Autophagy can be tumor suppressive as well as promotive in regulation of tumorigenesis and disease progression. Accordingly, the prognostic significance of autophagy key regulator Beclin 1 was varied among different tumors. Here, we detected the clinicopathological and prognostic effect of Beclin 1 in the subtypes of intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). Beclin 1 expression level was detected by immunohistochemistry staining in 106 ICC and 74 ECC patients. We found that Beclin 1 was lowly expressed in 126 (70%) cholangiocarcinoma patients, consist of 72 ICC and 54 ECC. Moreover, the cholangiocarcinoma patients with lymph node metastasis (N1) had a lower Beclin 1 level than that of N0 subgroup (P=0.012). However, we did not detect any correlations between Beclin 1 and other clinicopathological features, including tumor subtypes, vascular invasion, HBV infection, liver cirrhosis, cholecystolithiasis and TNM stage. Survival analysis showed that, compared with the high expression subset, Beclin 1 low expression was correlated with a poorer 3-year progression-free survival (PFS, 69.1% VS 46.8%, P=041) for cholangiocarcinoma. Importantly, our stratified univariate and multivariate analysis confirmed that Beclin 1 lowly expressed ICC had an inferior PFS as well as overall survival than ECC, particularly than that of Beclin 1 highly expressed ECC patients. Thus, our study demonstrated that Beclin 1low expression, correlated with lymph node metastasis, and might be a negative prognostic biomarker for cholangiocarcinoma. Combined Beclin 1 level with the anatomical location might lead to refined prognosis for the subtypes of ICC and ECC.
Infantile hemangiomas are the most common benign vascular tumors in infancy and childhood. As hemangioma could regress spontaneously, it generally does not require treatment unless proliferation interferes with normal function or gives rise to risk of serious disfigurement and complications unlikely to resolve without treatment. Various methods for treating infant hemangiomas have been documented, including wait and see policy, laser therapy, drug therapy, sclerotherapy, radiotherapy, surgery and so on, but none of these therapies can be used for all hemangiomas. To obtain the best treatment outcomes, the treatment protocol should be individualized and comprehensive as well as sequential. Based on published literature and clinical experiences, we established a treatment guideline in order to provide criteria for the management of head and neck hemangiomas. This protocol will be renewed and updated to include and reflect any cutting-edge medical knowledge, and provide the newest treatment modalities which will benefit our patients.
Hemangiomas; treatment; head and neck; sclerotherapy; drug therapy
To characterize the white matter structural changes at the tract level and tract group level, comprehensive analysis with four metrics derived from DTI, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD) and radial diffusivity (RD), was conducted. Tract groups, namely limbic, commissural, association and projection tracts, include white matter tracts of similar functions. DTI data were acquired from 61 subjects (26 AD, 11 subjects with amnestic mild cognitive impairment or aMCI, 24 age-matched controls). An atlas-based approach was used to survey 30 major cerebral white matter tracts with the measurements of FA, MD, AxD and RD. Regional cortical atrophy and cognitive functions of AD patients were also measured to correlate with the structural changes of white matter. Synchronized structural changes of cingulum bundle and fornix, both of which are part of limbic tract group, were revealed. Widespread yet distinctive structural changes were found in limbic, commissural, association and projection tract groups between control and AD subjects. Specifically, FA, MD and RD of limbic tracts, FA, MD, AxD and RD of commissural tracts, MD, AxD and RD of association tracts and MD and AxD of projection tracts are significantly different between AD patients and control subjects. In contrast, the comparison between aMCI and control subjects shows disruption only in the limbic and commissural tract groups of aMCI subjects. MD values of all tract groups of AD patients are significantly correlated to cognitive functions. Difference between AD and control and that between MCI and control indicates a progression pattern of white matter disruption from limbic and commissural tract group to other tract groups. High correlation between FA, MD and RD measurements from limbic tracts and cortical atrophy suggests the disruption of the limbic tract group is caused by the neuronal damage.
Alzheimer’s disease; atlas; DTI; white matter tract; tract group; biomarker
Clinical studies have demonstrated the predictive values of changes in electrocardiographic (ECG) parameters for the preexisting myocardial ischemic infarction. However, a simple and early predictor for the subsequent development of myocardial infarction during the ischemic phase is of significant value for the identification of ischemic patients at high risk. The present study was undertaken by using non-human primate model of myocardial ischemic infarction to fulfill this gap. Twenty male Rhesus monkeys at age of 2–3 years old were subjected to left anterior descending artery ligation. This ligation was performed at varying position along the artery so that it produced varying sizes of myocardial infarction at the late stage. The ECG recording was undertaken before the surgical procedure, at 2 h after the ligation, and 8 weeks after the surgery for each animal. The correlation of the changes in the ECG waves in the early or the late stage with the myocardial infarction size was analyzed. The R wave depression and the QT shortening in the early ischemic stage were found to have an inverse correlation with the myocardial infarction size. At the late stage, the R wave depression, the QT prolongation, the QRS score, and the ST segment elevation were all closely correlated with the developed infarction size. The poor R wave progression was identified at both the early ischemic and the late infarction stages. Therefore, the present study using non-human primate model of myocardial ischemic infarction identified the decreases in the R wave and the QT interval as early predictors of myocardial infarction. Validation of these parameters in clinical studies would greatly help identifying patients with myocardial ischemia at high risk for the subsequent development of myocardial infarction.
Venous malformation is one of the most common benign vascular lesions, with approximately 40% of cases appearing in the head and neck. They can affect a patient’s appearance and functionality and even cause life-threatening bleeding or respiratory tract obstruction. The current methods of treatment include surgery, laser therapy, sclerotherapy, or a combined. The treatment of small and superficial venous malformations is relatively simple and effective; however, the treatment of deep and extensive lesions involving multiple anatomical sites remains a challenge for the physicians. For complex cases, the outcomes achieved with one single treatment approach are poor; therefore, individualized treatment modalities must be formulated based on the patient’s condition and the techniques available. Comprehensive multidisciplinary treatments have been adapted to achieve the most effective results. In this paper, based on the national and international literature, we formulated the treatment guidelines for head and neck venous malformations to standardize clinical practice. The guideline will be renewed and updated in a timely manner to reflect cutting-edge knowledge and to provide the best treatment modalities for patients.
Head and neck; venous malformation; treatment guidelines
Over the past decade, liposomes became a focal point in developing drug delivery systems. New liposomes, with novel lipid molecules or conjugates, and new formulations opened possibilities for safely and efficiently treating many diseases including cancers. New types of liposomes can prolong circulation time or specifically deliver drugs to therapeutic targets. This article concentrates on current developments in liposome based drug delivery systems for treating diseases of the gastrointestinal tract. We will review different types and uses of liposomes in the development of therapeutics for gastrointestinal diseases including inflammatory bowel diseases and colorectal cancer.
liposome; colorectal cancer; inflammatory bowel disease; drug delivery
Although behavioral deficits in bipolar disorder (BPD) are well described, the specific brain white matter (WM) disruptions have not been completely characterized, and neural mechanisms underlying dysfunction in BPD are not well established, particularly for youth with BPD and aggression. This preliminary study utilized diffusion tensor imaging (DTI) to investigate commissural tracts (corpus callosum [CC] and anterior commissure [AC]) in youth with BPD, because disruption of interhemispheric communication may contribute to the emotional deficits that are characteristic of the illness.
DTI was used to investigate WM in 10 youth (7–17 years of age) with BPD and 10 typically developing age-matched controls. Tract-based spatial statistics voxel-wise analysis was used to compare fractional anisotropy (FA) of the two groups. We specifically focused on five subdivisions of the midsagittal CC as well as on the decussation of AC, which connects the temporal lobes. Exploratory correlations between FA values and life history of aggression scores were calculated for the BPD group.
Youth with BPD had significantly lower FA values in the callosal genu and AC. FA values in the AC were negatively correlated with a life history of aggression in the BPD group.
These results contribute to a growing literature implicating a role for the genu of the CC in BPD and are the first to report WM variations in the AC of children with BPD. Taken together with the correlational data for aggression and the role of the AC in emotional processing, our data provide preliminary evidence for a possible association between the structural integrity of the WM of the AC and aggression in pediatric BPD.
The transjugular intrahepatic portosystemic shunt (TIPS) is an acceptable procedure that has proven benefits in the treatment of patients who have complications from portal hypertension due to liver cirrhosis. Delayed liver laceration is a rare complication of the TIPS procedure. We describe a patient with portal hypertension due to liver cirrhosis, who suddenly presented with abdominal hemorrhage and liver laceration 8 d after TIPS. Few reports have described complications after TIPS placement. To the best of our knowledge, this is the first report describing delayed liver laceration. This potential and serious complication appears to be specific and fatal for TIPS in portal hypertension. We advocate careful attention to the technique to avoid this complication, and timely treatment is extremely important.
Transjugular intrahepatic portosystemic shunt; Portal hypertension; Liver cirrhosis; Postoperative complications; Hemorrhage
Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor (TNFR) superfamily, is associated with anti-tumor immunity suppression. It is highly expressed in many tumors, and its expression can be regulated by the MAPK/MEK/ERK signaling pathway. The MAPK/MEK/ERK pathway has been reported to be a regulator in tumor occurrence, development and clonal expansion. External-signal regulated kinase (ERK) is a vital member of this pathway.
The expression of DcR3 and ERK1/2 in tumor tissues of gastric cancer patients was significantly higher than the non-cancerous group (P < 0.05). There was no statistical difference among tumor tissues from patients with different ages or gender, and even of different differentiation (P > 0.05). However, in patients with stage I gastric cancer, the DcR3 and ERK1/2 levels were significantly lower than patients with more advanced stages.
DcR3 and ERK1/2 play a vital role in the development of gastric cancer, and they may be new markers for indicating the efficiency of gastric cancer treatment in the future.
Farber disease is a rare lysosomal storage disorder (LSD) that manifests due to acid ceramidase (AC) deficiencies and ceramide accumulation. We present a preclinical gene therapy study for Farber disease employing a lentiviral vector (LV-huAC/huCD25) in three enzymatically normal nonhuman primates. Autologous, mobilized peripheral blood (PB) cells were transduced and infused into fully myelo-ablated recipients with tracking for at least 1 year. Outcomes were assessed by measuring the AC specific activity, ceramide levels, vector persistence/integration, and safety parameters. We observed no hematological, biochemical, radiological, or pathological abnormalities. Hematological recovery occurred by approximately 3 weeks. Vector persistence was observed in PB and bone marrow (BM) cells by qualitative and quantitative PCR. We did not observe any clonal proliferation of PB and BM cells. Importantly, AC-specific activity was detected above normal levels in PB and BM cells analyzed post-transplantation and in spleens and livers at the endpoint of the study. Decreases of ceramide in PB cells as well as in spleen and liver tissues were seen. We expect that this study will provide a roadmap for implementation of clinical gene therapy protocols targeting hematopoietic cells for Farber disease and other LSDs.
Farber disease is a rare autosomal recessive condition resulting from reduced or absent acid ceramidase (AC; EC 220.127.116.11) activity. In this study, Neschadim et al. present results from a preclinical study wherein autologous lentivector/AC–transduced hematopoietic cells were infused into enzymatically normal nonhuman primates. Animals were tracked for 1 year, and no hematological, biochemical, radiological, or pathological abnormalities were observed. Importantly, AC-specific activity was detected above normal levels in peripheral blood and bone marrow cells analyzed post transplantation and in spleens and livers at the endpoint of the study.
In the title molecule, C9H3Cl3O3, there are three short interactions involving the benzene H atoms and the chloroformyl Cl atoms. In the crystal, molecules stack along the a axis with no significant non-bonded interactions.
Accurate prognostication of locally advanced nasopharyngeal carcinoma (NPC) will benefit patients for tailored therapy. Here, we addressed this issue by developing a mathematical algorithm based on support vector machine (SVM) through integrating the expression levels of multi-biomarkers.
Ninety-seven locally advanced NPC patients in a randomized controlled trial (RCT), consisting of 48 cases serving as training set and 49 cases as testing set of SVM models, with 5-year follow-up were studied. We designed SVM models by selecting the variables from 38 tissue molecular biomarkers, which represent 6 tumorigenesis signaling pathways, and 3 EBV-related serological biomarkers. We designed 3 SVM models to refine prognosis of NPC with 5-year follow-up. The SVM1 displayed highly predictive sensitivity (sensitivity, specificity were 88.0% and 81.9%, respectively) by integrating the expression of 7 molecular biomarkers. The SVM2 model showed highly predictive specificity (sensitivity, specificity were 84.0% and 94.5%, respectively) by grouping the expression level of 12 molecular biomarkers and 3 EBV-related serological biomarkers. The SVM3 model, constructed by combination SVM1 with SVM2, displayed a high predictive capacity (sensitivity, specificity were 88.0% and 90.3%, respectively). We found that 3 SVM models had strong power in classification of prognosis. Moreover, Cox multivariate regression analysis confirmed these 3 SVM models were all the significant independent prognostic model for overall survival in testing set and overall patients.
Our SVM prognostic models designed in the RCT displayed strong power in refining patient prognosis for locally advanced NPC, potentially directing future target therapy against the related signaling pathways.
Alterations in white matter integrity of several cortical and subcortical circuits have been reported in relation to unipolar major depressive disorder. It is not clear whether these white matter changes precede the onset of illness. In all, 13 adolescent volunteers with no personal or family history of a psychiatric disorder (controls) and 18 adolescent volunteers with no personal history of a psychiatric illness including depression, but who were at high risk for developing unipolar depression by virtue of parental depression (high-risk youth), underwent diffusion tensor imaging studies. An automated tract-based spatial statistics method, a whole-brain voxel-by-voxel analysis, was used to analyze the scans. Population average diffusion parameter values were also calculated for each tract. Adolescents at high risk for unipolar depression had lower fractional anisotropy (FA) values in the left cingulum, splenium of the corpus callosum, superior longitudinal fasciculi, uncinate, and inferior fronto-occipital fasciculi than did controls. Altered white matter integrity in healthy adolescents at familial risk for unipolar depression suggests that it might serve as a vulnerability marker for the illness.
adolescent; corpus callosum; depression; high risk; magnetic resonance imaging; tract-based spatial statistical analysis; depression, unipolar/bipolar; neuroanatomy; biological psychiatry; psychiatry & behavioral sciences; adolescent; magnetic resonance imaging; depression; corpus callosum; high risk
Alterations in white matter integrity of several cortical and sub-cortical circuits have been reported in relation to unipolar major depressive disorder. It is not clear whether these white matter changes precede the onset of illness. Thirteen adolescent volunteers with no personal or family history of a psychiatric disorder (controls) and 18 adolescent volunteers with no personal history of a psychiatric illness including depression, but who were at high risk for developing unipolar depression by virtue of parental depression (high-risk youth), underwent diffusion tensor imaging studies. An automated tract-based spatial statistics (TBSS) method, a whole-brain voxel-by-voxel analysis, was used to analyze the scans. Population average diffusion parameter values also were calculated for each tract. Adolescents at high risk for unipolar depression had lower fractional anisotropy (FA) values in the left cingulum, splenium of the corpus callosum, superior longitudinal fasciculi, uncinate and inferior fronto-occipital fasciculi than controls. Altered white matter integrity in healthy adolescents at familial risk for unipolar depression suggests that it might serve as a vulnerability marker for the illness.
adolescent; corpus callosum; depression; high-risk; magnetic resonance imaging; tract-based spatial statistical analysis
In comparison with the previous determination [Saussine, Mimoun, Mitschler & Fisher (1980 ▶). Nouv. J. Chim.
4, 235–237] of the title compound, [V2(C4H10NO)4O3], the current study reports an improved precision of the derived geometric parameters, along with the deposition of all coordinates and displacement parameters. The two VV atoms are each surrounded by two deprotonated N,O-bidentate diethylhydroxylaminate groups, and a terminal and a bridging oxide ligand, in a distorted octahedral coordination geometry. The crystal packing is accomplished by van der Waals interactions.
Apoptosis plays an important role in embryonic development. PNAS-4 has been demonstrated to induce apoptosis in several cancer cells. In this study, we cloned Xenopus laevis PNAS-4 (xPNAS-4), which is homologous to the human PNAS-4 gene. Bioinformatics analysis for PNAS-4 indicated that xPNAS-4 shared 87.6% identity with human PNAS-4 and 85.5% with mouse PNAS-4. The phylogenetic tree of PNAS-4 protein was also summarized. An analysis of cellular localization using an EGFP-fused protein demonstrated that xPNAS-4 was localized in the perinuclear region of the cytoplasm. RT-PCR analysis revealed that xPNAS-4, as a maternally expressed gene, was present in all stages of early embryo development. Whole-mount in situ hybridization showed that xPNAS-4 was mainly expressed in ectoderm and mesoderm. Furthermore, microinjection of xPNAS-4 mRNA in vivo caused developmental defects manifesting as a small eye phenotype in the Xenopous embryos, and as a small eye or one-eye phenotype in developing zebrafish embryos. In addition, embryos microinjected with xPNAS-4 antisense morpholino oligonucleotides (MOs) exhibited a failure of head development and shortened axis.
The protein transduction domain from human immunodeficiency virus (HIV) Tat allows proteins to penetrate the cell membrane. Enhanced cellular uptake of therapeutic proteins could benefit a number of disorders. This is especially true for lysosomal storage disorders (LSDs) where enzyme replacement therapy (ERT) and gene therapy have been developed. We developed a novel recombinant lentiviral vector (LV) that engineers expression of α-galactosidase A (α-gal A)-Tat fusion protein for correction of Fabry disease, the second-most prevalent LSD with manifestations in the brain, kidney and heart. In vitro experiments confirmed mannose-6-phosphate independent uptake of the fusion factor. Next, concentrated therapeutic LV was injected into neonatal Fabry mice. Analysis of tissues at 26 wks demonstrated similar α-gal A enzyme activities but enhanced globotriaosylceramide (Gb3) reduction in hearts and kidneys compared with the α-gal A LV control. This strategy might advance not only gene therapy for Fabry disease and other LSDs, but also ERT, especially for cardiac Fabry disease.
The vaccinia virus (VACV) complement control protein (VCP) is the major protein secreted from VACV-infected cells. It has been reported that VCP binds to the surfaces of uninfected cells by interacting with heparan sulfate proteoglycans (HSPGs). In this study, we show that VCP is also expressed on the surfaces of infected cells and demonstrate that surface localization occurs independently of HSPGs. Since VCP does not contain a transmembrane domain, we hypothesized that VCP interacts with a membrane protein that localizes to the infected-cell surface. We show that the VACV A56 membrane protein is necessary for the cell surface expression of VCP and demonstrate that VCP and A56 interact in VACV-infected cells. Since the surface expression of VCP was abrogated by reducing agents, we examined the contribution of an unpaired cysteine residue on VCP to VCP surface expression and VCP's interaction with A56. To do this, we mutated the unpaired cysteine in VCP and generated a recombinant virus expressing the altered form of VCP. Following the infection of cells with the mutant virus, VCP was neither expressed on the cell surface nor able to interact with A56. Importantly, the cell surface expression of VCP was found to protect infected cells from complement-mediated lysis. Our findings suggest a new function for VCP that may be important for poxvirus pathogenesis and impact immune responses to VACV-based vaccines.
Tumor necrosis factor (TNF) and the type I TNF receptor (TNFRI), p55, are critical for resistance against primary infections with the intracellular bacterial pathogen Listeria monocytogenes. Importantly, however, susceptibility to primary listeriosis in cytokine-deficient mice does not preclude the development or expression of effective adaptive immunity against virulent L. monocytogenes. We used TNFRI−/− mice to study adaptive antilisterial immunity in the absence of interactions between TNF and TNFRI. Our experiments indicate that TNFRI−/− mice survive and clear high-dose challenges with an attenuated strain of L. monocytogenes that is incapable of cell-to-cell spread. Furthermore, TNFRI−/− mice immunized with attenuated L. monocytogenes go on to develop potent adaptive immunity to subsequent high-dose challenges with virulent L. monocytogenes. Interestingly, CD8+ T-cell depletion in vivo inhibits immunity to L. monocytogenes in the spleen but not in the liver of TNFRI−/− mice. The adaptive immune response in these animals is characterized by activation of listeriolysin O-specific CD8+ T cells, which are capable of transferring antilisterial immunity to naive wild-type C57BL/6 host mice. These experiments demonstrate the development and expression of potent CD8+ T-cell-mediated antilisterial immunity in the absence of TNFRI.
Infection of BALB/c mice with Listeria monocytogenes stimulates an antilisterial immune response evident by the appearance of H2-Kd-restricted CD8+ cytotoxic T lymphocytes (CTLs) specific for the nanomer peptides amino acids (aa) 91 to 99 of listeriolysin O (LLO 91–99) and aa 217 to 225 of the p60 molecule (p60 217–225). We have introduced point mutations at anchor residues within LLO 91–99 (92F) or p60 217–225 (218F), and BALB/c mice infected with L. monocytogenes strains containing these point mutations do not develop CTLs specific for LLO 91–99 or p60 217–225, respectively. We have used these strains to test whether primary CTL responses against L. monocytogenes-derived determinants can be stimulated within an environment of existing antilisterial immunity. We found that the development of a primary L. monocytogenes-specific CTL response is not altered by existing immunity to L. monocytogenes. For example, primary immunization with the p60 218F strain of L. monocytogenes followed by a secondary immunization with wild-type L. monocytogenes results in stimulation of p60 217–225-specific CTLs at primary response levels and LLO 91–99-specific effectors at levels consistent with a memory CTL response. Similarly, primary immunization with the 92F strain of L. monocytogenes followed by a secondary immunization with wild-type L. monocytogenes results in stimulation of LLO 91–99-specific CTLs at primary response levels and p60 217–225-specific effectors at levels consistent with a memory CTL response. These results provide additional support for the use of L. monocytogenes as a recombinant vaccine vector and show that antivector immunity does not inhibit the development of a primary CTL response when the epitope is delivered by L. monocytogenes as the vaccine strain.