CI: 1.317-6.923, P = 0.009), Alb level of <40 mg/L (HR: 0.350, 95% CI: 0.134-0.915, P = 0.032), and radiation therapy (HR: 0.430, 95% CI: 0.205-0.901, P = 0.025) were independent protective factors for ENKTL. We combined two inflammatory indexes NLR and Alb level to establish a modified systemic inflammation score (mSIS). These 184 patients were divided into 3 groups: group 1 (mSIS score of 0), group 2 (mSIS score of 1), and group 3 (mSIS score of 2). The mean OS of these three groups were 42 months (95% CI: 31.4-53.12), 77 months (95% CI: 68.5-87.5), and 89 months (95% CI: 71.4-82.7), respectively (P < 0.001). The Harrell's concordance index (C-index) of mSIS is 0.725. The mSIS could be used to discriminate patients categorized in the low-risk group of International Prognostic Index (IPI) (P < 0.001) and the low-risk and intermediate-risk prognostic index of natural killer cell lymphoma (PINK) group (P = 0.019). CONCLUSION: The pretreatment mSIS could be an independent prognostic factor for OS in patients with ENKTL and warrants further research.

Considerations for ultrasound exposure during transcranial MR acoustic radiation force imaging.

The aim of this study was to improve the sensitivity of magnetic resonance-acoustic radiation force imaging (MR-ARFI) to minimize pressures required to localize focused ultrasound (FUS) beams, and to establish safe FUS localization parameters for ongoing ultrasound neuromodulation experiments in living non-human primates. We developed an optical tracking method to ensure that the MR-ARFI motion-encoding gradients (MEGs) were aligned with a single-element FUS transducer and that the imaged slice was prescribed at the optically tracked location of the acoustic focus. This method was validated in phantoms, which showed that MR-ARFI-derived displacement sensitivity is maximized when the MR-ARFI MEGs were maximally aligned with the FUS propagation direction. The method was then applied in vivo to acquire displacement images in two healthy macaque monkeys (M fascicularis) which showed the FUS beam within the brain. Temperature images were acquired using MR thermometry to provide an estimate of in vivo brain temperature changes during MR-ARFI, and pressure and thermal simulations of the acoustic pulses were performed using the k-Wave package which showed no significant heating at the focus of the FUS beam. The methods presented here will benefit the multitude of transcranial FUS applications as well as future human applications.

Spatiotemporal trajectories of quantitative magnetization transfer measurements in injured spinal cord using simplified acquisitions.

PURPOSE: This study aims to systematically evaluate the accuracy and precision of pool size ratio (PSR) measurements from quantitative magnetization transfer (qMT) acquisitions using simplified models in the context of assessing injury-associated spatiotemporal changes in spinal cords of non-human primates. This study also aims to characterize changes in the spinal tissue pathology in individual subjects, both regionally and longitudinally, in order to demonstrate the relationship between regional tissue compositional changes and sensorimotor behavioral recovery after cervical spinal cord injury (SCI). METHODS: MRI scans were recorded on anesthetized monkeys at 9.4 T, before and serially after a unilateral section of the dorsal column tract. Images were acquired following saturating RF pulses at different offset frequencies. Models incorporating two pools of protons but with differing numbers of variable parameters were used to fit the data to derive qMT parameters. The results using different amounts of measured data and assuming different numbers of variable model parameters were compared. Behavioral impairments and recovery were assessed by a food grasping-retrieving task. Histological sections were obtained post mortem for validation of the injury. RESULTS: QMT fitting provided maps of pool size ratio (PSR), the relative amounts of immobilized protons exchanging magnetization compared to the "free" water. All the selected modeling approaches detected a lesion/cyst at the site of injury as significant reductions in PSR values. The regional contrasts in the PSR maps obtained using the different fittings varied, but the 2-parameter fitting results showed strong positive correlations with results from 5-parameter modeling. 2-parameter fitting results with modest (>3) RF offsets showed comparable sensitivity for detecting demyelination in white matter and loss of macromolecules in gray matter around lesion sites compared to 5-parameter fitting with fully-sampled data acquisitions. Histology confirmed that decreases of PSR corresponded to regional demyelination around lesion sites, especially when demyelination occurred along the dorsal column on the injury side. Longitudinally, PSR values of injured dorsal column tract and gray matter horns exhibited remarkable recovery that associated with behavioral improvement. CONCLUSION: Simplified qMT modeling approaches provide efficient and sensitive means to detect and characterize injury-associated demyelination in white matter tracts and loss of macromolecules in gray matter and to monitor its recovery over time.

[Research progress on identification and quality evaluation of glues medicines].

Glues medicines is a special kind of traditional Chinese medicine.As the market demand is large, the raw materials are in short supply and lacks proper quality evaluation technology, which causes inconsistent quality of products on the market. Its authentic identification and evaluation stay a problem to be solved. In this paper, the research progress of the methods and techniques of the evaluation of the identification and quality of glues medicines were reviewed. The researches of medicinal glue type identification and quality evaluation mainly concentrated in four aspects of medicinal materials of physical and chemical properties, trace elements, organic chemicals and biological genetic methods and techniques. The methods of physicochemical properties include thermal analysis, gel electrophoresis, isoelectric focusing electrophoresis, infrared spectroscopy, gel exclusion chromatography, and circular dichroism. The methods including atomic absorption spectrometry, X-ray fluorescence spectrometry, plasma emission spectrometry and visible spectrophotometry were used for the study of the trace elements of glues medicines. The organic chemical composition was studied by methods of composition of amino acids, content detection, odor detection, lipid soluble component, organic acid detection. Methods based on the characteristics of biogenetics include DNA, polypeptide and amino acid sequence difference analysis. Overall, because of relative components similarity of the glues medicines (such as amino acids, proteins and peptides), its authenticity and quality evaluation index is difficult to judge objectively, all sorts of identification evaluation methods have different characteristics, but also their limitations. It indicates that further study should focus on identification of evaluation index and various technology integrated application combining with the characteristics of the production process.

MRI evaluation of regional and longitudinal changes in Z-spectra of injured spinal cord of monkeys.

PURPOSE: In principle, MR methods that exploit magnetization transfer (MT) may be used to quantify changes in the molecular composition of tissues after injury. The ability to track such changes in injured spinal cord may allow more precise assessment of the state of neural tissues. METHODS: Z-Spectra were obtained from the cervical spinal cord before and after a unilateral dorsal column lesion in monkeys at 9.4T. The amplitudes of chemical exchange saturation transfer (CEST) and nuclear Overhauser enhancement (NOE) effects from multiple proton pools, along with nonspecific semisolid MT effects from immobile macromolecules, were quantified using a five-peak Lorenzian fitting of each Z-spectrum. RESULTS: Abnormal tissues/cysts that formed around lesion sites exhibited relatively low correlations between their Z-spectra and that of normal gray matter (GM). Compared with normal GM, cysts showed strong CEST but weak semisolid MT and NOE effects after injury. The abnormal tissues around lesion sites were heterogeneous and showed different regional Z-spectra. Different regional correlations between proton pools were observed. Longitudinally, injured spinal cord tissue exhibited remarkable recovery in all subjects. CONCLUSION: Characterization of multiple proton pools from Z-spectra permitted noninvasive, regional, quantitative assessments of changes in tissue composition of injured spinal cord over time. Magn Reson Med 79:1070-1082, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Tripchlorolide induces autophagy in lung cancer cells by inhibiting the PI3K/AKT/mTOR pathway and improves cisplatin sensitivity in A549/DDP cells.

Tripchlorolide (T4) has been shown to induce A549 lung cancer cell death predominantly by activating an autophagy pathway. However, the underlying mechanism remains unclear. Herein, we demonstrated that compared with T4 treatment alone, pretreatment with wortmannin (an inhibitor of phosphatidylinositol 3-kinase), perifosine (an inhibitor of AKT) or rapamycin (an inhibitor of mTOR) combined with a subsequent T4 treatment significantly impaired the cell viability of A549 and A549/DDP lung cancer cells. We found that either treatment scheme markedly reduced the activity of P13K and AKT. Expression of LC3II increased in parallel to the increase of the T4 concentration in both A549 and A549/DDP cells and was repressed by overexpression of AKT. The expression levels of PI3-K, PI3-P, AKT, TSC2, mTOR, p70S6K and 4E-BP1 were minimally affected by the wortmannin, perifosine, or rapamycin plus T4 treatments, but their phosphorylated products were greatly affected in A549 lung cancer cells and slightly affected in A549/DDP lung cancer cells. These results indicate that T4 induces autophagy in lung cancer cells by inhibiting the PI3K/AKT/mTOR signaling pathway. We further found that T4 decreased expression of MDR1 and improved cisplatin sensitivity of A549/DDP cells. Altogether, these results have meaningful implications for tumor therapy in the future.

Experimental study on the inhibition effect of miR-106a inhibitor on tumor growth of ovarian cancer xenografts mice.

OBJECTIVE: To study the inhibition effect of miR-106a inhibitor on tumor growth of ovarian cancer xenografts mice. METHODS: BALB/c mice were selected as experimental animals, ovarian cancer SKOV-3 cells transfected with miR-106a inhibitor and its negative control were inoculated subcutaneously, intratumoral injection of miR-106a inhibitor and its negative control were continued after tumor formation, and they were enrolled as treatment group and model group, respectively. Tumor volume and weight as well as Ki-67 and programmed cell death 4 (PDCD4) expression were determined; miR-106a inhibitor and its negative control as well as miR-106a mimic and its negative control were transfected into SKOV-3 cells, and expression of PDCD4 in cells was determined. RESULTS: Tumor tissue volume and weight as well as mRNA expression and protein expression of Ki-67 in treatment group were significantly lower than those in the model group while mRNA expression and protein expression of PDCD4 were significantly higher than those in the model group; transfection of miR-106a mimic could decrease mRNA expression and protein expression of PDCD4 in SKOV-3 cells, and transfection of miR-106a inhibitor could increase mRNA expression and protein expression of PDCD4 in SKOV-3 cells. CONCLUSIONS: Transfection of miR-106a inhibitor can inhibit the growth of tumor in ovarian cancer xenografts mice through increasing the expression of PDCD4.

Etomidate plus propofol versus propofol alone for sedation during gastroscopy: a randomized prospective clinical trial.

BACKGROUND AND AIMS: Sedation with propofol alone during gastroscopy has many side effects. Etomidate has advantages in terms of circulation and respiration compared to propofol. We hypothesized that etomidate plus propofol during gastroscopy would be more safe and effective than propofol alone. METHODS: Four hundred (n = 400) patients were randomly divided into a propofol group (P group) and a etomidate plus propofol group (EP group). The P group was given the first dose of 1 % propofol 1 mg/kg before gastroscopy, and the EP group was given 1 % propofol 0.5 mg/kg plus etomidate 0.1 mg/kg. Repeated doses of 10-20 mg propofol or 5-10 mg propofol plus 1-2 mg etomidate were administered to maintain an adequate level of sedation. The sedation depth was maintained by bispectral index value of 40-60. RESULTS: The EP group had a lower incidence of systolic hypotension (13.0 vs. 32.5 %; P < 0.0001), bradycardia (8.5 vs. 16.5 %; P = 0.0226), mild hypoxemia (6.5 vs. 18.0 %; P = 0.0007), and severe hypoxemia (2.5 vs. 10.0 %; P = 0.0031) compared to the P group. Also, the satisfaction of anesthetist and gastroscopist with EP was higher than that of P group (P < 0.0001; P = 0.018, respectively). CONCLUSION: Etomidate plus propofol had few effects on respiration and circulation in patients undergoing gastroscopy and was more safe and effective than propofol alone.