Optimization and impact of sensitivity mode on abbreviated scan protocols with population-based input function for parametric imaging of [18F]-FDG for a long axial FOV PET scanner.

BACKGROUND: The long axial field of view, combined with the high sensitivity of the Biograph Vision Quadra PET/CT scanner enables the precise deviation of an image derived input function (IDIF) required for parametric imaging. Traditionally, this requires an hour-long dynamic PET scan for [18F]-FDG, which can be significantly reduced by using a population-based input function (PBIF). In this study, we expand these examinations and include the scanner's ultra-high sensitivity (UHS) mode in comparison to the high sensitivity (HS) mode and evaluate the potential for further shortening of the scan time. METHODS: Patlak Ki and DV estimates were determined by the indirect and direct Patlak methods using dynamic [18F]-FDG data of 6 oncological patients with 26 lesions (0-65 min p.i.). Both sensitivity modes for different number/duration of PET data frames were compared, together with the potential of using abbreviated scan durations of 20, 15 and 10 min by using a PBIF. The differences in parametric images and tumour-to-background ratio (TBR) due to the shorter scans using the PBIF method and between the sensitivity modes were assessed. RESULTS: A difference of 3.4 ± 7.0% (Ki) and 1.2 ± 2.6% (DV) was found between both sensitivity modes using indirect Patlak and the full IDIF (0-65 min). For the abbreviated protocols and indirect Patlak, the UHS mode resulted in a lower bias and higher precision, e.g., 45-65 min p.i. 3.8 ± 4.4% (UHS) and 6.4 ± 8.9% (HS), allowing shorter scan protocols, e.g. 50-65 min p.i. 4.4 ± 11.2% (UHS) instead of 7.3 ± 20.0% (HS). The variation of Ki and DV estimates for both Patlak methods was comparable, e.g., UHS mode 3.8 ± 4.4% and 2.7 ± 3.4% (Ki) and 14.4 ± 2.7% and 18.1 ± 7.5% (DV) for indirect and direct Patlak, respectively. Only a minor impact of the number of Patlak frames was observed for both sensitivity modes and Patlak methods. The TBR obtained with direct Patlak and PBIF was not affected by the sensitivity mode, was higher than that derived from the SUV image (6.2 ± 3.1) and degraded from 20.2 ± 12.0 (20 min) to 10.6 ± 5.4 (15 min). Ki and DV estimate images showed good agreement (UHS mode, RC: 6.9 ± 2.3% (Ki), 0.1 ± 3.1% (DV), peak signal-to-noise ratio (PSNR): 64.5 ± 3.3 dB (Ki), 61.2 ± 10.6 dB (DV)) even for abbreviated scan protocols of 50-65 min p.i. CONCLUSIONS: Both sensitivity modes provide comparable results for the full 65 min dynamic scans and abbreviated scans using the direct Patlak reconstruction method, with good Ki and DV estimates for 15 min short scans. For the indirect Patlak approach the UHS mode improved the Ki estimates for the abbreviated scans.

Comparison of laparoscopic common bile duct exploration and endoscopic retrograde cholangiopancreatography combined with laparoscopic cholecystectomy for patients with gallbladder and common bile duct stones a meta-analysis of randomized controlled trials.

OBJECTIVE: This study aimed to compare the efficacy and safety of laparoscopic common bile duct exploration (LCBDE) and endoscopic retrograde cholangiopancreatography (ERCP) combined with laparoscopic cholecystectomy (LC) to determine which one provides a better outcome for patients with gallbladder and common bile duct stones. MATERIALS AND METHODS: An electronic literature search was undertaken using Embase, Medline, PubMed, and Cochrane Library databases up to April 2022. For quality assessment of included studies, randomized controlled trials (RCTs) were assessed by utilizing the Jadad scale. The primary outcome includes surgical success rate, retained stone rate, stone clearance rate, major morbidity, and mortality. The second outcome includes conversion to open surgery rate, postoperative pancreatitis, bile leakage, cholangitis, hemorrhage, pneumonia, and surgical-site infection. RESULTS: 14 randomized controlled trials with 2,181 patients were included. No significant difference was seen between the two groups in terms of surgical success, stone clearance, retained stones, operation time, and total morbidity. LC-LCBDE had higher rate of bile leakage [relative risk (RR): 4.52; 95% confidence interval (CI): 2.19-9.31] and lower rate of postoperative pancreatitis (RR: 0.25; 95% CI: 0.13-0.46), cholangitis (RR: 0.17; 95% CI: 0.05-0.67), and hemorrhage (RR: 0.18; 95% CI: 0.07-0.42). CONCLUSIONS: Both LC+LCBDE and LC+ERCP are safe, effective, and minimal-invasive treatments for concomitant gallbladder and CBD stones. LC-LCBDE was associated with comparable effects compared with LC+ERCP in terms of surgical success rate, stone clearance rate, retained stones rate, operation time, and total morbidity. At the same time, LC-LCBDE had a higher rate of bile leakage and a lower rate of postoperative pancreatitis, cholangitis, and hemorrhage.

Acupuncture combined with exercise training at different time points on nerve repair of cerebral ischemia-reperfusion injury in rats and its effects on the expressions of Nestin, bFGF and EGF.

OBJECTIVE: The aim of the study was to observe the neuroreparative effect of electroacupuncture in rats with cerebral ischemia-reperfusion injury, and to explore the difference in the therapeutic effect of acupuncture on different acupoint groups after cerebral ischemia-reperfusion. MATERIALS AND METHODS: Experimental rats were randomly divided into: sham operation group, model group, electroacupuncture group, rehabilitation group, and Diankang group (electroacupuncture + rehabilitation training). There were 24 rats in each group, and the focal cerebral ischemia-reperfusion model was established by Zea-Longa suture method. After modeling, it took 4 hours to electroacupuncture at Baihui and Dazhui points, which was used to observe the changes of nerve function in rats with signs of keel nerve function defect. Protein expression was detected by immunohistochemistry. RESULTS: Compared with the model group, the EA 3d, 7d, 10d groups and the rehabilitation group had no significant difference in promoting the expression of Nestin (p>0.05). There was a significant difference (p<0.01). After cerebral ischemia-reperfusion injury, the expression of bFGF and EGF on the ischemic side was stronger. The peak of bFGF expression appeared earlier, and the peak of EGF expression appeared later. The expression of bFGF and EGF in cerebral ischemic cortex at different time points of ischemia in electroacupuncture group, rehabilitation group and Diankang group was increased, and the response was enhanced. The effect of Diankang group on the upregulation of bFGF and EGF was more significant (p<0.01, p<0.05). CONCLUSIONS: Under the influence of different effects, Diankang is superior to simple treatment in improving ischemic neurological dysfunction. This may be related to the fact that Diankang can promote the proliferation of neural stem cells and the expression of neurotrophic factors on the ischemic side of the rat brain.

Red cell distribution in critically ill patients with chronic obstructive pulmonary disease.

BACKGROUND: Red blood cell distribution width (RDW) is associated with increased mortality risk in patients with chronic obstructive pulmonary disease (COPD). However, limited data are available for critically ill patients with COPD. METHODS: Data from the Medical Information Mart for Intensive Care III V1.4 database were analyzed in this retrospective cohort research. The International Classification of Diseases codes were used to identify critically ill patients with COPD. The first value of RDW was extracted within the first 24 h after intensive care unit admission. The endpoint was 28-day all-cause mortality. Multivariable logistic regression analysis was performed to examine the relationship between RDW and 28-day mortality. Age, sex, ethnicity, anemia status, comorbidities, clinical therapy, and disease severity score were considered for subgroup analysis. RESULTS: A total of 2,344 patients were included with mean (standard deviation) age of 72.3 (11.3) years, in which 1,739 (53.6%) patients were men. The increase in RDW was correlated with an increased risk of 28-day mortality in the multivariate logistic regression model (odds ratio [OR] 1.15; 95% confidence interval [CI] 1.09-1.21). In comparison with the low-RDW group, the middle and high-RDW groups tended to have higher risks of 28-day all-cause mortality (OR [95% CI] 1.03 [0.78-1.34]; OR [95% CI] 1.70 [1.29-2.22]; P trend < 0.0001). Subgroup analyses show no evidence of effect modifications on the correlation of RDW and 28-day all-cause mortality. CONCLUSION: An increase in RDW was associated with an increased risk of 28-day all-cause mortality in critically ill patients with COPD. Further studies are required to investigate this association.

[Effects and mechanism of pressure treatment on hemodynamic changes in patients with hypertrophic scar secondary to extensive burns].

Objective: To investigate the hemodynamic changes of the main arteries and veins of the extremities and the heart in patients with hypertrophic scar secondary to extensive burns after pressure treatment, and to analyze the relevant mechanisms. Methods: A retrospective before-after self-control study was conducted. From January 2017 to February 2022, 37 patients with hypertrophic scar secondary to extensive burns who met the inclusion criteria were hospitalized in the Burn Rehabilitation Department of Guangdong Industrial Injury Rehabilitation Hospital, including 25 males and 12 females, aged 23-52 years. The patients were admitted to the hospital within 12 weeks after wound healing, and within one week after admission, rehabilitation therapists, occupational therapists, and tailors custom-made pressure products such as full-body pressure garment, pressure pants, vests, split finger gloves, split finger socks, hoods, and plastic collars, with the pressure at each part maintained at 2.67-4.00 kPa when wearing. Before the first treatment with pressure products (hereinafter referred to as before pressure treatment) and at 1 h of the first treatment with pressure products (hereinafter referred to as 1 h of pressure treatment), color Doppler ultrasonography was performed to check the pulse rate of the axillary artery, the lumen diameter, peak systolic velocity (PSV), and resistance index of the axillary artery and femoral artery on the left side, the lumen diameter, cross-sectional area, and average blood flow velocity of the axillary vein and femoral vein, and the mitral valve E peak, mitral valve A peak, tricuspid valve E peak, aortic valve PSV, and pulmonary valve PSV of the heart; an optical chromatographic skin detector was used to detect the red color, red pigment, and surface brightness of the scar on the back of the hand to reflect the filling and distribution of the scar microvessels. Data were statistically analyzed with paired sample t test. Results: Compared with those before pressure treatment, the PSV of the axillary artery of patients was significantly slowed down at 1 h of pressure treatment (t=55.42, P<0.01); the average blood flow velocity of the axillary vein was significantly accelerated (t=-60.50, P<0.01); the pulse rate, lumen diameter, and resistance index of the axillary artery, as well as the lumen diameter and cross-sectional area of the axillary vein did not change obviously (P>0.05); the average blood flow velocity of the femoral vein was significantly accelerated (t=-80.52, P<0.01); the lumen diameter, PSV, and resistance index of the femoral artery, as well as the lumen diameter and cross-sectional area of the femoral vein had no significant change (P>0.05); the mitral valve E peak and mitral valve A peak of the heart decreased significantly (with t values of 10.71 and 21.96, respectively, P<0.01); the tricuspid valve E peak of the heart increased significantly (t=7.57, P<0.01); the PSV of the aortic valve and pulmonary valve of the heart did not change obviously (P>0.05). At 1 h of pressure treatment, the red color and red pigment values of the scar on the back of the hand of patients were 15.3±1.1 and 16.8±1.2, respectively, which were significantly lower than 24.5±1.3 and 23.8±1.2 before pressure treatment (with t values of 8.32 and 8.04, respectively, P<0.01). The brightness value of the scar surface on the back of the hand of patients at 1 h of pressure treatment was similar to that before pressure treatment (P>0.05). Conclusions: After pressure treatment for the hypertrophic scar in patients secondary to extensive burn, the average blood flow velocity of the axillary vein and femoral vein in patients are obviously accelerated, the PSV of the axillary artery is significantly slowed down, the peak values of mitral valve E and mitral valve A of the heart are significantly decreased, and the tricuspid valve E peak is significantly increased. These hemodynamic changes may be related to the reduction of microvascular blood flow in the local area of scar after systemic pressure treatment.

[Research progress on mechanisms of traditional Chinese medicine in prevention and treatment of postoperative peritoneal adhesion].

Peritoneal adhesion is one of the common complications after abdominal operation, which could seriously affect the quality of life in patients. Although the development of modern surgical technology and the improvement of doctors' operation level have reduced the incidence of peritoneal adhesion to a certain extent, due to the lack of special treatment drugs, the therapeutic effect still cannot meet the expectations and requirements of clinicians and patients. Traditional Chinese medicines(TCM) have unique advantages and remarkable curative effect in the treatment of peritoneal adhesion, and they can play an important role in regulating multiple pathological links. However, the relevant researches and product development of TCM against peritoneal adhesion have not attracted enough attention from industry scholars. As for the related work that has been carried out, most of the studies on the efficacy and mechanism are not thorough and systematic enough, seriously restricting the industrial development in this field. In this paper, the efficacy and mechanism were systematically described and summarized based on the review of papers in the recent years, so as to provide a reference for the thorough study of TCM in the prevention and treatment of peritoneal adhesions, and promote the deep development and industrialization process of related products.

Targeted Sequencing Improves DIPSS-Plus Prognostic Scoring in Myelofibrosis Patients Undergoing Allogeneic Transplantation.

Primary myelofibrosis (MF) and secondary MF developing after polycythemia vera or essential thrombocythemia are clonal disorders of hematopoiesis. Currently the sole therapy offering the potential of cure is hematopoietic cell transplantation (HCT). Several risk classification systems including clinical, hematologic, and mutational parameters have been proposed. We analyzed the mutational landscape in addition to the Dynamic International Prognostic Scoring System (DIPSS)-plus in 55 patients with MF to determine the combined impact on post-HCT outcome. Mutations, analyzed in 75 genes, were most common in JAK2, CALR, ASXL1, TET2, GATA2, EZH2, U2AF1, and ETV6. Patients with ≥3 mutations in addition to JAK2 or CALR mutations had a higher post-transplantation relapse rate and nonrelapse mortality than patients with fewer mutations, independent of DIPSS-plus risk. The presence of higher numbers of mutations identified patients at the greatest risk of relapse within the highest overall risk group as determined by DIPSS-plus. These findings are consistent with molecular risk classifications for patients who do not undergo HCT and support the proposed transplantation risk classification incorporating mutational information.

Bulk Fermi Surfaces of the Dirac Type-II Semimetallic Candidates MAl_{3} (Where M=V, Nb, and Ta).

We report a de Haas-van Alphen (dHvA) effect study on the Dirac type-II semimetallic candidates MAl_{3} (where, M=V, Nb and Ta). The angular dependence of their Fermi surface (FS) cross-sectional areas reveals a remarkably good agreement with our first-principles calculations. Therefore, dHvA supports the existence of tilted Dirac cones with Dirac type-II nodes located at 100, 230 and 250 meV above the Fermi level ϵ_{F} for VAl_{3}, NbAl_{3} and TaAl_{3} respectively, in agreement with the prediction of broken Lorentz invariance in these compounds. However, for all three compounds we find that the cyclotron orbits on their FSs, including an orbit nearly enclosing the Dirac type-II node, yield trivial Berry phases. We explain this via an analysis of the Berry phase where the position of this orbit, relative to the Dirac node, is adjusted within the error implied by the small disagreement between our calculations and the experiments. We suggest that a very small amount of doping could displace ϵ_{F} to produce topologically nontrivial orbits encircling their Dirac node(s).

α-Mangostin, A Natural Xanthone, Induces Apoptosis and ROS Accumulation in Human Rheumatoid Fibroblast-Like Synoviocyte MH7A Cells.

BACKGROUND: Rheumatoid arthritis (RA) is a complicated and heterogeneous chronic disease with the characteristic of progressive joint destruction, deformity and disability. It is associated with not only genetic but also environmental factors. Many studies suggest that RA-derived fibroblast-like synoviocyte (RA-FLS) is involved in the pathogenic process of RA. The apoptosis and proliferation of RA-FLS is of great importance in the development and progression in RA. Nowadays, more and more traditional Chinese medicine (TCM) or natural products are studied in the treatment of RA. OBJECTIVE: To investigate the effects of several natural products and the apoptosisinduced effect of α-mangostin and its underlying mechanisms in RA-FLS MH7A cells. METHODS: The effects of natural products on MH7A cells were detected by MTT assay. Annexin V-FITC/PI double labeling and DAPI staining were adopted to observe the apoptosis induced by α-mangostin. The apoptosis related proteins were measured with western blotting analysis. ROS accumulation was determined by DHE staining. RESULTS: Xantones, including Garcinone C, α-mangostin and γ-mangostin, significantly inhibited the MH7A cell viability. And α-mangostin induces apoptosis in MH7A cells. Further study showed that α-mangostin increased the ratio of Bax/Bcl-2 and increased the ROS generation in MH7A cells. CONCLUSION: α-Mangostin induces the apoptosis of MH7A cells through increasing ROS accumulation and the ratio of Bax/Bcl-2, suggesting that α-mangostin should be benefit to the therapy of RA.

Massively parallel digital transcriptional profiling of single cells.

Characterizing the transcriptome of individual cells is fundamental to understanding complex biological systems. We describe a droplet-based system that enables 3' mRNA counting of tens of thousands of single cells per sample. Cell encapsulation, of up to 8 samples at a time, takes place in ∼6 min, with ∼50% cell capture efficiency. To demonstrate the system's technical performance, we collected transcriptome data from ∼250k single cells across 29 samples. We validated the sensitivity of the system and its ability to detect rare populations using cell lines and synthetic RNAs. We profiled 68k peripheral blood mononuclear cells to demonstrate the system's ability to characterize large immune populations. Finally, we used sequence variation in the transcriptome data to determine host and donor chimerism at single-cell resolution from bone marrow mononuclear cells isolated from transplant patients.

The HIF/PHF8/AR axis promotes prostate cancer progression.

Recent studies provide strong evidence that the androgen receptor (AR) signaling pathway remains active in castration-resistant prostate cancer (CRPC). However, the underlying mechanisms are not well understood. In this study, we demonstrate that plant homeo domain finger protein 8 (PHF8 )interacts with and functions as an essential histone demethylase activity-dependent AR coactivator. Furthermore, we demonstrate that the expression of PHF8 is induced by hypoxia in various prostate cancer cell lines. Knockdown of either hypoxia-inducible factor HIF2α or HIF1α almost completely abolished hypoxia-induced PHF8 expression. Importantly, we observed that PHF8 is highly expressed in clinical androgen deprived prostate cancer samples and expression of PHF8 correlates with increased levels of HIF1α and HIF2α. Moreover, elevated PHF8 is associated with higher grade prostate cancers and unfavorable outcomes. Our findings support a working model in which hypoxia in castrated prostate cancer activates HIF transcription factors which then induces PHF8 expression. The elevated PHF8 in turn promotes the AR signaling pathway and prostate cancer progression. Therefore, the HIF/PHF8/AR axis could serve as a potential biomarker for CRPC and is also a promising therapeutic target in combating CRPC.

Serum human epididymis protein 4 is associated with the treatment response of concurrent chemoradiotherapy and prognosis in patients with locally advanced non-small cell lung cancer.

AIM: To investigate the role of human epididymis protein 4 (HE4) in the diagnosis and prognosis of patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiotherapy (CRT). METHODS: A total of 218 patients with LA-NSCLC were enrolled. All patients underwent CRT. The treatment response to CRT was evaluated. The prognosis analysis was performed using relapse-free survival (RFS) and overall survival [1]. RESULTS: Our data show that the serum HE4 can discriminate patients who respond well to CRT from those who respond poorly. Higher serum HE4 had dramatically increased risk of being non-responders to CRT. Serum HE4 level is also associated with prognosis of patients after CRT. Patients with high HE4 level had shorter RFS and OS compared to those with low HE4 level. CONCLUSION: Our data suggest that serum HE4 may be a useful prognostic biomarker for LA-NSCLC patients who underwent CRT.

Dynamic change in natural killer cell type in the human ocular mucosa in situ as means of immune evasion by adenovirus infection.

The most severe form of virus-induced inflammation at the ocular surface is epidemic keratoconjunctivitis (EKC), often caused by group D human adenoviruses (HAdVs). We investigated the dynamics and mechanisms of changes in natural killer (NK) cell types in the human ocular mucosal surface in situ over the course of infection. In the acute phase of infection, the mature CD56(dim)NK cells that comprise a major subpopulation in the normal human conjunctiva are replaced by CD56(bright)NK cells recruited to the ocular surface by chemokines produced by the infected epithelium, and NKG2A-expressing CD56(dim) and CD56(bright) NK cells become the major subpopulations in severe inflammation. These NK cells attracted to the mucosal surface are however incapable of mounting a strong antiviral response because of upregulation of the inhibitory ligand human leukocyte antigen-E (HLA-E) on infected epithelium. Furthermore, group D HAdVs downregulate ligands for activating NK cell receptors, thus rendering even the mature NKG2A(-)NK cells unresponsive, an immune-escape mechanism distinct from other adenoviruses. Our findings imply that the EKC-causing group D HAdVs utilize these multiple pathways to inhibit antiviral NK cell responses in the initial stages of the infection.

Metabolic response of LLC xenografted mice to oxythiamine, as measured by [¹H] NMR spectroscopy.

Oxythiamine (OT) has been proven to be a potential anticancer drug. With the help of NMR-based metabonomics, we studied the metabolic changes within tumor-bearing mice with different levels of OT administration using a C57BL/6 mouse Lewis lung carcinoma tumor transplantation model. We administered different concentrations of OT (75, 150, 300, and 600 mg∙kg(-1)∙day(-1)) to the mice orally for 2 weeks, recorded animal weights and tumor volumes, sacrificed the animals, and collected blood and tumor mass samples for nuclear magnetic resonance determination. Compared with the findings for the control (untreated) group, the tumor weights and volumes of the 150, 300, and 600 mg∙kg-1∙day-1 groups decreased with no difference among these OT groups. A large metabolite difference was observed in plasma metabolites between the blank and control groups, which indicated the success of the tumor-bearing model. The metabolites in tumor associated with thiamine-dependent enzymes (TDEs) underwent considerable change between the OT and control groups, exhibiting concentration dependence and enzyme specificity. The restriction of TDEs by OT may be a major mechanism underlying its anticancer effect. The role of OT as a potential anticancer drug and a dehydrogenase inhibitor should therefore be taken into consideration in future tumor research.

Pretreatment With Erythropoietin Attenuates Intestinal Ischemia Reperfusion Injury by Further Promoting PI3K/Akt Signaling Activation.

BACKGROUND: Erythropoietin (EPO) has been shown to be beneficial in resolution of acute inflammation and intestinal ischemia/reperfusion (IR) injury is featured by the excessive immune response. The current research is designed to evaluate the effect and potential mechanisms of EPO on the intestinal IR injury. Therefore, the effect of EPO on intestinal IR injury was examined by the change of intestinal histology; the expression of pro-inflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and interferon γ (IFN-γ); and the protein levels of EPOR, p-EPOR, p85, p-p85, Akt, p-Akt, IκΒ-α, p-p65, and p65. MATERIALS AND METHODS: Thirty male Sprague-Dawley rats were randomly divided into three groups: sham group (sham), IR-saline group (IRI), and the IR-EPO group (EPO). Rats were treated with EPO (5000 U/kg) 1 hour before IR induction. A rat model of IR injury was established by ligating the superior mesenteric artery for 30 minutes, followed by reperfusion for 1 hour. Intestinal histology, pro-inflammatory cytokines, and mediators were assessed. The effect of EPO on PI3K/Akt/NF-κB signaling and EPOR were also measured. RESULTS: EPO significantly decreased the pathologic changes of intestinal and reduced the elevation of pro-inflammatory cytokines TNF-α, IL-1ß, and IFN-γ in intestinal and serum caused by IR which was associated with suppressing NF-κB activation by further promoting activation of PI3K/Akt signaling. CONCLUSIONS: EPO ameliorated the acute intestinal injury caused by IR, which was associated with further activating PI3K/Akt signaling to suppress NF-κΒ-mediating inflammation. Our findings suggest that EPO could be useful for preventing IR-induced intestinal injury.

Signal peptide peptidase-mediated nuclear localization of heme oxygenase-1 promotes cancer cell proliferation and invasion independent of its enzymatic activity.

Heme oxygenase-1 (HO-1) is a heme-degrading enzyme anchored in the endoplasmic reticulum by a carboxyl-terminal transmembrane segment (TMS). HO-1 is highly expressed in various cancers and its nuclear localization is associated with the progression of some cancers. Nevertheless, the mechanism underlying HO-1 nuclear translocation and its pathological significance remain elusive. Here we show that the signal peptide peptidase (SPP) catalyzes the intramembrane cleavage of HO-1. Coexpression of HO-1 with wild-type SPP, but not a dominant-negative SPP, promoted the nuclear localization of HO-1 in cells. Mass spectrometry analysis of cytosolic HO-1 isolated from HeLa cells overexpressing HO-1 and SPP revealed two adjacent intramembrane cleavage sites located after S275 and F276 within the TMS. Mutations of S275F276 to A275L276 significantly hindered SPP-mediated HO-1 cleavage and nuclear localization. Nuclear HO-1 was detected in A549 and DU145 cancer cell lines expressing high levels of endogenous HO-1 and SPP. SPP knockdown or inhibition significantly reduced nuclear HO-1 localization in A549 and DU145 cells. The positive nuclear HO-1 stain was also evident in lung cancer tissues expressing high levels of HO-1 and SPP. Overexpression of a truncated HO-1 (t-HO-1) lacking the TMS in HeLa and H1299 cells promoted cell proliferation and migration/invasion. The effect of t-HO-1 was not affected by a mutation in the catalytic site. However, blockade of t-HO-1 nuclear localization abolished t-HO-1-mediated effect. The tumorigenic effect of t-HO-1 was also demonstrated in the mouse model. These findings disclose that SPP-mediated intramembrane cleavage of HO-1 promotes HO-1 nuclear localization and cancer progression independent of HO-1 enzymatic activity.

MicroRNA-19b targets Mfn1 to inhibit Mfn1-induced apoptosis in osteosarcoma cells.

Accumulative evidence has confirmed that, miR-17-92, a typical polycistronic mRNA cluster, was up-regulated in various solid tumors, and play an important role in the occurrence and development progress of tumors. In our study, we detected the six members of miR-17-92 cluster in osteosarcoma cell line, finding that the expression of miR-17 and miR-19b was up-regulated significantly. Further studies have found that Mfn1 was one of the target genes of miR-19b and the transcription and expression level of Mfn1 were down-regulated by miR-19b. MTS, flow cytometry, TUNEL-DAPI, Annexin V-FITC and transwell assay demonstrated that Mfn1 significantly blocked the cell cycle, promoted apoptosis and inhibited proliferation and invasion of osteosarcoma cells. Whereas, miR-19b targets 3'UTR sequences of Mfn1 genes inhibit the expression of Mfn1, thus inhibited Mfn1 triggered anti-cancer effect. Taken together, miR-19b functions by targeting Mfn1 reduce the protein expression level, thus provides a novel target to understand the molecular biology and genetics mechanisms of occurrence and development of osteosarcoma, contributing to the diagnosis and therapy of osteosarcoma.