Background and Aims
It is widely accepted that fruit-set in plants is related to source–sink ratio. Despite its critical importance to yield, prediction of fruit-set remains an ongoing problem in crop models. Functional–structural plant models are potentially able to simulate organ-level plasticity of plants. To predict fruit-set, the quantitative link between source–sink ratio and fruit-set probability is analysed here via a functional–structural plant model, GreenLab.
Two experiments, each with four plant densities, were carried out in a solar greenhouse during two growth seasons (started in spring and autumn). Dynamic fruit-set probability was estimated by frequent observation on inflorescences. Source and sink parameter values were obtained by fitting GreenLab outputs for the biomass of plant parts (lamina, petiole, internode, fruit), at both organ and plant level, to corresponding destructive measurements at six dates from real plants. The dynamic source–sink ratio was calculated as the ratio between biomass production and plant demand (sum of all organ sink strength) per growth cycle, both being outputs of the model.
Key Results and Conclusions
Most sink parameters were stable over multiple planting densities and seasons. From planting, source–sink ratio increased in the vegetative stage and reached a peak after fruit-set commenced, followed by a decrease of leaf appearance rate. Fruit-set probability was correlated with the source–sink ratio after the appearance of flower buds. The relationship between fruit-set probability and the most correlated source–sink ratio could be quantified by a single regression line for both experiments. The current work paves the way to predicting dynamic fruit-set using a functional structure model.
Tomato; Solanum lycopersicum; fruit-set probability; time step; source–sink ratio; sink strength; functional–structural plant model; inverse modelling; plant plasticity
Rheumatoid arthritis (RA) is an autoimmune disease characterized by dysregulated and chronic systemic inflammatory responses that affect the synovium, bone, and cartilage causing damage to extra-articular tissue. Innate immunity is the first line of defense against invading pathogens and assists in the initiation of adaptive immune responses. Polymorphonuclear cells (PMNs), which include neutrophils, are the largest population of white blood cells in peripheral blood and functionally produce their inflammatory effect through phagocytosis, cytokine production and natural killer-like cytotoxic activity. TREM1 (triggering receptor expressed by myeloid cells) is an inflammatory receptor in PMNs that signals through the use of the intracellular activating adaptor DAP12 to induce downstream signaling. After TREM crosslinking, DAP12’s tyrosines in its ITAM motif get phosphorylated inducing the recruitment of Syk tyrosine kinases and eventual activation of PI3 kinases and ERK signaling pathways. While both TREM1 and DAP12 have been shown to be important activators of RA pathogenesis, their activity in PMNs or the importance of DAP12 as a possible therapeutic target have not been shown. Here we corroborate, using primary RA specimens, that isolated PMNs have an increased proportion of both TREM1 and DAP12 compared to normal healthy control isolated PMNs both at the protein and gene expression levels. This increased expression is highly functional with increased activation of ERK and MAPKs, secretion of IL-8 and RANTES and cytotoxicity of target cells. Importantly, based on our hypothesis of an imbalance of activating and inhibitory signaling in the pathogenesis of RA we demonstrate that inhibition of the DAP12 signaling pathway inactivates these important inflammatory cells.
The prevalence of type 2 diabetes continuously increases globally. The traditional Chinese medicine (TCM) can stratify the diabetic patients based on their different TCM syndromes and, thus, allow a personalized treatment. Metabolomics is able to provide metabolite biomarkers for disease subtypes. In this study, we applied a metabolomics approach using an ultraperformance liquid chromatography (UPLC) coupled with quadruple-time-of-flight (QTOF) mass spectrometry system to characterize the metabolic alterations of different TCM syndromes including excess and deficiency in patients diagnosed with diabetes mellitus (DM). We obtained a snapshot of the distinct metabolic changes of DM patients with different TCM syndromes. DM patients with excess syndrome have higher serum 2-indolecarboxylic acid, hypotaurine, pipecolic acid, and progesterone in comparison to those patients with deficiency syndrome. The excess patients have more oxidative stress as demonstrated by unique metabolite signatures than the deficiency subjects. The results provide an improved understanding of the systemic alteration of metabolites in different syndromes of DM. The identified serum metabolites may be of clinical relevance for subtyping of diabetic patients, leading to a personalized DM treatment.
Irisin is a novel myokine secreted in response to peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) activation through exercise. The first-degree relatives (FDRs) of type 2 diabetes mellitus (T2DM) patients bear a lifetime risk for developing T2DM, especially after 40 years old. However, the circulating irisin levels in middle-aged FDRs of T2DM is unclear. We therefore investigated the association between circulating irisin and pancreatic β-cell function in normal-glucose-tolerance (NGT) subjects.
In this cross-sectional study, we recruited 412 supposed healthy subjects aged 40-60 who were FDRs of T2DM patients but without previous diagnosis of T2DM. Of the 412 individuals, 254 had NGT and 60 were newly diagnosed T2DM based on the results of a 75 g oral glucose tolerance test (OGTT- World Health Organization diagnostic criteria). We measured irisin in the newly diagnosed T2DM group (n = 60) and in an age- and sex-matched NGT subgroups (n = 62). Serum irisin was quantified by ELISA, and its association with metabolic parameters was analysed by Pearson’s correlation and multiple linear regression analyses.
There was no significant difference in serum irisin between middle-aged newly diagnosed T2DM patients and the NGT control group. Circulating irisin was correlated with haemoglobin A1c (r = 0.202, p = 0.026) and estimated glomerular filtration rate (r = 0.239, p = 0.010). Multiple linear regression revealed that only homeostasis model assessment-β (HOMA-β) was associated with irisin in NGT subjects after adjusting for confounding factors. However, similar analysis in T2DM did not reveal a significant association between circulating irisin and metabolic parameters.
There was no significant difference in serum irisin between middle-aged newly diagnosed T2DM patients and the NGT controls. Serum irisin level was closely related to HOMA-β in NGT, suggesting that irisin may play a crucial role in pancreatic β-cell function.
Type 2 diabetes mellitus; First-degree relatives; Irisin; Pancreatic β-cell
Colorectal cancer (CRC) is one of the common malignant tumors worldwide. Both genetic and epigenetic changes are regarded as important factors of colorectal carcinogenesis. Loss of DACH1 expression was found in breast, prostate, and endometrial cancer. To analyze the regulation and function of DACH1 in CRC, 5 colorectal cancer cell lines, 8 cases of normal mucosa, 15 cases of polyps and 100 cases of primary CRC were employed in this study. In CRC cell lines, loss of DACH1 expression was correlated with promoter region hypermethylation, and re-expression of DACH1 was induced by 5-Aza-2'-deoxyazacytidine treatment. We found that DACH1 was frequently methylated in primary CRC and this methylation was associated with reduction in DACH1 expression. These results suggest that DACH1 expression is regulated by promoter region hypermethylation in CRC. DACH1 methylation was associated with late tumor stage, poor differentiation, and lymph node metastasis. Re-expression of DACH1 reduced TCF/LEF luciferase reporter activity and inhibited the expression of Wnt signaling downstream targets (c-Myc and cyclinD1). In xenografts of HCT116 cells in which DACH1 was re-expressed, tumor size was smaller than in controls. In addition, restoration of DACH1 expression induced G2/M phase arrest and sensitized HCT116 cells to docetaxel. DACH1 suppresses CRC growth by inhibiting Wnt signaling both in vitro and in vivo. Silencing of DACH1 expression caused resistance of CRC cells to docetaxel. In conclusion, DACH1 is frequently methylated in human CRC and methylation of DACH1 may serve as detective and prognostic marker in CRC.
DACH1; DNA methylation; Wnt signaling; colorectal cancer; chemosensitivity
Vedolizumab (VDZ) is a humanized monoclonal antibody in development for the treatment of inflammatory bowel disease. VDZ binds to the α4β7 integrin complex and inhibits its binding to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), thus preventing lymphocyte extravasation to gut mucosal tissues. To understand whether VDZ has additional effects that may affect its overall safety as a therapeutic molecule, we examined other potential actions of VDZ. In vitro assays with human peripheral blood lymphocytes demonstrated that VDZ fails to elicit cytotoxicity, lymphocyte activation, and cytokine production from memory T lymphocytes and does not interfere with the suppressive ability of regulatory T cells. Furthermore, we demonstrated that VDZ induces internalization of α4β7 and that the integrin is rapidly re-expressed and fully functional after VDZ withdrawal. These studies provide insight into the mechanisms underlying the observed safety profile of VDZ in clinical trials.
in vitro; inflammatory bowel disease; integrin; lymphocyte binding; receptor internalization; safety profile; vedolizumab
Previous studies have identified hyperlipidemia as a potential risk factor for dementia and Alzheimer’s disease. However, studies on cholesterol measured in late-life and cognitive function have been inconsistent. Few studies have explored nonlinear relationships or considered interactions with other biomarker measures.
A cross-sectional sample of 1,889 participants from four rural counties in the People’s Republic of China was included in this analysis. Serum total cholesterol, high-density lipoprotein, triglycerides, and homocysteine levels were measured in fasting blood samples. A composite cognitive score was derived based on nine standardized cognitive test scores. Analysis of covariance models were used to investigate the association between biomarker measures and the composite cognitive scores.
There was a significant interaction between the homocysteine quartile group and the cholesterol quartile group on cognitive scores (P=0.0478). In participants with normal homocysteine levels, an inverse U-shaped relationship between total cholesterol level and cognitive score was found, indicating that both low and high cholesterol levels were associated with lower cognitive scores. In participants with high homocysteine levels, no significant association between cholesterol and cognition was found.
The relationship between cholesterol levels and cognitive function depends upon homocysteine levels, suggesting an interactive role between cholesterol and homocysteine on cognitive function in the elderly population. Additional research is required to confirm our findings in other populations, and to explore potential mechanisms underlying the lipid–homocysteine interaction.
cholesterol; homocysteine; cognitive function
Ethanol induces hypoxia and elevates HIF-1α in the liver. CYP2E1 plays a role in the mechanisms by which ethanol generates oxidative stress, fatty liver and liver injury. The current study evaluated whether CYP2E1 contributes to ethanol-induced hypoxia and activation of HIF-1α in vivo and whether HIF-1α protects against or promotes CYP2E1-dependent toxicity in vitro. Wild type (WT), CYP2E1-knockin (KI) and CYP2E1 knockout (KO) mice were fed ethanol chronically; pair fed controls received isocaloric dextrose. Ethanol produced liver injury in the KI mice to a much greater extent than in the WT and KO mice. Protein levels of HIF-1α and downstream targets of HIF-1α activation were elevated in the ethanol-fed KI mice compared to the WT and KO mice. Levels of HIF prolylhydroxlase 2 which promotes HIF-1α degradation were decreased in the ethanol-fed KI mice in association with the increases in HIF-1α. Hypoxia occurred in the ethanol-fed CYP2E1 KI mice as shown by an increased area of staining using the hypoxia-specific marker pimonidazole. Hypoxia was lower in the ethanol-fed WT mice and lowest in the ethanol fed KO mice and all the dextrose-fed mice. In situ double staining showed that pimonidazole and CYP2E1 were co-localized to the same area of injury in the hepatic centrilobule. Increased protein levels of HIF-1α were also found after acute ethanol treatment of KI mice. Treatment of HepG2 E47 cells which express CYP2E1 with ethanol plus arachidonic (AA) acid or ethanol plus buthionine sulfoximine (BSO) which depletes GSH caused loss of cell viability to greater extent than in HepG2 C34 cells which do not express CYP2E1. These treatments elevated protein levels of HIF-1α to a greater extent in E47 cells than C34 cells. 2-Methoxyestradiol, an inhibitor of HIF-1α, blunted the toxic effects of ethanol plus AA and ethanol plus BSO in the E47 cells in association with inhibition of HIF-1α. The HIF-1α inhibitor also blocked the elevated oxidative stress produced by ethanol/AA or ethanol/BSO in the E47 cells. These results suggest that CYP2E1 plays a role in ethanol-induced hypoxia, oxidative stress and activation of HIF-1α and that HIF-1α contributes to CYP2E1-dependent ethanol-induced toxicity. Blocking HIF-1α activation and actions may have therapeutic implications for protection against ethanol/CYP2E1-induced oxidative stress, steatosis and liver injury.
Ethanol; CYP2E1; Hepatotoxicity; Oxidative Stress; HIF-1α
The aim of the present study was to investigate the expression level of TWIST1 in B-cell non-Hodgkin lymphoma (BNHL) and its association with the clinicopathological characteristics of BNHL. Expression levels of TWIST1 were analyzed in patients with BNHL (n=45) and lymphadenosis (n=21) using immunohistochemical staining and western blot analysis. In addition, the mRNA expression levels of TWIST1 in the peripheral blood were detected by fluorescent quantitative polymerase chain reaction. The positive rate of TWIST1 expression in the BNHL tissue was 82.2%, which was significantly higher compared with the lymphadenosis tissue (5%; P<0.05). In addition, the protein expression level of TWIST1 in the BNHL tissue was higher compared with the lymphadenosis tissue. TWIST1 expression was also higher in stage III/IV BNHL tissues than in stage I/II tissues (P<0.05). The tissues were staged following the Ann Arbor system. Furthermore, the mRNA expression level of TWIST1 in the peripheral blood of the BNHL tissue (3.03±0.03) was higher compared with the lymphadenosis tissue, and the mRNA expression level of TWIST1 was higher in stage III/IV (4.41±0.12) tissues than in stage I/II BNHL (2.03±0.08) tissues. In conclusion, TWIST1 expression was higher in the tissue and peripheral blood of patients with BNHL when compared with those with lymphadenosis. Thus, TWIST1 expression was associated with the clinicopathological stage of BNHL.
B cell non-Hodgkin; lymphoma; TWIST1; immunohistochemistry staining
Acute alcohol drinking induces steatosis, and effective prevention of steatosis can protect liver from progressive damage caused by alcohol. Increased oxidative stress has been reported as one mechanism underlying alcohol-induced steatosis. We evaluated whether cannabidiol, which has been reported to function as an antioxidant, can protect the liver from alcohol-generated oxidative stress-induced steatosis. Cannabidiol can prevent acute alcohol-induced liver steatosis in mice, possibly by preventing the increase in oxidative stress and the activation of the JNK MAPK pathway. Cannabidiol per se can increase autophagy both in CYP2E1-expressing HepG2 cells and in mouse liver. Importantly, cannabidiol can prevent the decrease in autophagy induced by alcohol. In conclusion, these results show that cannabidiol protects mouse liver from acute alcohol-induced steatosis through multiple mechanisms including attenuation of alcohol-mediated oxidative stress, prevention of JNK MAPK activation, and increasing autophagy.
Alcohol; Steatosis; Cannabidiol; Oxidative stress; Autophagy; Free radicals
C5 palsy is a serious but poorly understood complication after posterior cervical decompression that could lead to muscle weakness, brachialgia and numbness of the upper limbs. The incidence of C5 palsy varies greatly between studies. The risk factors are inconclusive and even conflicting.
To perform a systematic review on the incidence and risk factors of C5 palsy after posterior cervical decompression.
Materials and Methods
Four databases, PubMed, Embase, Web of Science and Cochrane CENTRAL, were searched to identify eligible studies. Either a fixed- or a random-effects model was used to calculate the pooled odd ratio (RR) or standardized mean difference (SMD) with its 95% confidence interval (95%CI).
Of the 589 pre-recruited studies, 25 were included in this study for systematic review. The pooled incidence of C5 palsy after posterior decompression was 5.8% (95%CI: 4.4–7.2%). The incidence after open-door laminoplasty, double-door laminoplasty and laminectomy was 4.5%, 3.1% and 11.3%, respectively. The significant risk factors of C5 palsy were OPLL (OR, 2.188; 95%CI, 1.307–3.665), narrower intervertebral foramen (SMD, −0.972; 95%CI, −1.398 to −0.545), laminectomy (vs. open-door laminoplasty, OR, 2.988; 95%CI, 1.298–6.876), excessive spinal cord drift (SMD, 1.289, 95%CI, 0,197–2.381) and male gender (OR, 1.54; 95%CI, 1.036–2.301).
The results of this systematic review suggest that patients with excessive spinal cord drift, preexisting intervertebral foramenal stenosis, OPLL, laminectomy and male gender are at high risk for postoperative C5 palsy, and risk-reduction options should be considered for such patients.
The significant roles of genetic variants in myasthenia gravis (MG) pathogenesis have been demonstrated in many studies, and recently it has been revealed that aberrant level/regulation of microRNAs (miRNAs) might contribute to the initiation and progression of MG. However, the dysfunction of miRNA associated with single nucleotide polymorphisms (miRSNPs) has not been well investigated in MG. In this study, we created a contemporary catalog of 89 MG risk genes via manual literature-mining. Based on this risk gene catalog, we obtained 18 MG risk pathways. Furthermore, we identified 93 miRNAs that target MG risk pathways and revealed the miRSNPs ‘switches’ in miRNA regulation in the MG risk pathways by integrating the database information of miRSNPs. We also constructed a miRNA-mediated SNP switching pathway network (MSSPN) to intuitively analyze miRNA regulation of MG risk pathways and the relationship of the polymorphism ‘switch’ with these changes in regulation. Moreover, we carried out in-depth dissection on the correlation between hsa05200 (pathway in cancer) and MG development, and elaborated the significance of 4 high-risk genes. By network analysis and literature mining, we proposed a potential mechanism of miRSNPs→gene→pathway effects on MG pathogenesis, especially for rs28457673 (miR-15/16/195/424/497 family)→IGF1R→hsa05200 (pathway in cancer). Therefore, our studies have revealed a functional role for genetic modulators in MG pathogenesis at a systemic level, which could be informative for further miRNA and miRSNPs studies in MG.
Fluorapatite with low solubility is a promising biomaterial due to its structure, which is similar to hydroxyapatite. In this study a bioactive composite of nanofluorapatite (n-FA) and polyamide 12 (PA12) was fabricated. The results revealed that the mechanical properties (such as compressive strength and elastic modulus), hydrophilicity, and antibacterial properties of n-FA/PA12 composite were obviously improved by adding n-FA into PA12 as compared with PA12. In addition, cell proliferation of MC3T3-E1 cells cultured on n-FA/PA12 composite was significantly higher than with PA12, and alkaline phosphatase activity of MC3T3-E1 cells on the n-FA/PA12 composite was expressed at obviously higher levels as compared with PA12. The results suggest that n-FA/PA12 composite could support cell proliferation and differentiation, showing good cytocompatibility. Histological evaluation indicates that n-FA/PA12 composite enhances the efficiency of new bone formation with the introduction of n-FA into PA12, and the quantity of the newly formed bone for n-FA/PA12 composite is significantly higher than with PA12. In conclusion, n-FA/PA12 composite exhibits good biocompatibility and osteogenesis, which might be used for various orthopedic prostheses and dental implants.
nanofluorapatite; bioactive composites; cell behavior; orthopedic implants
Mechanism of ossification of the posterior longitudinal ligament (OPLL) has not been elucidated clearly. Surgical decompression is usually necessary for the patients with neurological symptoms. Anterior decompression and resection of OPLL seems to be a radical surgical option, because the spinal cord is compressed from the anterior direction.
Among 229 patients who underwent ACF for OPLL between January 2001 and December 2007 in our hospital, a total of 133 patients responded to the invitation and made return visits, with a follow-up rate of 58.1%. For these patients, clinical data were collected from medical and operative records. Neurological status were evaluated by using the Japanese Orthopedic Association (JOA) scoring system. Radiological evaluations including C2-7 lordotic angle, sagittal vertical axis (SVA), occupying rate of OPLL, double-layer sign and high-intensity zone were obtained from all the patients. Complications and causes of revision surgery were also investigated. Correlations between the long-term surgical outcome and various prognostic factors were statistically analyzed.
Eighty-four males and forty-nine females completed the follow-up, with a mean age at operation of 56.8 years. The overall average JOA score significantly increased, with a mean recovery rate of 64.1%±14.2%. The mean C2-7 lordotic angle and SVA were also significantly improved, and fusion rate was satisfactory. The incidence of complications was consistent to the previous reports and most of them were controllable by suitable treatments. Multiple regression analysis showed that number of corpectmies and preoperative JOA score were important predictors of surgical outcome.
ACF is a reliable and effective method for treating OPLL patients in terms of neurological recovery, maintenance of radiological parameters, fusion rate and complications. Number of corpectomies and preoperative JOA score are important predictors for the clinical outcome when this procedure is used.
Anterior cervical discectomy and fusion (ACDF) with titanium- or polyetheretherketone (PEEK)-cage reconstruction is widely used in the treatment of cervical spondylotic myelopathy (CSM). This study was to compare outcomes of titanium and PEEK cages in the treatment of multilevel CSM.
Between November 2002 and December 2004, a total of 80 patients with 3-level CSM were randomized in a 1:1 ratio to titanium group and PEEK group. The overall follow-up period of the patients ranged from 86 to 116 months (average 99.7 months). Clinical and radiological results were compared between titanium group and PEEK group.
At the final follow-up, the clinical outcomes including JOA score, NDI score, and the excellent and good rates of clinical outcomes in the PEEK group were better than those in the titanium group. More loss of the Cobb angles and the intervertebral height was observed in the titanium group, resulting in the radiological parameters in the titanium group becoming inferior to the PEEK group at the final follow-up. Cage subsidence rates were 34.5 and 5.4 % in the titanium and PEEK groups, respectively. Fusion was observed in all patients of two groups at the final follow-up. Two patients presented with cage dislocation without clinical symptoms in the titanium group.
In surgical treatment of multilevel CSM, PEEK cage is superior to titanium cage in maintenance of intervertebral height and cervical lordosis, resulting in better clinical outcomes in the long-term follow-up.
Anterior cervical discectomy and fusion; Titanium; PEEK; Cervical spondylotic myelopathy
Se is an antioxidant micronutrient and has been studied for its potential role in CVD prevention. The purpose of the present study was to conduct a systematic review of the literature on the relationship between Se and hypertension.
We conducted a systematic literature search in PubMed and OVID of studies on Se levels and hypertension or blood pressure published in English up to June 2011. Articles meeting inclusion criteria were reviewed and the following information was gathered from each publication: study setting, participant demographics, exclusion criteria, intervention if applicable, medium of Se measure, mean level of Se, outcome definition, relationship between Se and the outcome variable, significance of this relationship, and covariates. In studies that also reported glutathione peroxidase levels, we extracted results on the relationship between glutathione peroxidase and hypertension.
Twenty-five articles were included. Approximately half of the studies reported no significant relationship between Se and hypertension. Of the remaining studies, about half found that higher Se levels were associated with lower blood pressure and the other half found the opposite relationship. The studies varied greatly in terms of study population, study design and Se levels measured in participants.
Based on the present systematic review, there is no conclusive evidence supporting an association between Se and hypertension. Randomized controlled trials and prospective studies with sufficient sample size in populations with different Se levels are needed to fully investigate the relationship between Se and hypertension.
Selenium; Hypertension; Blood pressure
Investigators from academia and industry gathered on April 4 and 5, 2013, in Washington DC at the Arrowhead’s 2nd Annual Cancer Immunotherapy Conference. Two complementary concepts were discussed: cancer “stem cells” as targets and therapeutic platforms based on stem cells.
Immunotherapy; Cancer stem cells; Hematopoietic stem cells; Adoptive T cell therapy; Antibodies; Vaccines
Studies concerning the effect of different types of leisure activities on various cognitive domains are limited. This study tests the hypothesis that mental, physical, and social activities have a domain-specific protection against cognitive decline.
A cohort of a geographically defined population in China was examined in 2003–2005 and followed for an average of 2.4 years. Leisure activities were assessed in 1,463 adults aged 65 years and older without cognitive or physical impairment at baseline, and their cognitive performances were tested at baseline and follow-up examinations.
High level of mental activity was related to less decline in global cognition (β = −.23, p < .01), language (β = −.11, p < .05), and executive function (β = −.13, p < .05) in ANCOVA models adjusting for age, gender, education, history of stroke, body mass index, Apolipoprotein E genotype, and baseline cognition. High level of physical activity was related to less decline in episodic memory (β = −.08, p < .05) and language (β = −.15, p < .01). High level of social activity was associated with less decline in global cognition (β = −.11, p < .05). Further, a dose-response pattern was observed: although participants who did not engage in any of the three activities experienced a significant global cognitive decline, those who engaged in any one of the activities maintained their cognition, and those who engaged in two or three activities improved their cognition. The same pattern was observed in men and in women.
Leisure activities in old age may protect against cognitive decline for both women and men, and different types of activities seem to benefit different cognitive domains.
Cognitive function; Leisure activities; Mental activity; Physical activity; Social activity
Despite tremendous efforts over the course of many years, the quest for an effective HIV vaccine by the classical method of active immunization remains largely elusive. However, two recent studies in mice and macaques have now demonstrated a new strategy designated as Vectored ImmunoProphylaxis (VIP), which involves passive immunization by viral vector-mediated delivery of genes encoding broadly neutralizing antibodies (bnAbs) for in vivo expression. Robust protection against virus infection was observed in preclinical settings when animals were given VIP to express monoclonal neutralizing antibodies. This unorthodox approach raises new promise for combating the ongoing global HIV pandemic. In this article, we survey the status of antibody gene transfer, review the revolutionary progress on isolation of extremely bnAbs, detail VIP experiments against HIV and its related virus conduced in humanized mice and macaque monkeys, and discuss the pros and cons of VIP and its opportunities and challenges towards clinical applications to control HIV/AIDS endemics.
antibody gene transfer; human immunodeficiency virus; vectored immunoprophylaxis; broadly neutralizing antibody; adeno-associated virus-based vectors
Anterior approach was extensively used in surgical treatment of multilevel cervical spondylotic myelopathy. Following anterior decompression, many different reconstructive techniques (multilevel ACDF, hybrid construct and long corpectomy) all had satisfied outcomes. However, there are few studies focusing on the comparison of these three reconstructed techniques. The aim of this retrospective study was to analyze the complications of these three different methods.
This study retrospectively reviewed the complications in 286 consecutive patients with multilevel CSM who underwent anterior cervical surgery from 2005 to 2010. This case series had 166 men and 120 women whose mean age at surgery was 53.8 years (range from 33 to 74 years). Radiographic evaluation was taken the day after surgery, and the flexion–extension X-rays were added 3, 12 and 24 months postoperatively to evaluate the fusion condition. Preoperative versus postoperative neurologic function and clinical outcome were evaluated using scoring systems such as the Japanese Orthopedic Association (JOA score), Neck Disability Index (NDI score) and 36-Item Short-Form Health Survey (SF-36 score).
There were no significant differences in JOA scores, NDI scores and SF-36 scores of the pairwise comparison among the three groups. The complications in our series included graft migration, collapse or displacement, hoarseness, dysphagia, C5 palsy, cerebral fluid leakage and wound infection. Sixty-one patients developed complications after surgery and the rate of complication was 21.33 %. Patients in the long corpectomy group had the highest rate of complications; the other two groups had a much lower rate of complications by the latest follow-up. The patients in the multilevel ACDF group had the highest fusion rate by the last follow-up. Patients who had C2–3 and C3–4 segments involved had a higher rate of postoperative hoarseness and dysphagia.
Most of the complications of the three reconstructive techniques subsided gradually after conservative treatment; none of them needed revision surgery. The multilevel ACDF approach has the lowest rate of non-union, but a slightly higher morbidity of the laryngeal nerve-related complication if proximal segments were involved. The long corpectomy approach should be selected prudently because of the high rate of complication.
Multilevel cervical spondylotic myelopathy; Complications; Anterior approach
Myelodysplastic syndromes (MDSs) are hematopoietic stem cell disorders with a high potential to develop into acute myeloid leukemia (AML). We have recently demonstrated that naïve T cells, but not memory T cells, from MDS patients exhibit a pronounced deficiency in the mRNA coding for the catalytic subunit of telomerase (hTERT). We discuss the importance of this finding for lymphocytic homeostasis in MDS patients.
bone marrow failure; myelodysplastic syndrome; telomere; T lymphocyte
Myleodysplastic syndromes (MDS) are premalignant diseases characterized by cytopenias, myeloid dysplasia, immune dysregulation with association to autoimmunity, and variable risk for acute myeloid leukemia (AML) transformation. Studies of Forkhead-box P3 (FoxP3)+ regulatory T-cells (Tregs) indicate that the number and/or activation state may influence cancer progression in these patients. Focusing on patients with a lower-risk for leukemia transformation, 18 (34.6%) of 52 patients studied displayed an altered Treg compartment compared to age-matched controls. Delineation of unique Treg subsets revealed that an increase in the absolute number of CD4(+)FoxP3(+)CD25(+)CD127(low)CD45RA(−)CD27(−) Tregs (effector memory Tregs; TregEM) was significantly associated with anemia (p=0.046), reduced hemoglobin (p=0.038), and blast counts ≥5% (p=0.006). In healthy donors, this TregEM population constitutes only 2% of all Tregs (1–6 Treg cells/μl) in peripheral blood, but when isolated, exhibit greater suppressive activity in vitro. With a median follow-up of 3.1 years (range-2.7 to 4.9) from sample acquisition, increased numbers of TregEM cells proved to have independent prognostic importance in survival estimates suggesting that enumeration of this Treg subset may be a more reliable indicator of immunological escape than FoxP3+ T-cells as a whole. Based on multivariate analyses, TregEM impacted survival independently from myeloblast characteristics, cytopenias, karyotype and comorbidities. Based on these findings, TregEM cell expansion may be synonymous with human Treg activation and indicate microenvironmental changes conducive to transformation in MDS.
The goal of the current study was to evaluate whether CYP2E1 plays a role in binge-ethanol induced steatosis and if autophagy impacts CYP2E1-mediated hepatotoxicity, oxidative stress and fatty liver formation produced by ethanol. Wild type (WT), CYP2E1 knockin (KI) and CYP2E1 knockout (KO) mice were gavaged with 3g/kg body wt ethanol twice a day for four days. This treatment caused fatty liver, elevation of CYP2E1 and oxidative stress in WT and KI mice but not KO mice. Autophagy was impaired in ethanol-treated KI mice compared to KO mice as reflected by a decline in the LC3-II/LC3-I ratio and lower total LC-3 and Beclin-1 levels coupled to increases in P62, pAKT/AKT and mTOR. Inhibition of macroautophagy by administration of 3-methyladenine enhanced the binge ethanol hepatotoxicity, steatosis and oxidant stress in CYP2E1 KI, but not CYP2E1 KO mice. Stimulation of autophagy by rapamycin blunted the elevated steatosis produced by binge ethanol. Treatment of HepG2 E47 cells which express CYP2E1 with 100 mM ethanol for 8 days increased fat accumulation and oxidant stress but decreased autophagy. Ethanol had no effect on these reactions in HepG2 C34 cells which do not express CYP2E1. Inhibition of autophagy elevated ethanol toxicity, lipid accumulation and oxidant stress in the E47, but not C34 cells. The antioxidant N-acetylcysteine, and CYP2E1 inhibitor chlormethiazole blunted these effects of ethanol. These results indicate that CYP2E1 plays an important role in binge ethanol-induced fatty liver. We propose that CYP2E1-derived reactive oxygen species inhibit autophagy, which subsequently causes accumulation of lipid droplets. Inhibition of autophagy promotes binge ethanol induced hepatotoxicity, steatosis and oxidant stress via CYP2E1.
Binge ethanol; Autophagy; Steatosis; hepatotoxicity; CYP2E1; Oxidative Stress
Recent evidences show that cationic fluxes play a pivotal role in cell apoptosis. In this study, the roles of Cl− channels in paclitaxel-induced apoptosis were investigated in nasopharyngeal carcinoma CNE-2Z cells. Chloride current and apoptosis were induced by paclitaxel and inhibited by chloride channel blockers. Paclitaxel-activated current possessed similar properties to volume-activated chloride current. After ClC-3 was knocked-down by ClC-3-siRNA, hypotonicity-activated and paclitaxel-induced chloride currents were obviously decreased, indicating that the chloride channel involved in paclitaxel-induced apoptosis may be ClC-3. In early apoptotic cells, ClC-3 was up-regulated significantly; over-expressed ClC-3 was accumulated in cell membrane to form intercrossed filaments, which were co-localized with α-tubulins; changes of ultrastructures and decrease of flexibility in cell membrane were detected by atomic force microscopy. These suggest that ClC-3 is a critical target of paclitaxel and the involvement of ClC-3 in apoptosis may be associated with its accumulation with membrane microtubules and its over activation.