The therapeutic efficiency of bone marrow mononuclear cells (BMMNCs) autologous transplantation for myocardial infarction (MI) remains low. Here we developed a novel strategy to improve cardiac repair by preconditioning BMMNCs via angiotensin II type 2 receptor (AT2R) stimulation.
Methods and Results
Acute MI in rats led to a significant increase of AT2R expression in BMMNCs. Preconditioning of BMMNCs via AT2R stimulation directly with an AT2R agonist CGP42112A or indirectly with angiotensin II plus AT1R antagonist valsartan led to ERK activation and increased eNOS expression as well as subsequent nitric oxide generation, ultimately improved cardiomyocyte protection in
vitro as measured by co-culture approach. Intramyocardial transplantation of BMMNCs preconditioned via AT2R stimulation improved survival of transplanted cells in ischemic region of heart tissue and reduced cardiomyocyte apoptosis and inflammation at 3 days after MI. At 4 weeks after transplantation, compared to DMEM and non-preconditioned BMMNCs group, AT2R stimulated BMMNCs group showed enhanced vessel density in peri-infarct region and attenuated infarct size, leading to global heart function improvement.
Preconditioning of BMMNCs via AT2R stimulation exerts protective effect against MI. Stimulation of AT2R in BMMNCs may provide a new strategy to improving therapeutic efficiency of stem cells for post MI cardiac repair.
MicroRNA-200c (miR-200c) influences sensitivity to chemotherapy and radiotherapy in vitro. This study was designed to investigate the prognostic potential of serum miR-200c in patients with advanced esophageal squamous cancer (ESCC). The serum levels of miR-200c was assayed by quantitative RT-PCR in 157 healthy subjects and 157 patients with advanced ESCC who were treated with platinum-based chemotherapy. The serum levels of miR-200c in advanced ESCC patients was significantly increased compared with those in controls (P < 0.001). Serum miR-200c expression was significantly associated with TNM stage (P = 0.037) and treatment response (P = 0.021). Patients with high expression of serum miR-200c had a higher risk for death than those with low expression of serum miR-200c (adjusted hazard ratios = 1.665, 95% confidence intervals: 1.135-2.443, P = 0.009). In conclusion, serum miR-200c may serve as predictor of survival for advanced ESCC and provide information for personalized therapy in advanced ESCC.
Esophageal squamous cancer; microRNA; miR-200c; platinum; chemotherapy
Chronic kidney disease (CKD) is a prevalent life-threatening disease frequently associated with hypertension, progression to renal fibrosis and eventual renal failure. While the pathogenesis of CKD remains largely unknown, an increased inflammatory response is known to be associated with the disease and has long been speculated to contribute to disease development. However, the causative factors, the exact role of the increased inflammatory cascade in CKD and the underlying mechanisms for its progression remain unidentified. Here we report that interleukin-6 (IL-6) expression levels were significantly increased in the kidneys collected from CKD patients and further elevated in CKD patients characterized with hypertension. Functionally, we determined that angiotensin II (Ang II) is a causative factor responsible for IL-6 induction in the mouse kidney and that genetic deletion of IL-6 significantly reduced hypertension and key features of CKD including renal injury and progression to renal fibrosis in Ang II-infused mice. Mechanistically, we provide both human and mouse evidence that IL-6 is a key cytokine functioning downstream of Ang II signaling to directly induce fibrotic gene expression and preproendothelin-1 (prepro-ET-1) mRNA expression in the kidney. Overall, both the mouse and human studies reported here provide evidence that Ang II induces IL-6 production in the kidney and that, in addition to its role in hypertension, increased IL-6 may play an important pathogenic role in CKD by inducing fibrotic gene expression and ET-1 gene expression. These findings immediately suggest the IL-6 signaling is a novel therapeutic target to manage this devastating disorder affecting millions worldwide.
Renin Angiotensin System; Cytokines; Hypertension; Chronic Kidney Disease; Endothelin-1
The identification of biomarkers in colorectal cancer (CRC) diagnosis and therapy is important in achieving early cancer diagnosis and improving patient outcomes. The aim of this study was to examine clinical significance of miR-218 expression in sera and tissues from CRC patients. A total of 189 cases and 30 healthy subjects were included. The expression levels of miR-218, SLIT2 and SLIT3 were measured by quantitative reverse transcription PCR (qRT-PCR). The relationship between miR-218 expression and clinicopathological characteristics was investigated. The expression levels of miR-218, SLIT2 and SLIT3 in CRC tissues were decreased than those in adjacent normal tissues (all P < 0.05). miR-218 expression was significantly associated with TNM stage, lymph node metastasis (LNM) and differentiation (all P < 0.05). Patients with low miR-218 expression had shorter survival time than those with high miR-218 expression (P = 0.036). Furthermore, the expression levels of serum miR-218 in CRC patients were lower than those in controls (P = 0.005). An increased level of serum miR-218 was found 1 month after surgery (P = 0.026). In conclusion, the miR-218 may has important roles in the development and progression of CRC and be a potential diagnostic and prognostic biomarker of CRC.
Colorectal cancer; miR-218; microRNA; survival; expression
Microwave irradiation as the energy source for one–step direct transesterification of fatty acids in human serum lipids was examined in solvent system of methanol: hexane: acetyl chloride based on Lepage & Roy assay. Innovative and explosion proof single–mode or multimode microwave accelerate reaction system was employed. Recoveries were calculated as the percentage of fatty acid concentrations measured by microwave assay to those by reference method Lepage & Roy assay that utilized conductive heating at 100 °C for 60 min. At conditions of 100 °C for 1 min in Single–mode (S4–100×1), or 125 °C for 5 min in Multimode (M5–125×5), the recoveries were 100–103% for the total fatty acids and 96–106% for each categorized fatty acid, including saturates, monounsaturates, n-6 PUFA, and n-3 PUFA. For individual PUFA, the mean recoveries were 102–105% for 18:2n-6 and 18:3n-3; 99, 109, and 95% for 20:4n-6, 20:5n-3, and 22:6n-3, respectively. Thus, fatty acid concentrations determined by microwave fatty acid assay were accurate to those results by the reference method, when the microwave conditions were optimal. In summary, the microwave irradiation could replace conductive heating in one–step direct transesterification, and reduce duration from 60 min to 5 min or less. This methodology may be applied in both the absolute and relative quantification of serum total fatty acids.
Lepage & Roy; Acetyl chloride; in situ; Transesterification; GC; Fatty acid profile
The origin of the variation in the regioselectivity of the nucleophilic ring-opening of a series of bicyclic aziridinium ions derived from N-alkylprolinols was investigated by quantum chemical computations (M06-2X/6-31+G(d,p)—SMD). These aziridiniums differ only in the degree and the stereochemistry of fluoro substitution at C(4). With the azide ion as nucleophile, the ratio of the piperidine to the pyrrolidine product was computed. An electrostatic gauche effect influences the conformation of the adjoining five-membered ring in the fluorinated bicyclic aziridinium. This controls the regioselectivity of the aziridinium ring-opening.
aziridinium; fluorine; gauche effect; nitrogen heterocycles; computational chemistry
Some synthetic chemicals, which have been shown to disrupt thyroid hormone (TH) function, have been detected in surface waters and people have the potential to be exposed through water-drinking. Here, the presence of thyroid-active chemicals and their toxic potential in drinking water sources in Yangtze River Delta were investigated by use of instrumental analysis combined with cell-based reporter gene assay. A novel approach was developed to use Monte Carlo simulation, for evaluation of the potential risks of measured concentrations of TH agonists and antagonists and to determine the major contributors to observed thyroid receptor (TR) antagonist potency. None of the extracts exhibited TR agonist potency, while 12 of 14 water samples exhibited TR antagonistic potency. The most probable observed antagonist equivalents ranged from 1.4 to 5.6 µg di-n-butyl phthalate (DNBP)/L, which posed potential risk in water sources. Based on Monte Carlo simulation related mass balance analysis, DNBP accounted for 64.4% for the entire observed antagonist toxic unit in water sources, while diisobutyl phthalate (DIBP), di-n-octyl phthalate (DNOP) and di-2-ethylhexyl phthalate (DEHP) also contributed. The most probable observed equivalent and most probable relative potency (REP) derived from Monte Carlo simulation is useful for potency comparison and responsible chemicals screening.
A 55-year-old male presented with a rapidly expanding mass on the right side of the neck and progressive hoarseness. An electronic laryngoscopy and a computed tomography scan were performed, and the patient was subsequently diagnosed with tumors of the larynx and the thyroid gland. An en bloc near-total thyroidectomy combined with a total laryngectomy was performed. The final pathological analysis revealed a collision tumor that was derived from a laryngeal squamous cell carcinoma and a papillary thyroid carcinoma. Collision tumors of the head and neck are rare. The therapy for a collision tumor should consist of a combination of the treatments that are normally used for each focus.
laryngeal squamous cell carcinoma; papillary thyroid carcinoma; collision tumor
AIM: To develop a fuzzy classification method to score the texture features of pancreatic cancer in endoscopic ultrasonography (EUS) images and evaluate its utility in making prognosis judgments for patients with unresectable pancreatic cancer treated by EUS-guided interstitial brachytherapy.
METHODS: EUS images from our retrospective database were analyzed. The regions of interest were drawn, and texture features were extracted, selected, and scored with a fuzzy classification method using a C++ program. Then, patients with unresectable pancreatic cancer were enrolled to receive EUS-guided iodine 125 radioactive seed implantation. Their fuzzy classification scores, tumor volumes, and carbohydrate antigen 199 (CA199) levels before and after the brachytherapy were recorded. The association between the changes in these parameters and overall survival was analyzed statistically.
RESULTS: EUS images of 153 patients with pancreatic cancer and 63 non-cancer patients were analyzed. A total of 25 consecutive patients were enrolled, and they tolerated the brachytherapy well without any complications. There was a correlation between the change in the fuzzy classification score and overall survival (Spearman test, r = 0.616, P = 0.001), whereas no correlation was found to be significant between the change in tumor volume (P = 0.663), CA199 level (P = 0.659), and overall survival. There were 15 patients with a decrease in their fuzzy classification score after brachytherapy, whereas the fuzzy classification score increased in another 10 patients. There was a significant difference in overall survival between the two groups (67 d vs 151 d, P = 0.001), but not in the change of tumor volume and CA199 level.
CONCLUSION: Using the fuzzy classification method to analyze EUS images of pancreatic cancer is feasible, and the method can be used to make prognosis judgments for patients with unresectable pancreatic cancer treated by interstitial brachytherapy.
Digital image processing; Fuzzy classification; Endoscopic ultrasonography; Pancreatic cancer; Interstitial brachytherapy; Prognosis
It has been proved that hepatitis B virus (HBV) infection alters the metastatic pattern and affects survival in colorectal cancer (CRC) and hepatocellular carcinoma (HCC), while the influence of HBV infection on metastatic pattern and survival in patients with pancreatic cancer (PC) has not been investigated yet.
We conducted an investigation to evaluate the impact of HBV infection on metastatic pattern and overall survival in PC. We collected the data of 460 PC patients treated in our hospital from 1999 to 2010. Serum HBV markers were tested with enzyme-linked immunosorbent assay. The impact of HBV infection on metastatic pattern and overall survival was analyzed.
We found that the incidence of synchronous liver metastasis was significantly higher in patients with HBsAg positive than those with HBsAg negative (46.0% vs 32.0%, P < 0.05), and higher in chronic HBV infection (CHB) group than both non HBV infection and resolved HBV infection group (61.1% vs 33.9%, P < 0.05, and 61.1% vs 28.7%, P < 0.05, respectively). What’s more, Kaplan-Meier analysis showed that CHB, resolved HBV infection and non HBV infection group had significant longer overall survival (OS) compared with inactive HBsAg carriers (IC) group (P=0.037, P=0.009, and P=0.019 respectively). But, in the multivariate analysis, only the CHB and non HBV infection group had significant better overall survival compared with IC group (P=0.010 and P=0.018 respectively).
Our study found that HBV infection increased synchronous liver metastasis rate, and HBV infection status was an independent prognostic factor in PC patients.
Hepatitis B virus; Pancreatic cancer; Liver metastasis; Survival
The accuracy of the diagnosis is vital when administrative databases are used for pharmacoepidemiologic and outcome studies. Data pertaining to the utility of databases for rheumatoid arthritis (RA) is sparse and variable. We assessed the utility of various diagnostic algorithms to identify RA patients within the Veterans Health Administration (VHA) databases.
Using the ICD code for RA at two visits, at least six months apart, we identified 1779 patients between 10/1/1998 and 9/30/2009 in our local Veteran Affairs Medical Center administrative database. Disease Modifying Anti Rheumatic Drugs (DMARD) use was ascertained from the pharmacy database. Cases were analyzed based on DMARD therapy and RA codes at clinic visits. 543 patients' medical records selected by stratification and random selection on the basis of their visits were reviewed to ascertain the clinicians' diagnoses and clinical criteria documentation. Positive predictive values (PPV) were calculated for various database case identification algorithms using diagnosis of RA by medical record review as the gold standard.
PPV for identification of RA with two RA codes six months apart was 30.9%. Addition of DMARD therapy increased the PPV to 60.4%. The PPV further increased to 91.4% when having RA code at the last VAMC rheumatology clinic visit criterion was added.
An algorithm using only two administrative RA codes six months apart had a low PPV for correctly identifying patients with RA in the VHA database. Including DMARD therapy and requiring a RA code at the last visit with a rheumatologist increased the performance of the data extraction algorithm.
Rheumatoid Arthritis; Health Services Research; Computerized records; Databases; ICD codes
Aggregatibacteractinomycetemcomitansis a gram-negative facultative capnophile involved in pathogenesis of aggressive forms of periodontal disease. In the present study, we interrogated the ability of A. actinomycetemcomitans to stimulate innate immune signaling and cytokine production then established that A.actinomycetemcomitans causes bone loss in a novel rat calvarial model. In vitro studies indicated that A. actinomycetemcomitansstimulated considerable production of soluble cytokines, TNF-α, IL-6, and IL-10 in both primary bone marrow derived macrophages and NR8383 macrophages. Immunoblot analysis indicated that A. actinomycetemcomitansexhibits sustained activation of all major mitogen activated protein kinase (MAPK) pathways, as well as the negative regulator of MAPK signaling, MAPK phosphatase-1 (MKP-1),for at least 8 hours. In a rat calvarial model of inflammatory bone loss, high and low doses of formalin fixed A. actinomycetemcomitanswere microinjected into the supraperiostealcalvarial space for 1 to 2 weeks.Histological staining and micro-computed tomography (μCT) of rat calvariae revealed a significant increase of inflammatoryand fibroblast infiltrate and increased bone resorptionas measured by total lacunar pit formation.From these data, we provide new evidence thatfixed whole cell A. actinomycetemcomitansstimulation elicits a pro-inflammatory host response through sustained MAPK signaling leading to enhanced bone resorption within the rat calvarial bone.
periodontal disease; host immune response; cytokines; bone loss
The electronic structures and excitation properties of dye sensitizers determine the photon-to-current conversion efficiency of dye sensitized solar cells (DSSCs). In order to understand the different performance of porphyrin dye sensitizers YD2 and YD2-o-C8 in DSSC, their geometries and electronic structures have been studied using density functional theory (DFT), and the electronic absorption properties have been investigated via time-dependent DFT (TDDFT) with polarizable continuum model for solvent effects. The geometrical parameters indicate that YD2 and YD2-o-C8 have similar conjugate length and charge transfer (CT) distance. According to the experimental spectra, the HSE06 functional in TDDFT is the most suitable functional for describing the Q and B absorption bands of porphyrins. The transition configurations and molecular orbital analysis suggest that the diarylamino groups are major chromophores for effective CT excitations (ECTE), and therefore act as electron donor in photon-induced electron injection in DSSCs. The analysis of excited states properties and the free energy changes for electron injection support that the better performance of YD2-o-C8 in DSSCs result from the more excited states with ECTE character and the larger absolute value of free energy change for electron injection.
porphyrin dye sensitizers; excited states; electronic structures; density functional theory; absorption spectra
AIM: To provide long-term survival results of operable duodenal gastrointestinal stromal tumors (DGISTs) in a tertiary center in China.
METHODS: In this retrospective study, the pathological data of 28 patients with DGISTs who had been treated surgically at the Second Department of General Surgery, Sir Run Run Shaw Hospital (SRRSH) from June 1998 to December 2006 were reviewed. All pathological slides were examined by a single pathologist to confirm the diagnosis. In patients whose diagnosis was not confirmed by immunohistochemistry at the time of resection, representative paraffin blocks were reassembled, and sections were studied using antibodies against CD117 (c-kit), CD34, smooth muscle actin (SMA), vimentin, S-100, actin (HHF35), and desmin. Operative procedures were classified as wedge resection (WR, local resection with pure closure, without duodenal transection or anastomosis), segmental resection [SR, duodenal transection with Roux-Y or Billroth II gastrojejunostomy (G-J), end-to-end duodenoduodenostomy (D-D), end-to-end or end-to-side duodenojejunostomy (D-J)], and pancreaticoduodenectomy (PD, Whipple operation with pancreatojejunostomy). R0 resection was pursued in all cases, and at least R1 resection was achieved. Regional lymphadenectomy was not performed. Clinical manifestations, surgery, medical treatment and follow-up data were retrospectively analyzed. Related studies in the literature were reviewed.
RESULTS: There were 12 males and 16 females patients, with a median age of 53 years (20-76 years). Their major complaints were “gastrointestinal bleeding” (57.2%) and “nonspecific discomfort” (32.1%). About 14.3%, 60.7%, 17.9%, and 7.1% of the tumors originated in the first to fourth portion, respectively, with a median size of 5.8 cm (1.6-20 cm). Treatment was by WR in 5 cases (17.9%), SR in 13 cases (46.4%), and by PD in 10 cases (35.7%). The morbidity and mortality rates were 35.7% and 3.6%, respectively. The median post-operative stay was 14.5 d (5-47 d). During a follow-up of 61 (23-164) mo, the 2-year and 5-year relapse-free survival was 83.3% and 50%, respectively. Eighty-four related articles were reviewed.
CONCLUSION: Surgeons can choose to perform limited resection or PD for operable DGISTs if clear surgical margins are achieved. Comprehensive treatment is necessary.
Gastrointestinal stromal tumors; Duodenum; Limited resection; Pancreaticoduodenectomy; Survival
The association between type 2 diabetes and low testosterone has been well recognized. However, testosterone levels in men with prediabetes have been rarely reported. We aimed to investigate whether prediabetes was associated with an increased risk of testosterone deficiency.
This study included 1,306 men whose sex hormones was measured during a medical examination. Serum total testosterone and sex hormone-binding globulin were measured; free and bioavailable testosterone concentrations were calculated by Vermeulen’s formula. Prediabetes was defined by impaired fasting glucose (IFG), impaired postprandial glucose (IPG), or glycated hemoglobin (HbA1c) 5.7%-6.4%. Logistic regression was performed to obtain the odds ratios (OR) for subnormal total testosterone (<300 ng/dL) or free testosterone (<6 ng/dL) in prediabetic and diabetic men compared with normoglycemic individuals, while adjusting for age, BMI, waist circumference, and metabolic syndrome (MetS).
Normoglycemia, prediabetes, and diabetes were diagnosed in 577 (44.2%), 543 (41.6%), and 186 (14.2%) men, respectively. Prediabetes was associated with an increased risk of subnormal total testosterone compared to normoglycemic individuals (age-adjusted OR=1.87; 95%CI=1.38-2.54). The risk remained significant in all multivariate analyses. After adjusting for MetS, the OR in prediabetic men equals that of diabetic patients (1.49 versus 1.50). IFG, IPG, and HbA1c 5.7%-6.4% were all associated with an increased risk of testosterone deficiency, with different levels of significance in multivariate analyses. However, neither prediabetes nor diabetes was associated with subnormal free testosterone in multivariate analyses.
Prediabetes is associated with an increased risk of testosterone deficiency, independent of obesity and MetS. After adjusting for MetS, the risk equals that of diabetes. Our data suggest that testosterone should be measured routinely in men with prediabetes.
In the title complex, [Cu(C9H4O6)(H2O)3]n, the CuII cation exhibits a distorted square-pyramidal coordination geometry involving five O atoms from two monodentate 5-carboxybenzene-1,3-dicarboxylate anions and three water molecules. The 5-carboxybenzene-1,3-dicarboxylate anions bridge CuII cations into zigzag polymeric chains running along the b-axis direction. These chains are further linked by O—H⋯O hydrogen bonds between coordinating water molecules or carboxyl groups and carboxylate groups into a three-dimensional supramolecular architecture. In the crystal, π–π stacking is observed between parallel benzene rings of adjacent chains, the centroid–centroid distances being 3.584 (3) and 3.684 (3) Å.
Rapid cell division and expansion in early fruit development are important phases for cucumber fruit yield and quality. Kinesin proteins are microtubule-based motors responsible for modulating cell division and enlargement. In this work, the candidate kinesin genes involved in rapid cell division and expansion during cucumber fruit development were investigated. The morphological and cellular changes during early fruit development were compared in four cucumber genotypes with varied fruit size. The correlation between the expression profiles of cucumber kinesin genes and cellular changes in fruit was investigated. Finally, the biochemical characteristics and subcellular localizations of three candidate kinesins were studied. The results clarified the morphological and cellular changes during early cucumber fruit development. This study found that CsKF2–CsKF6 were positively correlated with rapid cell production; CsKF1 and CsKF7 showed a strongly positive correlation with rapid cell expansion. The results also indicated that CsKF1 localized to the plasma membrane of fast-expanding fruit cells, that CsKF2 might play a role in fruit chloroplast division, and that CsKF3 is involved in the function or formation of phragmoplasts in fruit telophase cells. The results strongly suggest that specific fruit-enriched kinesins are specialized in their functions in rapid cell division and expansion during cucumber fruit development.
Cell division; chloroplast; cucumber; expansion; fruit; kinesin; phragmoplast; plasma membrane.
Relation extraction in biomedical text mining systems has largely focused on identifying clause-level relations, but increasing sophistication demands the recognition of relations at discourse level. A first step in identifying discourse relations involves the detection of discourse connectives: words or phrases used in text to express discourse relations. In this study supervised machine-learning approaches were developed and evaluated for automatically identifying discourse connectives in biomedical text.
Materials and Methods
Two supervised machine-learning models (support vector machines and conditional random fields) were explored for identifying discourse connectives in biomedical literature. In-domain supervised machine-learning classifiers were trained on the Biomedical Discourse Relation Bank, an annotated corpus of discourse relations over 24 full-text biomedical articles (∼112 000 word tokens), a subset of the GENIA corpus. Novel domain adaptation techniques were also explored to leverage the larger open-domain Penn Discourse Treebank (∼1 million word tokens). The models were evaluated using the standard evaluation metrics of precision, recall and F1 scores.
Results and Conclusion
Supervised machine-learning approaches can automatically identify discourse connectives in biomedical text, and the novel domain adaptation techniques yielded the best performance: 0.761 F1 score. A demonstration version of the fully implemented classifier BioConn is available at: http://bioconn.askhermes.org.
Analysis; automated learning; controlled terminologies and vocabularies; discovery; display; image representation; knowledge acquisition and knowledge management; knowledge bases; knowledge representations; machine learning; natural language processing; NLP; ontologies; processing; text and data mining methods
Bone marrow-derived endothelial progenitor cells (EPCs) constitute an important endogenous system in the maintenance of endothelial integrity and vascular homeostasis. Cardiovascular risk factors are associated with a reduced number and functional capacity of EPCs. Here we investigated the effect of transplantation of bone marrow-derived cells from Dahl salt-resistant rat into age-matched Dahl salt-sensitive (DS) rat on blood pressure, endothelial function, and circulating EPC number. The recipient DS rats were fed a normal (0.5% NaCl, NS) or high salt (4% NaCl, HS) diet for 6 weeks after BMT. DS rats on a NS or a HS diet without BMT were used as controls. Hypertensive DS (HS-DS) rat (systolic blood pressure: 213 ± 4 mmHg vs. 152 ± 4 mmHg in NS, p<0.05) manifested impaired endothelium-dependent relaxation to acetylcholine (EDR), increased gene expression of vascular oxidative stress and proinflamamtory cytokines, and decreased eNOS expression. BMT on HS-DS rat significantly improved EDR and eNOS expression, reduced oxidative stress without reduction in SBP (206 ± 6 mmHg). Flow cytometry analysis showed that there was no difference in the number of circulating EPCs, demonstrated by expression of EPC markers CD34, cKit, and vascular endothelial growth factor, between hypertensive and normotensive rats. Surprisingly, BMT resulted in a 5–10 fold increase in the above-mentioned EPC markers in hypertensive, but not normotensive rat. These results suggest that DS rat has an impaired ability to increase bone marrow-derived EPCs in response to HS diet challenge, which may contribute to endothelial dysfunction.
Bone marrow transplantation; Endothelial progenitor cells; Endothelial function; Salt-sensitive hypertension
Immune-related pancytopenia (IRP) is one kind of bone marrow failure diseases which is related to autoantibodies. Autoantibodies have been detected on the membrane of various bone marrow (BM) hemopoietic cells by BM mononuclear-cell-Coombs test or flow cytometric analysis. There are autoantibodies in the BM supernatant of IRP patients, which can target several antigens on hematopoietic cells membranes by western blot. T follicular helper (Tfh) cells are the true helper cells for Ab responses, which represent one of the most numerous and important subsets of effector T cells. Dysregulation of Tfh cell function or expression of Tfh cell-associated molecules could contribute to the pathogenesis of autoimmune diseases. Currently, there are no studies regarding the role of Tfh cells in IRP patients. The percentages of Tfh cells, Tfh-related molecules ICOS, CD40L, IL-21, and Bcl-6 in BM were investigated in 90 patients with IRP, and 25 healthy controls. We observed that there exist increased quantity and hyperfunction of Tfh cells in IRP, and the results were correlated with patient characteristics. It was indicated that dysregulated Tfh cells might be involved in the pathogenesis of IRP and that inhibition of Tfh cells effector molecules might provide opportunities for new therapeutic approaches to IRP and even other human autoimmune diseases.
Nimotuzumab is a humanized IgG1 monoclonal antibody specifically targeting EGFR. In this study, we aimed to investigate the molecular mechanisms of nimotuzumab in its effects of enhancing cancer cell radiosensitivity.
Lung cancer A549 cells and breast cancer MCF-7 cells were pretreated with or without nimotuzumab for 24 h before radiation to perform the clonogenic survival assay and to analyze the cell apoptosis by flow ctyometry. γ-H2AX foci were detected by confocal microscopy to assess the effect of nimotuzumab on radiation induced DNA repair. EGFR activation was examined and the levels of DNA damage repair related proteins in A549 cells at different time point and at varying doses exposure after nimotuzumab and radiation treatment were examined by Western blot. Pretreatment with nimotuzumab reduced clonogenic survival after radiation, inhibited radiation-induced EGFR activation and increased the radiation-induced apoptosis in both A549 cells and MCF-7 cells. The foci of γ-H2AX 24 h after radiation significantly increased in nimotuzumab pretreated cells with different doses. The phosphorylation of AKT and DNA-PKcs were remarkably inhibited in the combination group at each dose point as well as time point.
Our results revealed that the possible mechanism of nimotuzumab enhancing the cancer radiosensitivity is that nimotuzumab inhibited the radiation-induced activation of DNA-PKcs through blocking the PI3K/AKT pathway, which ultimately affected the DNA DSBs repair.
Mitogen Activating Protein (MAPK) kinase phosphatase-1 (MKP-1) has been shown to be a key negative regulator of the MAP kinase pathways of the innate immune system. The impact of MKP-1 in an endodontic model has yet to be studied. Thus, the purpose of this study was to determine the role of MKP-1 in a bacterial-driven model of pathological endodontic bone loss.
Pulps were exposed in both lower 1st molars of 10-week old mkp-1+/+ and mkp-1−/− mice and left open to the oral environment for either 3 or 8 weeks. At sacrifice, mandibles were harvested and scanned by microcomputed tomography (μCT) to determine periapical bone loss. Histopathological scoring was then performed on the samples to determine the amount of inflammatory infiltrate within the periapical microenvironment.
Significant bone loss and inflammatory infiltrate were found in all experimental groups when compared to control. No statistical difference was found between mkp-1+/+ and mkp-1−/− at either time point with respect to bone loss or inflammatory infiltrate. At 8 weeks, male mkp-1−/− mice were found to have significantly more bone loss and inflammatory infiltrate when compared to female mkp-1−/− mice. There was also a significant correlation between an increase in bone loss and increase in inflammatory infiltrate.
A sexual dimorphism exists in the periapical inflammatory process, where male mkp-1−/− mice have more inflammation than female mkp-1−/− mice. The increase in inflammatory infiltrate correlates to more bone loss in the male mice.
MAP kinase phophatase-1; sexual dimorphism; periapical bone loss; inflammation
The unabated circulation of the highly pathogenic avian influenza A virus/H5N1 continues to be a serious threat to public health worldwide. Because of the high frequency of naturally occurring mutations, the emergence of H5N1 variants with high virulence has raised great concerns about the potential transmissibility of the virus in humans. Recent studies have shown that laboratory-mutated or reassortant H5N1 viruses could be efficiently transmitted among mammals, particularly ferrets, the best animal model for humans. Thus, it is critical to establish effective strategies to combat future H5N1 pandemics. In this study, we identified a broadly neutralizing monoclonal antibody (MAb), HA-7, that potently neutralized all tested strains of H5N1 covering clades 0, 1, 2.2, 2.3.4, and 184.108.40.206 and completely protected mice against lethal challenges of H5N1 viruses from clades 1 and 2.3.4. HA-7 specifically targeted the globular head of the H5N1 virus hemagglutinin (HA). Using electron microscopy technology with three-dimensional reconstruction (3D-EM), we discovered that HA-7 bound to a novel and highly conserved conformational epitope that was centered on residues 81 to 83 and 117 to 122 of HA1 (H5 numbering). We further demonstrated that HA-7 inhibited viral entry during postattachment events but not at the receptor-binding step, which is fully consistent with the 3D-EM result. Taken together, we propose that HA-7 could be humanized as an effective passive immunotherapeutic agent for antiviral stockpiling for future influenza pandemics caused by emerging unpredictable H5N1 strains. Our study also provides a sound foundation for the rational design of vaccines capable of inducing broad-spectrum immunity against H5N1.
Nutritional evaluation is important for patients with esophageal cancer, but the impact of undernutrition on outcome of those patients is not well elucidated. Our aim is to assess the impact of baseline nutritional status on overall survival (OS) in Chinese patients with esophageal squamous cell carcinoma (ESCC) and to detect a most appropriate indicator for nutritional evaluation.
502 patients from Southern China diagnosed as ESCC in Sun Yat-Sen University Cancer Center were included. A series of nutritional indicators were introduced to evaluate the baseline nutritional status. Kaplan-Meier method was used to estimate the 5-year OS and the log-rank test was used to determine the survival differences. Cox proportional hazards model was used in the univariate and multivariate analyses of OS.
With a median follow up time of 30 months, the median OS for the entire patient group was 37.3 months with the 5-year OS rate of 43.0%. Only performance status, AJCC 6th stage and body mass index (BMI) were the independent prognostic factors in multivariate analysis of OS. The median OS for patients with BMI less than 18.5, patients with BMI within 18.5-24.9 and patients with BMI more than 24.9 were 19.2, 43.2 and 51.6 months, respectively, with the 5-year OS rates of 25.2%, 46.1% and 48.1% (P<0.001). Patients with BMI <18.5 tended to present with a more advanced stage disease and a poorer tumor grade.
Baseline nutritional status is predictive of OS in Chinese patients with ESCC. BMI is a steady indicator for nutritional evaluation and a sensitive prognostic parameter for ESCC patients. Treatment optimization in ESCC patients with low BMI should integrate the modalities and individual nutritional support.
Nutritional parameters; body mass index (BMI); prognostic value; esophageal squamous cell carcinoma