Dexmedetomidine combined with ropivacaine for erector spinae plane block after posterior lumbar spine surgery: a randomized controlled trial.

PURPOSE: Due to lumbar spinal surgery is frequently accompanied with moderate-to-severe postoperative pain, it is necessary to find an effective postoperative analgesia for patients with this surgery. This study aimed to observe the analgesic effect of dexmedetomidine combined with ropivacaine erector spinae plane block (ESPB) used in posterior lumbar spine surgery. METHODS: In this clinical trial, patients undergoing posterior lumbar spine surgery were recruited and randomly divided into two groups: intervention and control. The intervention group (Group E) received 0.375% ropivacaine with 1 µg/kg dexmedetomidine in a total of 20 ml for ESPB; the control group (Group C) received 20 ml ropivacaine 0.375% for ESPB. US-guided ESPB was performed preoperatively in all patients. Demographics, anesthesia time, surgery time, and ASA grade from the participants were recorded at baseline. The primary clinical outcome measures were 2-, 4-, 8-, 12-, 24-and 48-h visual analog scale (VAS) pain scores after surgery at rest and movement state. Other end points included opioid consumption, number of PCIA presses, flurbiprofen-axetil consumption, quality of recovery and pain management after surgery. RESULTS: One hundred twenty patients were enrolled in the study (mean [SD] ages: Group E, 54.77 [8.61] years old; Group C,56.40 [7.87] years old; P = 0.280). The mean anesthesia time was 152.55 (15.37) min in Group E and 152.60 (16.47) min in Group C (P = 0.986). Additionally, the surgery time was 141.70 (15.71) min in Group E compared to 141.48 (17.13) min in Group C (P = 0.943). In addition, we found that the VAS pain scores in the resting state during the postoperative period at 8-48 h were lower in Group E than in Group C. However, the VAS pain scores in the active state were lower in Group E at 12-48 h (P < 0.05). More importantly, the consumption of opioids and flurbiprofen-axetil after surgery was also lower in Group E (P < 0.05). Subsequently, we administered questionnaires on the quality of recovery and pain management after surgery that were positively correlated with the postoperative analgesic effect. It was worth affirming that the QoR-15 scores and APS-POQ-R questionnaire results were different between the two groups, further confirming that the combination of drugs not only could obtain an ideal analgesic effect but also had no obvious adverse reactions (P < 0.05). CONCLUSIONS: All the findings suggested that dexmedetomidine could significantly relieve postoperative pain and reduce the consumption of opioids in patients undergoing posterior lumbar spine surgery without obvious adverse reactions as a local anesthetic adjuvant. Further studies with larger sample sizes and different drug dosages may be useful in understanding the potential clinical benefits of dexmedetomidine.

Effect of different rehydration temperatures on the survival of human vitrified-warmed oocytes.

PURPOSE: To evaluate the effect of different exposure temperatures during the dilution process on the survival rate of vitrified oocytes and following development. METHODS: Patients were divided at random into two groups for different dilution temperature (20-22 °C, RT group; 37 °C,37 °C group) according to computer-generated random numbers on the day of oocyte warming. The survival and fertilization rates of vitrified oocytes as well as the implantation and clinical pregnancy rates of the resulting embryos were recorded. RESULTS: A total of 662 and 676 oocytes were warmed in the 37 °C group and RT group, respectively, and significant difference was observed in the survival rate between 37 °C group (88.37%) and RT group (79.88%) (P = 0.0000). There was significant difference between the survival rate of 37 °C group (87.27%) and RT group (75.64%) in nondonor patients (P = 0.0001). Multiple linear regression analysis showed that dilution temperature (ß = 0.079, P = 0.017) and clinical outcomes of fresh cycles (ß = 0.063, P = 0.001) were significantly and independently associated with survival rate. No significant difference was found between the 37 °C group and RT group in: fertilization rate (66.67 versus 65.37%), implantation rate (20.0 versus 19.46%), clinical pregnancy rate (37.5 versus 35.0%). CONCLUSIONS: In conclusion, the results of this study give supportive evidence of the application of 37 °C in the dilution process, especially for oocytes of poor quality. Further studies with well-controlled experimental groups are needed to optimize protocols for human oocyte vitrification.

Prediction of TBM penetration rate for different surrounding rocks and cutter head diameters.

The penetration rate (PR) of tunnel boring machines (TBMs) is often used to evaluate tunneling performance and predict construction period costs. However, most penetration rate (PR) prediction models are based on a single specific project, which leads to poor universality of the models.Furthermore, the value of the cutter head speed set for the prediction of the construction period in the survey and planning stages depends on manual experience and lacks theoretical guidance. Therefore, based on a set of engineering data from TBM of different surrounding rocks and diameters, this study statistically analyzed the distribution law of the cutter head speed (N) and the relationship between the field penetration index (FPI), geological parameters (uniaxial compressive strength (UCS) and the integrity coefficient of the rock mass (Kv)), and penetration (P). The results show that the FPI is strongly correlated with the geological parameters and the P. The geological and tunnelling parameters are the main factors affecting the penetration rate (PR). On the basis of this, prediction models of the FPI and P and a calculation model of the cutter head speed were developed, and a prediction model of the PR was obtained. The accuracy and reliability of this model were verified and analyzed for the EHe (EH) project. The average prediction error was 15.15 %.

Granzyme B PET Imaging in Response to In Situ Vaccine Therapy Combined with αPD1 in a Murine Colon Cancer Model.

Immune checkpoint inhibitors (ICIs) block checkpoint receptors that tumours use for immune evasion, allowing immune cells to target and destroy cancer cells. Despite rapid advancements in immunotherapy, durable response rates to ICIs remains low. To address this, combination clinical trials are underway assessing whether adjuvants can enhance responsiveness by increasing tumour immunogenicity. CpG-oligodeoxynucleotides (CpG-ODN) are synthetic DNA fragments containing an unmethylated cysteine-guanosine motif that stimulate the innate and adaptive immune systems by engaging Toll-like receptor 9 (TLR9) present on the plasmacytoid dendritic cells (pDCs) and B cells. Here, we have assessed the ability of AlF-mNOTA-GZP, a peptide tracer targeting granzyme B, to serve as a PET imaging biomarker in response to CpG-ODN 1585 in situ vaccine therapy delivered intratumourally (IT) or intraperitoneally (IP) either as monotherapy or in combination with αPD1. [18F]AlF-mNOTA-GZP was able to differentiate treatment responders from non-responders based on tumour uptake. Furthermore, [18F]AlF-mNOTA-GZP showed positive associations with changes in tumour-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells, and decreases in suppressive F4/80+ cells. [18F]AlF-mNOTA-GZP tumour uptake was mediated by GZB expressing CD8+ cells and successfully stratifies therapy responders from non-responders, potentially acting as a non-invasive biomarker for ICIs and combination therapy evaluation in a clinical setting.

Imaging Kv1.3 Expressing Memory T Cells as a Marker of Immunotherapy Response.

Immune checkpoint inhibitors have shown great promise, emerging as a new pillar of treatment for cancer; however, only a relatively small proportion of recipients show a durable response to treatment. Strategies that reliably differentiate durably-responding tumours from non-responsive tumours are a critical unmet need. Persistent and durable immunological responses are associated with the generation of memory T cells. Effector memory T cells associated with tumour response to immune therapies are characterized by substantial upregulation of the potassium channel Kv1.3 after repeated antigen stimulation. We have developed a new Kv1.3 targeting radiopharmaceutical, [18F]AlF-NOTA-KCNA3P, and evaluated whether it can reliably differentiate tumours successfully responding to immune checkpoint inhibitor (ICI) therapy targeting PD-1 alone or combined with CLTA4. In a syngeneic colon cancer model, we compared tumour retention of [18F]AlF-NOTA-KCNA3P with changes in the tumour immune microenvironment determined by flow cytometry. Imaging with [18F]AlF-NOTA-KCNA3P reliably differentiated tumours responding to ICI therapy from non-responding tumours and was associated with substantial tumour infiltration of T cells, especially Kv1.3-expressing CD8+ effector memory T cells.

Prognostic Signatures of Metabolic Genes and Metabolism-Related Long Non-coding RNAs Accurately Predict Overall Survival for Osteosarcoma Patients.

In this study, we identified eight survival-related metabolic genes in differentially expressed metabolic genes by univariate Cox regression analysis based on the therapeutically applicable research to generate effective treatments (n = 84) data set and genotype tissue expression data set (n = 396). We also constructed a six metabolic gene signature to predict the overall survival of osteosarcoma (OS) patients using least absolute shrinkage and selection operator (Lasso) Cox regression analysis. Our results show that the six metabolic gene signature showed good performance in predicting survival of OS patients and was also an independent prognostic factor. Stratified correlation analysis showed that the metabolic gene signature accurately predicted survival outcomes in high-risk and low-risk OS patients. The six metabolic gene signature was also verified to perform well in predicting survival of OS patients in an independent cohort (GSE21257). Then, using univariate Cox regression and Lasso Cox regression analyses, we identified an eight metabolism-related long noncoding RNA (lncRNA) signature that accurately predicts overall survival of OS patients. Gene set variation analysis showed that the apical surface and bile acid metabolism, epithelial mesenchymal transition, and P53 pathway were activated in the high-risk group based on the eight metabolism-related lncRNA signature. Furthermore, we constructed a competing endogenous RNA (ceRNA) network and conducted immunization score analysis based on the eight metabolism-related lncRNA signature. These results showed that the six metabolic gene signature and eight metabolism-related lncRNA signature have good performance in predicting the survival outcomes of OS patients.

Granzyme B PET Imaging of Combined Chemotherapy and Immune Checkpoint Inhibitor Therapy in Colon Cancer.

PURPOSE: Chemotherapeutic adjuvants, such as oxaliplatin (OXA) and 5-fluorouracil (5-FU), that enhance the immune system, are being assessed as strategies to improve durable response rates when used in combination with immune checkpoint inhibitor (ICI) monotherapy in cancer patients. In this study, we explored granzyme B (GZB), released by tumor-associated immune cells, as a PET imaging-based stratification marker for successful combination therapy using a fluorine-18 (18F)-labelled GZB peptide ([18F]AlF-mNOTA-GZP). METHODS: Using the immunocompetent CT26 syngeneic mouse model of colon cancer, we assessed the potential for [18F]AlF-mNOTA-GZP to stratify OXA/5-FU and ICI combination therapy response via GZB PET. In vivo tumor uptake of [18F]AlF-mNOTA-GZP in different treatment arms was quantified by PET, and linked to differences in tumor-associated immune cell populations defined by using multicolour flow cytometry. RESULTS: [18F]AlF-mNOTA-GZP tumor uptake was able to clearly differentiate treatment responders from non-responders when stratified based on changes in tumor volume. Furthermore, [18F]AlF-mNOTA-GZP showed positive associations with changes in tumor-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells and GZB+ NK+ cells. CONCLUSIONS: [18F]AlF-mNOTA-GZP tumor uptake, driven by changes in immune cell populations expressing GZB, is able to stratify tumor response to chemotherapeutics combined with ICIs. Our results show that, while the immunomodulatory mode of action of the chemotherapies may be different, the ultimate mechanism of tumor lysis through release of Granzyme B is an accurate biomarker for treatment response.

Atorvastatin ameliorates depressive behaviors and neuroinflammatory in streptozotocin-induced diabetic mice.

Depression is a chronic and progressive syndrome and commonly associated with several neuropsychiatric comorbidities, of which depression is the most studied. It has been demonstrated that statins also have anti-inflammatory and immunomodulatory properties, which being explored for potential benefits in depression. However, the role of statins in the treatment of diabetes-related depression has not been well examined. Herein, we investigated the effects of atorvastatin on depressive behaviors and neuroinflammation in streptozotocin-induced diabetic mice. Our data indicated that oral administration of atorvastatin at 10 or 20 mg/kg for 3 weeks markedly ameliorated diabetes-associated depressive behaviors reflected by better performance in sucrose preference test (SPT), tail suspension test (TST), and novelty-suppressed feeding test (NSFT). The study further showed that atrovastatin decreased the expression of nucleus NF-κB p65 expression and ameliorated neuroinflammatory responses in prefrontal cortex as evidenced by less Iba-1-positive cells and lower inflammatory mediators including IL-1ß and TNF-α. As expected, atorvastatin-treated diabetic mice exhibited significant improvement of hyperlipidemia rather than hyperglycemia. These results suggest that atorvastatin has the potential to be employed as a therapy for diabetes-related depression.

Rhenium-based molecular rectangular boxes with large inner cavity and high shape selectivity towards benzene molecule.

The self-assembly of rhenium-based rectangular boxes with a large inner cavity can be achieved via a simple one-step synthetic route; these molecules selectively recognize planar aromatic molecules, benzene in particular.

[Geographical features of malaria in Yunnan Province].

OBJECTIVE: To understand the geographical features of malaria in Yunnan Province, so as to provide the reference for malaria elimination. METHODS: The data of malaria in Yunnan Province from 2012 to 2015 were collected and analyzed. RESULTS: Totally 2 586 malaria cases were reported in Yunnan Province from 2012 to 2015, in which 274 (10.60%) were local cases and 2 311 (89.37%) were abroad imported, and one (0.03%) was domestic imported. The imported malaria cases and local cases were analyzed according to the sources and locations respectively, and the arithmetic means of the numbers of imported and local cases were 96.29 and 10.96 respectively, the standard deviations of the numbers of imported and local cases were 421.18 and 19.12 respectively, and the difference of the means was not significant (Z = - 0.326, P > 0.10). Both the imported and local malaria cases could be clustered into five sections by the number of 5. The Herfendal-Hirshman indexes of the imported and local malaria cases were 8 121 and 1 598 respectively. CONCLUSIONS: There is no significant difference of the distribution between the imported and local malaria cases, and they should be attaching equal importance. The non-uniform degree of imported cases is higher than that of the local cases, while both of them could be divided into five major clusters in the prevention and control work.

Monitoring gene expression profile changes in bladder transitional cell carcinoma using cDNA microarray.

PURPOSE: Differential gene expression profiles between normal bladder mucosas and bladder transitional cell carcinomas TCC were detected. MATERIALS AND METHODS: cDNA microarrays were prepared by spotting PCR products of 12,800 human genes onto specially treated glass slides. The cDNA probes were prepared by labeling normal bladder mucosa mRNA and TCC tissue mRNA with Cy3-dUTP and Cy5-dUTP respectively through reverse transcription. The arrays were then hybridized against the cDNA probe mixture and the fluorescent signals were scanned. The ratios of Cy5/Cy3 were computed. Northern analysis was used to confirm the results of microarray hybridization. RESULTS: Eighty-three genes (0.65%), whose ratios of Cy5/Cy3 were greater than 4.0 or less than 0.25, were screened out after 10 groups of hybridization. In the cancerous tissues 28 of them showed higher expression and 55 lower. Twenty-three genes are unregistered in GenBank. These differentially expressed genes are always involved in the physiological processes such as signal transduction, apoptosis and cell cycle, etc. CONCLUSIONS: This technique provides a powerful method for quantitative analysis of the expression levels of thousands of genes in parallel, and is used to identify genes involved in TCC carcinogenesis. The data obtained by this means are comparable to those obtained by other methods. Using cDNA microarrays to define alterations in gene expression associated with a specific cancer may be an efficient way to uncover the clues to specific molecular derangements that account for its pathogenesis and thus identify potential targets for therapeutic intervention.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) mediates p38 mitogen-activated protein kinase activation and signal transduction in peripheral blood mononuclear cells from patients with lupus nephritis.

Forty-two patients with systemic lupus erythematosus (SLE), including 26 patients with renal damage and 16 without, and 20 healthy controls were included in the study. The isolated peripheral blood mononuclear cells (PBMCs) were treated with a p38 inhibitor (SB203580) or anti-tumor necrosis factor-like weak inducer of apoptosis (TWEAK) mAb, with or without phytohemagglutinin/phorbol myristate acetate (PHA/PMA) stimulation. Western blot experiments were used to evaluate the protein expression of TWEAK and p38 MAPK in PBMCs .Next, the contents of interleukin-10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1) in the supernatant were measured by ELISA. The results showed that expression of TWEAK protein in PBMCs from lupus nephritis patients was significantly higher than that from SLE patients without renal damage and healthy controls. PHA/PMA simulation could upregulate the productions of TWEAK and p-p38MAPK in PBMCs from patients with SLE. Anti-TWEAK mAb treatment downregulated both TWEAK and p-p38 MAPK expression in PBMCs, as well as IL-10 and MCP-1 in the supernatant; SB203580 had the same effect on cytokine production in PBMC, but had no effect on the expression of TWEAK. Our results suggested that TWEAK-p38 MAPK-IL-10, MCP-1 signaling pathway in PBMC played an important pathogenic role in lupus nephritis.

Luminescence quenching of Re(I) molecular rectangles by quinones.

The rhenium-based rectangles [{Re(CO)(3)(mu-bpy)Br}{Re(CO)(3)(mu-L)Br}](2) (I, L = 4,4'-dipyridylacetylene (dpa); II, L = 4,4'-dipyridylbutadiyne (dpb); III, L = 1,4-bis(4'-pyridylethynyl)benzene (bpeb); bpy = 4,4'-bipyridine) are emissive in solution at room temperature. The presence of extended pi conjugation leads to an increase in electron delocalization, which, in turn, results in improved luminescence and lower nuclear reorganization energy. These rectangles, upon electronic excitation, undergo facile electron transfer (ET) reactions with quinones and both the dynamic and static quenching contribute to the reaction. Spectral and electrochemical measurements show that quinone 7,7,8,8-tetracyanoquinodimethane (TCNQ) binds strongly to rectangle I. The driving force dependence of k(et), deduced from the luminescence quenching of rectangles with quinones, can be well accounted for within the context of the Marcus theory of electron transfer.

Photoluminescence electron-transfer quenching of rhenium(I) rectangles with amines.

Electron-transfer (ET) reactions from aromatic amines to excited states of rhenium(I)-based molecular rectangles [{Re(CO)3(mu-bpy)Br}{Re(CO)3(mu-L)Br}]2 (bpy = 4,4'-bipyridine, L = 4,4'-dipyridylacetylene (dpa), I; L = 4,4'-dipyridylbutadiyne (dpb), II; and L = 1,4-bis(4'-pyridylethynyl)benzene (bpeb), III) were investigated in a dichloromethane solution using luminescence quenching techniques. Direct evidence for the ET reaction was obtained from the detection of the amine cation radical in this system using time-resolved transient absorption spectroscopy. The values of the luminescence quenching rate constants, kq, of the 3MLCT excited state of Re(I) rectangles with amines were found to be higher than those for the monomeric Re(I) complexes and other Re(I)-based metallacyclophanes. The observed kq values were correlated well with the driving force (Delta G degrees) for the ET reactions. In addition, a semiclassical theory of ET was successfully applied to the photoluminescence quenching of Re(I) rectangles with amines.

Gondola-shaped luminescent tetrarhenium metallacycles with crown-ether-like multiple recognition sites.

The self-assembly of gondola-shaped tetrarhenium metallacyclophanes was achieved in near quantitative yield from Re(CO)3 corners, a ditopic heterocyclic clip, and a bischelating-bridging unit using an orthogonal-bonding approach. The highly luminescent metallacycles contain crown-ether-like recognition sites, which are capable of selectively recognizing metal ions and planar aromatic molecules.

CH...pi interaction for rhenium-based rectangles: an interaction that is rarely designed into a host-guest pair.

Alkoxy- and thiolato-bridged Re(I) molecular rectangles [{(CO)3Re(mu-ER)2Re(CO)3}2(mu-bpy)2] (ER = SC4H9, 1a; SC8H17, 1b; OC4H9, 2a; OC12H25, 2b; bpy = 4,4'-bipyridine) exhibit strong interactions with several planar aromatic molecules. The nature of their binding was studied by spectral techniques and verified by X-ray diffraction analysis. Standard absorption and fluorescence titrations showed that a relatively strong 1:1 interaction occurs between aromatic guests such as pyrene and these rectangles. The results of a single-crystal X-ray diffraction analysis show that the recognition of 1 with a pyrene molecule is mainly due to CH...pi interactions and the face of the guest pyrene is located over the edges of the bpy linkers of 1. This is a fairly novel example of an interaction that is rarely designed into a host-guest pair. Furthermore, the interaction of 1 with Ag+ results in the self-organization of supramolecular arrays, as revealed by solid-state data.

Self-assembly of octarhenium-based neutral luminescent rectangular prisms.

Self-assembly of rhenium-based nanoscale rectangular prismatic boxes has been achieved in quantitative conversion. The fac-rhenium corner provided three mutually perpendicular coordination sites and served as a good candidate for the construction of 3-D boxes. These are the first Re-based, neutral, luminescent prisms of M(8)L(2)L'(8) type that has been characterized crystallographically. Their luminescent properties and molecular recognition capabilities make these molecular prisms interesting supramolecules.

Synthesis and photophysical properties of neutral luminescent rhenium-based molecular rectangles.

A series of neutral luminescent molecular rectangles [[Re(CO)(3)(mu-bpy)Br][Re(CO)(3)(mu-L)Br]](2) (1-4) having fac-Re(CO)(3)Br as corners and 4,4'-bipyridine (bpy) as the bridging ligand on one side and other bipyridyl ligands of varying length (L) on the other side have been synthesized and characterized. The crystal structure of 1 shows a rectangular cavity with the dimensions of 11.44 x 7.21 A. When the cavity size is tuned from 1 to 4, a dimension of 11.4 x 20.8 A could be achieved, as revealed by the molecular modeling. These rectangles exhibit luminescence in solution at room temperature. In particular, compound 4 containing 1,4-bis(4'-pyridylethynyl)benzene (bpeb) as bridging ligand shows the excited-state lifetime of 495 ns. Fine-tuning of the cavity size of the rectangles improves their excited-state properties. These properties facilitate the study of excited-state electron-transfer reactions with electron acceptors and donors and host-guest binding. Crystallographic information: 1.6CH(3)COCH(3) is monoclinic, P2(1)/c, with a = 12.0890(2), b = 24.2982(2), and c = 12.8721(2) A, beta = 107.923(1) degrees, and Z = 2.