The brain effortlessly recognizes objects even when the visual information belonging to an object is widely separated, as well demonstrated by the Kanizsa-type illusory contours (ICs), in which a contour is perceived despite the fragments of the contour being separated by gaps. Such large-range visual completion has long been thought to be preattentive, whereas its dependence on top-down influences remains unclear. Here, we report separate modulations by spatial attention and task relevance on the neural activities in response to the ICs. IC-sensitive event-related potentials that were localized to the lateral occipital cortex were modulated by spatial attention at an early processing stage (130–166 ms after stimulus onset) and modulated by task relevance at a later processing stage (234–290 ms). These results not only demonstrate top-down attentional influences on the neural processing of ICs but also elucidate the characteristics of the attentional modulations that occur in different phases of IC processing.
Lantibiotics are ribosomally synthesized (methyl)lanthionine containing peptides which can efficiently inhibit the growth of Gram-positive bacteria. As lantibiotics kill bacteria efficiently and resistance to them is difficult to be obtained, they have the potential to be used in many applications, e.g., in pharmaceutical industry or food industry. Nisin can inhibit the growth of Gram-positive bacteria by binding to lipid II and by making pores in their membrane. The C-terminal part of nisin is known to play an important role during translocation over the membrane and forming pore complexes. However, as the thickness of bacterial membranes varies between different species and environmental conditions, this property could have an influence on the pore forming activity of nisin. To investigate this, the so-called “hinge region” of nisin (residues NMK) was engineered to vary from one to six amino acid residues and specific activity against different indicators was compared. Antimicrobial activity in liquid culture assays showed that wild type nisin is most active, while truncation of the hinge region dramatically reduced the activity of the peptide. However, one or two amino acids extensions showed only slightly reduced activity against most indicator strains. Notably, some variants (+2, +1, −1, −2) exhibited higher antimicrobial activity than nisin in agar well diffusion assays against Lactococcus lactis MG1363, Listeria monocytogenes, Enterococcus faecalis VE14089, Bacillus sporothermodurans IC4 and Bacillus cereus 4153 at certain temperatures.
lantibiotics; nisin; hinge region; membrane; diffusion
Inhibitors of the transcription factor STAT3 target STAT3-dependent tumorigenesis but patients often develop diarrhea from unknown mechanisms. Here we showed that STAT3 deficiency increased morbidity and mortality after Citrobacter rodentium infection with decreased secretion of cytokines including IL-17 and IL-22 associated with the transcription factor RORγt. Administration of the cytokine IL-22 was sufficient to rescue STAT3-deficient mice from lethal infection. Although STAT3 was required for IL-22 production in both innate and adaptive arms, using conditional gene deficient mice we observed that STAT3 expression in RORγt+ innate lymphoid cells (ILC3s), but not T cells, was essential for the protection. However, STAT3 was required for RORγt expression in T helper cells, but not in ILC3s. Activated STAT3 could directly bind to the Il22 locus. Thus, cancer therapies that utilize STAT3 inhibitors increase the risk for pathogen-mediated diarrhea through direct suppression of IL-22 from gut ILCs.
Absence of a regenerative pathway for damaged retina following injury or disease has led to experiments utilizing stem cell transplantation for retinal repair, and encouraging results have been obtained in rodents. The swine eye is a closer anatomical and physiological match to the human eye, but embryonic stem cells have not been isolated from pig, and photoreceptor differentiation has not been demonstrated with swine induced pluripotent stem cells (iPSC). Here, we subjected swine iPSC to a rod photoreceptor differentiation protocol consisting of floating culture as embryoid bodies followed by differentiation in adherent culture. Real time PCR and immunostaining of differentiated cells demonstrated loss of expression of the pluripotent genes POU5F1, NANOG and SOX2 and induction of rod photoreceptor genes RCVRN, NRL, RHO and ROM1. While these differentiated cells displayed neuronal morphology, culturing on a Matrigel substratum triggered a further morphological change resulting in concentration of RHO and ROM1 in outer segment-like projections resembling those on primary cultures of rod photoreceptors. The differentiated cells were transplanted into the subretinal space of pigs treated with iodoacetic acid to eliminate rod photoreceptors. Three weeks after transplantation, engrafted RHO+ cells were evident in the outer nuclear layer where photoreceptors normally reside. A portion of these transplanted cells had generated projections resembling outer segments. These results demonstrate that swine iPSC can differentiate into photoreceptors in culture and these cells can integrate into the damaged swine neural retina thus laying a foundation for future studies using the pig as a model for retinal stem cell transplantation.
photoreceptor differentiation; swine retina; induced pluripotent stem cells; retinal transplantation
Several studies have implied that the time of radiation exposure for patients and operators during the transradial approach for coronary angiography (TRA) is associated with the use of different guidewire or catheter and operator’s finesse. This study aimed to assess the effects of non-hydrophilic or hydrophilic guidewire and operator expertise on fluoroscopy time and procedure time of TRA and further effects on the procedure safety.
A total of 1035 consecutive patients undergoing TRA were recruited prospectively and respectively divided into non-hydrophilic guidewire and hydrophilic guidewire group, or well-experienced group and less-experienced group. The primary endpoints were fluoroscopy time and procedure time. Secondary endpoints included contrast volume, cost, guidewire exchange, switchover and complications.
TRA by non-hydrophilic guidewire group showed shorter fluoroscopy time and procedure time compared with hydrophilic guidewire group, similar results were found between well-experienced group and less-experienced group. Moreover, using of non-hydrophilic guidewire significantly reduced the incidence of hematoma and abnormal guidewie advancement, well-experienced group showed less dosage of contrast volume, lower incidence of radial artery spasm and frequency of guidewire exchange.
TRA by non-hydrophilic guidewire and well-experienced operator can decrease radiation exposure of patients and operators through reducing the fluoroscopy time and procedure time and further increase procedure safety. These will contribute to the optimization of TRA procedure and promote its widely application.
Coronary angiography; Transradial approach; Fluoroscopy time; Procedure time
Previous studies have shown that phthalate exposure can suppress steroidogenesis. However, the affected components of the steroidogenic pathway, and the mechanisms involved, remain uncertain. We show that incubating MA-10 Leydig cells with mono-(2-ethylhexyl) phthalate (MEHP) resulted in reductions in luteinizing hormone (LH)-stimulated cAMP and progesterone productions. cAMP did not decrease in response to MEHP when the cells were incubated with cholera toxin or forskolin. Incubation of MEHP-treated cells with dibutyryl-cAMP, 22-hydroxycholesterol or pregnenolone inhibited the reductions in progesterone. Increased levels of reactive oxygen species (ROS) occurred in response to MEHP. In cells in which intracellular glutathione was depleted by buthionine sulfoximine pretreatment, the increases in ROS and decreases in progesterone in response to MEHP treatment were exacerbated. These results indicate that MEHP inhibits MA-10 Leydig cell steroidogenesis by targeting LH-stimulated cAMP production and cholesterol transport, and that a likely mechanism by which MEHP acts is through increased oxidative stress.
Phthalate; MEHP; Leydig Cell; Oxidative Stress; Steroidogenesis
Objective: LGGs (low-grade gliomas) are sometimes encountered by chance during radiological examinations. These incidentally discovered LGGs (IDLGGs) were relatively under-studied in the literature. The purpose of current study is to review a cohort of patients with IDLGGs surgically treated in our institution for their clinical and histological aspects and determine their IDH1 and 1p19q status. Methods: All patients with hemispheric LGGs receiving operation in our institution between 2001 and 2004 were reviewed. Clinical, radiological and treatment data of the patients were collected and IDLGGs were retrieved and compared with symptomatic LGGs. Histological review was carried out and formalin-fixed paraffin embedded (FFPE) tissues of IDLGGs were examined for IDH1/IDH2 mutation and 1p/19q codeletion. Results: Twenty three IDLGGs (10.4%) were identified while 196 patients had symptomatic LGGs. The reasons for patients with IDLGGs having radiological examination included trauma (47.8%), dizziness (26.1%), unrelated headache (21.7%), and health checkup (4.4%). Clinically, patients with IDLGGs had higher preoperative KPS (P < 0.001), smaller tumor volume (P = 0.014), lower frequency of eloquent areas involvement (P < 0.001) and higher rate of complete resection (P = 0.037) comparing to those with symptomatic LGGs. Histologically, there is a preponderance of oligodendroglial differentiation with 6 oligodendrogliomas and 11 oligoastrocytomas but there were also 6 astrocytomas. IDH1 mutation and 1p/19q co-deletion were detected in 95.7% (22/23) and 69.6% (16/23) of IDLGGs, respectively. The latter encompassed all but one of the cases of oligodendroglial tumors. Patients with IDLGGs had longer overall survival than those with symptomatic LGGs (P = 0.027). Conclusions: We conclude that the majority of IDLGGs are IDH1 mutated and are predominantly oligodendroglial tumors. With a median follow-up of 9.3 years to our series, we conclude that patients with IDLGGs had better prognosis than those with symptomatic LGGs. The favorable prognosis of IDLGGs may be accounted by the higher practicability of extensive resection, non-eloquent tumor location and smaller tumor volume. Frequent IDH1 mutation and 1p/19q co-deletion in IDLGGs may also contribute to the favorable prognosis of this subgroup of patients.
Low-grade glioma; incidental; surgery; pathology; prognosis
In clear cell renal cell carcinoma (ccRCC), inactivation of the tumor suppressor von Hippel-Lindau (VHL) occurs in the majority of the tumors and is causal for the pathogenesis of ccRCC. Recently a large-scale genomic sequencing study of ccRCC tumors revealed that enzymes that regulate histone H3 lysine 4 trimethylation (H3K4Me3), such as JARID1C/KDM5C/SMCX and MLL2, were mutated in ccRCC tumors, suggesting that H3K4Me3 might play an important role in regulating gene expression and tumorigenesis. In this study, we report that in VHL-deficient ccRCC cells the overall H3K4Me3 levels were significantly lower than that of VHL+/+ counterparts. Furthermore, this was HIF-dependent, as depletion of HIF subunits by shRNA in VHL-deficient ccRCC cells restored H3K4Me3 levels. In addition, we demonstrated that only loss of JARID1C, not JARID1A or JARID1B, abolished the difference of H3K4Me3 levels between VHL−/− and VHL+/+ cells, and JARID1C displayed HIF-dependent expression pattern. JARID1C in VHL−/− cells was responsible for the suppression of HIF-responsive genes IGFBP3, DNAJC12, COL6A1, GDF15, and DEP-1. Consistent with these findings, the H3K4Me3 levels at the promoters of IGFBP3, DNAJC12, COL6A1, and GDF15 were lower in VHL−/− cells than in VHL+/+ cells, and the differences disappeared after JARID1C depletion. Although HIF2α is an oncogene in ccRCC, some of its targets might have tumor suppressive activity. Consistent with this, knockdown of JARID1C in 786-O VHL−/− ccRCC cells significantly enhanced tumor growth in a xenograft model, suggesting that JARID1C is tumor suppressive and its mutations are tumor-promoting in ccRCC. Thus, VHL inactivation decreases H3K4Me3 levels through JARID1C, which alters gene expression and suppresses tumor growth.
von Hippel-Lindau; hypoxia inducible factor; JARID1C/KDM5C/SMCX; trimethyl H3K4; gene expression
Transpalpebral or trans-eyelid approach is a modified trans-orbital access to lesions of anterior cranial fossa and sellar region. But whether this approach is also suitable for tumors extending laterally to the temporal lobe or middle cranial fossa is not clarified. We would like to share our experiences from the cadaveric anatomy study to clinical operations. We used 5 cadavers to study trans-eyelid approaches in a step-by-step fashion. And then assisted by an experienced ophthalmologist for incisions, we treated 3 female patients via this approach: One with spheno-orbital meningioma, one with sellar tuberculum meningioma, and the other with medial sphenoidal wing meningioma. After studying the cadavers, we made several revisions to the previously reported approach: 1) move the incision close to the edge of the eyelid, which resembled the double-eyelid incision. 2) A vascularized periosteum flap was dissected for repairing the opened frontal sinus and reconstruction of the skull base. 3) The dura was sutured up with a slice of temporalis muscle. Then we treated 3 patients by this approach. All tumors were totally resected as Simpson Grade I. Complications included orbital apex syndrome and transient oculomotor paralysis because of tumor invasion into orbit and cavernous sinus. No cerebrospinal fluid leakage. We find that trans-eyelid approach is suitable for lesions not only at anterior cranial base or sellar region, but also extending to middle cranial base, especially around sphenoidal wings within 2 cm range or spheno-orbital region. Thus, we propose whether it appropriate to nominate this approach as ‘trans-eyelid pterional approach’, since it may treat some anterior and middle cranial fossa lesions with a mini-craniotomy around pterion.
Transeyelid; skull base; meningioma; minimal invasive neurosurgery
Unlike adaptive immune cells that require antigen recognition and functional maturation during infection, innate lymphoid cells (ILCs) usually respond to pathogens promptly and serve as the first line of defense in infectious diseases. RAR-related orphan receptors (RORγt)+ ILCs are one of the innate cell populations that have recently been intensively studied. During the fetal stage of development, RORγt+ ILCs (e.g., lymphoid tissue inducer-LTi cells) are required for lymphoid organogenesis. In adult mice, RORγt+ ILCs are abundantly present in the gut to exert immune defensive functions. Under certain circumstances, however, RORγt+ ILCs can be pathogenic and contribute to intestinal inflammation. Aryl hydrocarbon receptor (Ahr), a ligand-dependent transcriptional factor, is widely expressed by various immune and non-immune cells. In the gut, the ligand for Ahr can be derived/generated from diet, microflora, and/or host cells. Ahr has been shown to regulate different cell populations in the immune system including RORγt+ ILCs, T helper (Th)17/22 cells, γδT cells, regulatory T cells (Tregs), Tr1 cells, and antigen presenting cells (APCs). In this review, we will focus on the development and function of RORγt+ ILCs, and discuss the role of Ahr in intestinal immunity and inflammation in mice and in humans. Better understanding the function of Ahr in the gut is important for developing new therapeutic means to target Ahr in future treatment of infectious and autoimmune diseases.
Innate lymphoid cell; Aryl hydrocarbon receptor; Intestinal immunity and inflammation
Application of artificial ligament in anterior cruciate ligament reconstruction is one of the research focuses of sports medicine but the biological tendon–bone healing still remains a problem. The preliminary study of hydroxyapatite (HAP) coating on the polyethylene terephthalate (PET) surface could effectively induce the osteoblast differentiation, but the tendon–bone healing was still not stable. As a green synthesis process, the biomimetic mineralization can simulate the natural bone growth in vitro and in vivo.
HAP crystals were grown under the guide of silk fibroin (SF) PET surface by biomimetic route. Several techniques including scanning electron microscopy, attenuated total reflectance Fourier transform infrared spectroscopy, X-ray diffraction, and energy-dispersive X-ray spectroscopy were utilized for proving the introduction of both SF and HAP. The viability and osseointegration of bone marrow stromal cells on the surface of three kinds of ligament, including PET group (non-coating group), PET+SF group (SF-coating group), and PET+SF+HAP group (combined HAP- and SF-coating group), were analyzed by CCK-8 assays and alkaline phosphatase (ALP) detection. Seventy-two mature male New Zealand rabbits were randomly divided into three groups. Among them, 36 rabbits were sacrificed for mechanical testing, and histological examination for the others.
The SF and SF+HAP were successfully coated on the surface of PET fiber. The CCK-8 assay showed that the cell proliferation on PET+SF+HAP group was better than the other two groups from 24 to 120 hours. After 14 days of culture, the cells in the PET+SF+HAP group delivered higher levels of ALP than the other two groups. After 3 days of culture, the expression level of integrin β1 in the PET+SF+HAP group and PET+SF group were higher than in the PET group. The mean load to failure and the stiffness value of the PET+SF+HAP group were both higher than the other two groups. Hematoxylin and eosin staining showed that new bone tissue formation was only found in the PET+SF+HAP group 8 weeks postoperatively. Masson staining showed that in the PET+SF+HAP group 8 weeks postoperatively, the PET fibers were almost completely encircled by collagen. Histomorphometric analysis showed that the width of the graft–bone interface in the PET+SF+HAP group was narrower than that in the other two groups 4 and 8 weeks postoperatively. The mRNA level of BMP-7 in the PET+SF+HAP groups was significantly higher than those in the other two groups 4 and 8 weeks postoperatively.
The study showed that the combined SF and HAP coating by biomimetic route on the surface of PET artificial ligament could induce graft osseointegration in the bone tunnel, providing theoretical and experimental foundation for manufacturing novel artificial ligaments meeting the clinical needs.
biomineralization; tendon–bone healing; ligament reconstruction
The expression profile of high-mobility group box 2 (HMGB2) in patients with glioblastoma multiforme (GBM) and its clinical signature with underlying mechanisms were not fully explored.
HMGB2 protein levels were measured in 51 GBM patients by immunohistochemical studies. To clarify the precise role of HMGB2 on cell invasion and viability of 3 GBM cell lines, we did in vitro and in vivo analyses with lentivirus vectors and small interfering RNA. Transwell invasion assays and wound-healing assays were used to analyze the invasion of GBM cells. Expression of p53 and matrix metalloproteinase 2/tissue inhibitors of metalloproteinase 2 (MMP2/TIMP2) protein was analyzed by Western blot.
HMGB2 protein expression was significantly higher in GBM than in controlled brain tissues (P < .0001). HMGB2 overexpression was significantly correlated with shorter overall survival time, which was the only independent prognostic factor for overall survival in a multivariate analysis (P = .017). HMGB2 knockdown by small interfering RNA decreased cell viability and invasion in vitro and significantly decreased tumor volume in vivo, which might be involved in the change of p53 expression and the balance of MMP2/TIMP2. Moreover, silencing of HMGB2 could significantly increase the sensitivity of GBM cells to temozolomide chemotherapy.
Our present data suggest that HMGB2 expression is a significant prognostic factor and might play an important role in cell invasion and temozolomide-induced chemotherapeutic sensitivity of GBM. This study highlights the importance of HMGB2 as a novel prognostic marker and an attractive therapeutic target of GBM.
glioblastoma; high-mobility group box 2; prognosis; invasion; temozolomide
The cellular protein quality control system in association with aggresome formation contributes to protecting cells against aggregation-prone protein-induced toxicity. p62/Sequestosome 1 (p62) is a multifunctional protein which plays an important role in protein degradation and aggregation. Although poly-ubiquitination is usually required for p62-mediated protein degradation and aggresome formation, several p62 substrates are processed to form aggregate in an ubiquitination-independent manner. In this study we demonstrate that p62 directly interacts with pathogenic Machado Joseph Disease (MJD)-associated protein ataxin-3 with polyglutamine (polyQ) expansion. Moreover, p62 could regulate the aggresome formation of pathogenic ataxin-3 and protect cells against pathogenic ataxin-3-induced cell death.
ataxin-3; polyglutamine; p62; aggregation; aggresome
Aryl hydrocarbon receptor (Ahr) is crucial for the maintenance and function of group 3 innate lymphoid cells (ILCs), which are important in gut immunity. Because Ahr promotes T helper 17 (Th17) cell differentiation in vitro, it is reasonable to expect that Ahr would enhance Th17 cells in vivo. Instead, we show that Ahr deficiency caused increased intestinal Th17 cells, raising the possibility that group 3 ILCs could negatively regulate Th17 cells. Reduced innate interleukin-22 (IL-22) in Ahr-deficient mice allowed expansion of commensal segmented filamentous bacteria (SFB), known to promote Th17 cells. Compared to Rorc+/+Ahr−/− mice, Rorcgfp/+Ahr−/− mice had further reduced group 3 ILCs and were prone to spontaneous colitis with increased SFB and Th17 cells. Innate expression of Ahr played a protective role in T-cell-mediated experimental colitis by suppressing pathogenic Th17 cells. Our data reveal an intricate balance between ILCs and Th17 cells regulated by Ahr and commensal flora.
Background and Aim. CC chemokine ligand 18 (CCL18) promotes malignant behaviors of various human cancer types. However, its involvement in human prostate cancer has not been fully elucidated. The aim of this study was to investigate the role of CCL18 in PCa. Methods. Expression of CCL18 at mRNA and protein levels was detected using real-time qRT-PCR and immunohistochemistry analysis. We analyzed the associations of CCL18 expression with clinical features of human PCa. The effects of PCa cell migration, invasion, and apoptosis were tested. The efficiency of CCL18 on prostate tumor growth was assessed in a subcutaneous xenograft model. Results. CCL18 expression was upregulated (both P < 0.01) in PCa tissues compared with those in noncancerous prostate tissues. CCL18 upregulation was correlated with high Gleason score (P = 0.034) of patients with PCa. rCCL18 stimulation in PCa cells promoted cell migration and invasion but decreased DU145 cells apoptosis rate. Furthermore, subcutaneous homografts models showed the increased tumor growth and tumor vascularization with the CCL18 stimulation, and the expression of Ki67, PCNA, and CD31 in CCL18 stimulation mice was also significantly increased. Conclusions. Our data offer the convincing evidence that the upregulation of CCL18 may be involved in the malignant progression of PCa.
There has been an increasing trend in the incidence of stroke worldwide in recent years, and the number of studies focusing on the risk factors for stroke has also increased every year. To comprehensively evaluate the risk factors of stroke identified in prospective Western and Asian cohort studies.
Population-based cohort studies on stroke were searched in databases (PubMed, EMBASE, Web of Science, Google Scholar, etc.), and the library of the Third Military Medical University was manually searched for relevant information. A meta-analysis of Western and Asian studies on risk factors was performed. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to assess the final group of cohort studies.
After screening, 22 prospective cohort studies were included in the analyses of this investigation. Two factors, smoking and alcohol consumption, showed statistically significant differences between Western and Asian populations, and the results were as follows (W/A): 2.05 (95% CI, 1.68 ~ 2.49)/1.27 (95% CI, 1.04 ~ 1.55) and 0.89 (95% CI, 0.76 ~ 1.04)/1.28 (95% CI, 1.07 ~ 1.53). The factor BMI = 18.5-21.9 kg/m2 showed statistically significant differences only in Western populations, 0.96 (95% CI, 0.93 ~ 0.99); the factor SBP = 120-139 mm Hg showed statistically significant differences only in Asian populations, 2.29 (95% CI, 1.04 ~ 5.09).
The prevalences of risk factors affect the stroke morbidity in Western and Asian populations, which may be biased by race. The meta-analysis of population-based studies suggests that different preventive measures should be adopted for Western and Asian population groups that are at high risk for stroke.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-776) contains supplementary material, which is available to authorized users.
Stroke; Risk factors; Prospective study; Epidemiology; Systematic review; Public health
It is obvious that tablet image tracking exerts a notable influence on the efficiency and reliability of high-speed drug mass production, and, simultaneously, it also emerges as a big difficult problem and targeted focus during production monitoring in recent years, due to the high similarity shape and random position distribution of those objectives to be searched for. For the purpose of tracking tablets accurately in random distribution, through using surface fitting approach and transitional vector determination, the calibrated surface of light intensity reflective energy can be established, describing the shape topology and topography details of objective tablet. On this basis, the mathematical properties of these established surfaces have been proposed, and thereafter artificial neural network (ANN) has been employed for classifying those moving targeted tablets by recognizing their different surface properties; therefore, the instantaneous coordinate positions of those drug tablets on one image frame can then be determined. By repeating identical pattern recognition on the next image frame, the real-time movements of objective tablet templates were successfully tracked in sequence. This paper provides reliable references and new research ideas for the real-time objective tracking in the case of drug production practices.
A2B5+ glioblastoma (GBM) cells have glioma stem-like cell (GSC) properties that are crucial to chemotherapy resistance and GBM relapse. T-cell-based antigens derived from A2B5+ GBM cells provide important information for immunotherapy. Here, we show that HEAT repeat containing 1 (HEATR1) expression in GBM tissues was significantly higher than that in control brain tissues. Furthermore, HEATR1 expression in A2B5+ U87 cells was higher than that in A2B5−U87 cells (P = 0.016). Six peptides of HEATR1 presented by HLA-A∗02 were selected for testing of their ability to induce T-cell responses in patients with GBM. When peripheral blood mononuclear cells from healthy donors (n = 6) and patients with glioma (n = 33) were stimulated with the peptide mixture, eight patients with malignant gliomas had positive reactivity with a significantly increased number of responding T-cells. The peptides HEATR1682–690, HEATR11126–1134, and HEATR1757–765 had high affinity for binding to HLA-A∗02:01 and a strong capacity to induce CTL response. CTLs against HEATR1 peptides were capable of recognizing and lysing GBM cells and GSCs. These data are the first to demonstrate that HEATR1 could induce specific CTL responses targeting both GBM cells and GSCs, implicating that HEATR1 peptide-based immunotherapy could be a novel promising strategy for treating patients with GBM.
We followed cone and rod development in the pig and we correlated development with the potential for cone and rod precursor integration and differentiation following subretinal transplantation.
Rod and cone precursors were identified during development by their position in the outer retina and by immunostaining for markers of differentiation. Embryonic retinal cells from green fluorescent protein (GFP)+ transgenic pigs at different developmental stages were transplanted into adult retinas and integration and differentiation was followed and quantified by immunostaining for markers of cone and rod differentiation.
Pig cones and rods are spatially segregated, allowing us to follow rod and cone development in situ. Gestation in the pig is 114 days. By embryonic day (E) 50, postmitotic cone progenitors had formed the outer two rows of the retina. These cone progenitors are marked by expression of Islet1 (ISL1) and Recoverin (RCVRN) (at this embryonic stage, RCVRN exclusively marks these cone precursors). By contrast, postmitotic neural retina leucine zipper (NRL)+ rod precursors, located interior to the cone precursors, did not appear until E65. At E50, before NRL+ rod precursors are evident, transplanted cells gave rise almost exclusively to cones. At, E57, transplanted cells gave rise to equal numbers of rods and cones, but by E65, transplanted cells gave rise almost exclusively to rods. Transplantation of cells at E85 or E105, as precursors initiate opsin expression, led to few integrated cells.
Consistent with their sequential appearances in embryonic retina, these results demonstrate sequential and surprisingly narrow developmental windows for integration/differentiation of cone and rod precursors following transplantation.
We demonstrate sequential and surprisingly narrow windows for differentiation of embryonic rod and cone progenitors into rods and cones following subretinal transplantation.
retinal transplantation; cones; precursors
Aberrant expression of microRNAs plays vital roles in tumor development and progression. As transcription factors (TFs) are the critical components of signaling cascades, specific targeting effects of microRNAs to specific TFs may determine the role of microRNAs in different cancers. In this study, we identified Nuclear Factor I/B (NFIB) as one of the targets of miR-365 which was previously verified as an onco-miR in cutaneous squamous cell carcinoma (CSCC). Down-regulation of NFIB was a general feature in both CSCC cell lines and tumors from patients which show drastically up-regulated miR-365 expression levels. The siRNA-based knockdown of NFIB mimic the carcinogenic transformation of normal cells by ectopically expression of miR-365 which indicates depletion of NFIB is necessary for miR-365 to exert its pro-carcinogenic function. NFIB may represent a functional barrier targeted by miR-365 to the development of CSCC. Further studies also discovered a conserved feedback regulatory circuitry formed by NFIB and miR-365 in CSCC development which may be potentially utilized as therapeutic target to improve the clinical CSCC treatment.
Medulloblastoma (MB) is one of the most common primary central nervous system tumors in children. Data is lacking of a large cohort of medulloblastoma patients in China. Also, our knowledge on the sensitivity of different molecular subgroups of MB to adjuvant radiation therapy (RT) or chemotherapy (CHT) is still limited. The authors performed a retrospective study of 173 medulloblastoma patients treated at two institutions from 2002 to 2011. Formalin-fixed paraffin embedded (FFPE) tissues were available in all the cases and sections were stained to classify histological and molecular subgroups. Univariate and multivariate analyses were used to investigate prognostic factors. Of 173 patients, there were 118 children and 55 adults, 112 males and 61 females. Estimated 5-year overall survival (OS) rates for all patients, children and adults were 52%, 48% and 63%, respectively. After multivariate analysis, postoperative primary radiation therapy (RT) and chemotherapy (CHT) were revealed as favorable prognostic factors influencing OS and EFS. Postoperative primary chemotherapy (CHT) was found significantly improving the survival of children (p<0.001) while it was not a significant prognostic factor for adult patients. Moreover, patients in WNT subtype had better OS (p = 0.028) than others (SHH and Non-SHH/WNT subtypes) given postoperative adjuvant therapies. Postoperative primary RT was found to be a strong prognostic factor influencing the survival in all histological and molecular subgroups (p<0.001). Postoperative primary CHT was found significantly to influence the survival of classic medulloblastoma (CMB) (OS p<0.001, EFS p<0.001), SHH subgroup (OS p = 0.020, EFS p = 0.049) and WNT subgroup (OS p = 0.003, EFS p = 0.016) but not in desmoplastic/nodular medulloblastoma (DMB) (OS p = 0.361, EFS p = 0.834) and Non-SHH/WNT subgroup (OS p = 0.127, EFS p = 0.055). Our study showed postoperative primary CHT significantly influence the survival of CMB, SHH subgroup and WNT subgroup but not in DMB and Non-SHH/WNT subgroup of MB.
Rebleeding is a serious complication of aneurysmal subarachnoid hemorrhaging. To date, there are conflicting data regarding the factors contributing to rebleeding and their significance.
A systematic review of PubMed and Embase databases was conducted for studies pertaining to aneurysmal subarachnoid hemorrhage (aSAH) and rebleeding in order to assess the associated risk factors. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated from fourteen studies comprised of a total of 5693 patients that met the inclusion criteria.
Higher rebleeding rates were observed < 6 h after the initial aSAH (OR = 3.22, 95% CI = 1.46–7.12), and were associated with high systolic blood pressure (OR = 1.93, 95% CI = 1.31–2.83), poor Hunt-Hess grade (III–IV) (OR = 3.43, 95% CI = 2.33–5.05), intracerebral or intraventricular hematomas (OR = 1.65, 95% CI = 1.33–2.05), posterior circulation aneurysms (OR = 2.15, 95% CI = 1.32–3.49), and aneurysms >10 mm in size (OR = 1.70, 95% CI = 1.35–2.14).
Aneurysmal rebleeding occurs more frequently within the first 6 hours after the initial aSAH. Risk factors associated with rebleeding include high systolic pressure, the presence of an intracerebral or intraventricular hematoma, poor Hunt-Hess grade (III-IV), aneurysms in the posterior circulation, and an aneurysm >10 mm in size.
Interactions between the novel Chk1 inhibitor MK-8776 and the HDAC inhibitor (HDACI) vorinostat were examined in human leukemia cells harboring wild-type (wt) or deficient p53. MK-8776 synergistically potentiated vorinostat-mediated apoptosis in various p53-wild type (wt) or -deficient leukemia cell lines, while p53 knock-down by shRNA sensitized p53-wt cells to lethality of this regimen. Leukemia cell lines carrying FLT3-ITD were also sensitive to the MK-8776/vorinostat regimen. Synergistic interactions were associated with inhibition of Chk1 activity, interference with the intra-S phase checkpoint, disruption of DNA replication, and down-regulation of proteins involved in DNA replication (e.g.,CDT1) and repair (e.g., CtIP and BRCA1), resulting in sharp increases in DNA damage, reflected by enhanced γH2A.X formation, and apoptosis. Moreover, leukemia cells expressing kinase-dead Chk1 (D130A) or Chk1 shRNA were significantly more sensitive to HDACIs compared to their wild-type counterparts, and displayed down-regulation of CtIP and BRCA1 phosphorylation following HDACI exposure. Finally, the MK-8776/vorinostat regimen was active in primary AML blasts, particularly against the CD34+/CD38-/CD123+ population enriched for leukemia-initiating cells. In contrast, identical regimens were relatively sparing toward normal cord blood CD34+ cells. Together, these findings indicate that the novel Chk1 inhibitor MK-8776 markedly potentiates HDACI lethality in leukemia cells displaying various genetic backgrounds through mechanisms involving disruption of the intra-S checkpoint, DNA replication, and DNA repair. They also argue that leukemic cells, including those bearing oncogenic mutations associated with poor prognosis e.g., p53 deletion/mutation or FLT3-ITD, may also be susceptible to this strategy.
Chk1 inhibitor; HDAC inhibitor; S phase; DNA damage/repair; leukemia
Following Schistosoma japonicum (S. japonicum) infection, granulomatous responses are induced by parasite eggs trapped in host organs, particular in the liver, during the acute stage of disease. While excessive liver granulomatous responses can lead to more severe fibrosis and circulatory impairment in chronically infected host. However, the exact mechanism of hepatic granuloma formation has remained obscure. In this study, we for the first time showed that follicular helper T (Tfh) cells are recruited to the liver to upregulate hepatic granuloma formation and liver injury in S. japonicum-infected mice, and identified a novel function of macrophages in Tfh cell induction. In addition, our results showed that the generation of Tfh cells driven by macrophages is dependent on cell–cell contact and the level of inducible costimulator ligand (ICOSL) on macrophages which is regulated by CD40–CD40L signaling. Our findings uncovered a previously unappreciated role for Tfh cells in liver pathology caused by S. japonicum infection in mice.
Schistosomiasis is a chronic helminthic disease that affects approximately 200 million people. After S. japonicum infection, parasite eggs are trapped in host liver and granulomas are induced to form around eggs. Severe granuloma subsequently results in serious liver fibrosis and circulatory impairment chronically. It is important to fully elucidate the mechanism of the granuloma formation. Here, we show that Tfh cells play a novel role of promoting the hepatic granuloma formation and liver injury, and identified a novel function of macrophages in Tfh cells induction in S. japonicum-infected mouse model. In addition, we show that the generation of Tfh cells driven by macrophages is cell–cell contact dependent and regulated by CD40-CD40L signaling. Our findings revealed a novel role and mechanism of macrophages in Tfh cell generation and the liver pathogenesis in S. japonicum-infected mouse model.