Chronic infections with human viruses, such as HIV and HCV, or mouse viruses, such as LCMV or Friend Virus (FV), result in functional exhaustion of CD8+ T cells. Two main mechanisms have been described that mediate this exhaustion: expression of inhibitory receptors on CD8+ T cells and expansion of regulatory T cells (Tregs) that suppress CD8+ T cell activity. Several studies show that blockage of one of these pathways results in reactivation of CD8+ T cells and partial reduction in chronic viral loads. Using blocking antibodies against PD-1 ligand and Tim-3 and transgenic mice in which Tregs can be selectively ablated, we compared these two treatment strategies and combined them for the first time in a model of chronic retrovirus infection. Blocking inhibitory receptors was more efficient than transient depletion of Tregs in reactivating exhausted CD8+ T cells and reducing viral set points. However, a combination therapy was superior to any single treatment and further augmented CD8+ T cell responses and resulted in a sustained reduction in chronic viral loads. These results demonstrate that Tregs and inhibitory receptors are non-overlapping factors in the maintenance of chronic viral infections and that immunotherapies targeting both pathways may be a promising strategy to treat chronic infectious diseases.
A loss of function, the so-called ‘exhaustion’ of CD8+ T cells, is a hallmark of many chronic infections. The T cell exhaustion is mediated by two main mechanisms, the expression of inhibitory receptors on CD8+ T cells and virus-induced expansion of regulatory T cells (Tregs), which suppress CD8+ T cell activity. Several mouse studies revealed a reactivation of CD8+ T cells and reduction in chronic viral loads after blockage of one of these pathways. These results initiated a number of clinical studies mainly with cancer patients, in which blocking antibodies were used to interfere with inhibitory receptor signaling or drugs that deplete Tregs. For the first time we combined the two therapeutic approaches by using transgenic mice in which Tregs can be selectively ablated and injection of blocking antibodies in a chronic retroviral infection. The results indicate that the combination therapy was superior to any single treatment in further augmenting CD8+ T cell responses and reducing chronic viral loads. Our findings demonstrate that Tregs and inhibitory receptors are non-overlapping factors in the maintenance of chronic viral infections and that immunotherapies targeting both pathways may be a promising new strategy to treat chronic infectious diseases.
Host range factors, expressed by the poxvirus family, determine the host tropism of species, tissue, and cell specificity. C7L family members exist in the genomes of most sequenced mammalian poxviruses, suggesting an evolutionarily conserved effort adapting to the hosts. In general, C7L orthologs influence the host tropism in mammalian cell culture, and for some poxviruses it is essential for the complete viral life cycle in vitro and in vivo. The C7L family members lack obvious sequence homology with any other known viral or cellular proteins. Here we review recent findings from an evolutionary perspective and summarize recent progress that broadens our view on the role of C7L family members in mediating poxvirus host range and antagonizing the host defense system.
Protracted social isolation of adult mice induced behavioral, transcriptional and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC) and impaired adult myelination. Social re-integration was sufficient to normalize behavioral and transcriptional changes. Short periods of isolation affected chromatin and myelin, but did not induce behavioral changes. Thus, myelinating oligodendrocytes in the adult PFC respond to social interaction with chromatin changes, suggesting that myelination acts as a form of adult plasticity.
HIF-1 activates various genes in cancer progression and metastasis. HIF-1α 1772 C/T and 1790 G/A polymorphisms are reportedly associated with cancer risk; however, the results are inconclusive.
A meta-analysis of 34 studies that involved 7522 cases and 9847 controls for 1772 C/T and 24 studies that involved 4884 cases and 8154 controls for 1790 G/A was conducted to identify the association of C/T and G/A polymorphisms with cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association.
HIF-1α 1772 C/T and 1790 G/A polymorphisms were associated with higher cancer risk in homozygote comparison (1772C/T: TT vs. CC: OR = 2.45, 95% CI: 1.52, 3.96; Pheterogeneity = 0.028; 1790G/A: AA vs. GG: OR=4.74, 95% CI: 1.78, 12.6; Pheterogeneity < 0.01), dominant model (1772C/T: TT/CT vs. CC: OR = 1.27, 95% CI: 1.04, 1.55; Pheterogeneity < 0.01, 1790G/A: AA/GA vs. GG: OR = 1.65, 95% CI: 1.05, 2.60; Pheterogeneity < 0.01), T allele versus C allele (T vs. C: OR = 1.42, 95% CI: 1.18, 1.70; Pheterogeneity < 0.01), and A allele versus G allele (A vs. G: OR = 1.83, 95% CI: 1.13, 2.96; Pheterogeneity < 0.01). On a subgroup analysis, the 1772 C/T polymorphism was significantly linked to higher risks for breast cancer, lung cancer, prostate cancer, and cervical cancer, whereas the 1790 G/A polymorphism was significantly linked to higher risks for lung cancer and prostate cancer. A significantly increased cancer risk was found in both Asians and Caucasians for 1772C/T polymorphism, whereas a significantly increased cancer risk was found in Caucasians in the heterozygote comparison and recessive model for 1790G/A polymorphism.
HIF-1α 1772 C/T and 1790 G/A polymorphisms are significantly associated with higher cancer risk.
Xeroderma pigmentosum group D (XPD) is an essential gene involved in the nucleotide excision repair (NER) pathway. Two commonly studied single nucleotide polymorphisms (SNPs) of XPD (Lys751Gln, A>C, rs13181; Asp312Asn, G>A, rs1799793) are implicated in the modulation of DNA repair capacity, thus related to the responses to platinum-based chemotherapy. Here we performed a meta-analysis to better evaluate the association between the two XPD SNPs and clinical outcome of platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients.
A comprehensive search of PubMed database was conducted to identify relevant articles. Primary outcomes included objective response (i.e., complete response + partial response vs. stable disease + progressive disease), progression-free survival (PFS) and overall survival (OS). The pooled and 95% confidence intervals (CIs) of ORs (odds ratios) and HRs (hazard ratios) were estimated using the fixed or random effect model.
Twenty-four studies were eligible according to the inclusion criteria. None of the XPD Lys751Gln/Asp312Asn polymorphisms was associated with objective response, PFS or OS in NSCLC patients treated with platinum drugs. However, in stratified analysis by ethnicity, the XPD Lys751Gln (A>C) polymorphism was not significantly associated with increased response in Caucasians (OR = 1.35, 95%CI = 1.0–1.83, P = 0.122 for heterogeneity) but was associated with decreased PFS in Asians (HR = 1.39, 95%CI = 1.07–1.81, P = 0.879 for heterogeneity). Furthermore, a statistically significant difference existed in the estimates of effect between the two ethnicities (P = 0.014 for TR; P<0.001 for PFS).
XPD Lys751Gln (A>C) may have inverse predictive and prognostic role in platinum-based treatment of NSCLC according to different ethnicities. Further studies are needed to validate our findings.
Maintaining a balance between ATP synthesis and heat generation is crucial for adapting to changes in climate. Variation in the mitochondrial DNA (mtDNA), which encodes 13 subunits of the respiratory chain complexes, may contribute to climate adaptation by regulating thermogenesis and the use of bioenergy. However, studies looking for a relationship between mtDNA haplogroups and climate have obtained mixed results, leaving unresolved the role of mtDNA in climate adaptation. Since mtDNA content can regulate human bioenergy processes and is known to influence many physiological traits and diseases, it is possible that mtDNA content contributes to climate adaptation in human populations. Here, we analyze the distribution of mtDNA content among 27 Chinese ethnic populations residing across China and find a significant association between mtDNA content and climate, with northern populations having significantly higher mtDNA content than southern populations. Functional studies have shown that high mtDNA content correlates with an increase in the expression of energy metabolism enzymes, which may accelerate thermogenesis. This suggests that the significantly higher mtDNA content observed in northern populations may confer a selective advantage in adapting to colder northern climates
The fruit of Schisandra chinensis has been used in the traditional Chinese medicine for thousands of years. Accumulating evidence suggests that Schisandrin B (Sch B) has cardioprotection effect on myocardial ischemia in
vitro. However, it is unclear whether Sch B has beneficial effects on continuous myocardial ischemia in vivo. The aim of the present study was to investigate whether Sch B could improve cardiac function and attenuate myocardial remodeling after myocardial infarction (MI) in mice. Mice model of MI was established by permanent ligation of the left anterior descending (LAD) coronary artery. Then the MI mice were randomly treated with Sch B or vehicle alone. After treatment for 3 weeks, Sch B could increase survival rate, improve heart function and decrease infarct size compared with vehicle. Moreover, Sch B could down-regulate some inflammatory cytokines, activate eNOS pathway, inhibit cell apoptosis, and enhance cell proliferation. Further in vitro study on H9c2 cells showed similar effects of Sch B on prevention of hypoxia-induced inflammation and cell apoptosis. Taken together, our results demonstrate that Sch B can reduce inflammation, inhibit apoptosis, and improve cardiac function after ischemic injury. It represents a potential novel therapeutic approach for treatment of ischemic heart disease.
Adenoid cystic carcinoma (ACC) is an unusual salivary gland malignancy that remains poorly understood. Standard treatment, including surgery with postoperative radiation therapy have attained reasonable local control rates, but the propensity for distant metastases has limited any improvement in survival over time. Our understanding of the molecular mechanisms driving adenoid cystic carcinoma is quite rudimentary, due to the infrequent nature of its occurrence.
An extensive literature review was performed on salivary gland adenoid cystic carcinoma and basic science research findings.
This review highlights many findings that are emerging about the carcinogenesis of ACC including cytogenetics, tumor suppressor genes, oncogenes, epigenetic alterations, mitochondrial alterations, and biomarker studies.
While there have been many discoveries, much still remains unknown about this rare malignancy.
molecular; genetics; DNA; adenoid cystic carcinoma
Sarcoidosis is a systemic granulomatous disease, which is thought to result from an aberrant immune response. CD4+ T lymphocytes play an important role in the development of granulomas. Previously, the immunopathogenesis of sarcoidosis was focused on Th1/Th2 disturbances. The aim of this study was to evaluate the balance between newer CD4+ T lymphocytes, i.e., Treg and Th17 cells. In our studies, a decrease in Treg cells and an increase in Th17 cells were observed in the peripheral blood and BALF of sarcoidosis patients. A significant increase in the Th17/Treg cell ratio was observed in sarcoidosis patients. After treatment with prednisone, the expression of Foxp3 mRNA was elevated in the peripheral blood, and expression of (ROR)γt mRNA showed a downward trend. These findings suggest that sarcoidosis is associated with an imbalance between Th17 and Treg cells in peripheral blood and BALF. Therefore, targeting the cytokines that affect the Th17/Treg ratio could provide a new promising therapy for pulmonary sarcoidosis.
granulomatous disease; sarcoidosis; regulatory T cells; Th17 cells; corticosteroids
Low pathogenic avian influenza virus (LPAIV) usually causes mild disease or asymptomatic infection in poultry. However, some LPAIV strains can be transmitted to humans and cause severe infection. Genetic rearrangement and recombination of even low pathogenic influenza may generate a novel virus with increased virulence, posing a substantial risk to public health. Southern China is regarded as the world “influenza epicenter”, due to a rash of outbreaks of influenza in recent years. In this study, we conducted an epidemiological survey of LPAIV at different live bird markets (LBMs) in Guangxi province, Southern China. From January 2009 to December 2011, we collected 3,121 cotton swab samples of larynx, trachea and cloaca from the poultry at LBMs in Guangxi. Virus isolation, hemagglutination inhibition (HI) assay, and RT-PCR were used to detect and subtype LPAIV in the collected samples. Of the 3,121 samples, 336 samples (10.8%) were LPAIV positive, including 54 (1.7%) in chicken and 282 (9.1%) in duck. The identified LPAIV were H3N1, H3N2, H6N1, H6N2, H6N5, H6N6, H6N8, and H9N2, which are combinations of seven HA subtypes (H1, H3, H4, H6, H9, H10 and H11) and five NA subtypes (N1, N2, N5, N6 and N8). The H3 and H9 subtypes are predominant in the identified LPAIVs. Among the 336 cases, 29 types of mixed infection of different HA subtypes were identified in 87 of the cases (25.9%). The mixed infections may provide opportunities for genetic recombination. Our results suggest that the LPAIV epidemiology in poultry in the Guangxi province in southern China is complicated and highlights the need for further epidemiological and genetic studies of LPAIV in this area.
Background. The characteristics of treatment based on syndrome differentiation (TBSD) cause great challenges to evaluate the effectiveness of the clinical methods. Objectives. This paper aims to evaluate the influence of physician to personalized medicine in the process of TBSD. Methods. We performed a randomized, triple-blind trial involving patients of primary insomnia treated by 3 physicians individually and independently. The patients (n = 30) were randomly assigned to receive treatments by the 3 physicians for every visit. However, they always received the treatment, respectively, prescribed by the physician at the first visit. The primary outcome was evaluated, respectively, by the Pittsburgh Sleep Quality Index (PSQI) and the TCM symptoms measuring scale. The clinical practices of the physicians were recorded at every visit including diagnostic information, syndrome differentiation, treating principles, and prescriptions. Results. All patients in the 3 groups (30 patients) showed significant improvements (>66%) according to the PSQI and TCM symptoms measuring scale. Conclusion. The results indicate that although with comparable effectiveness, there exist significant differences in syndrome differentiation, the treating principles, and the prescriptions of the approaches used by the 3 physicians. This means that the physician should be considered as an important factor for individualized medicine and the related TCM clinical research.
NMO and ATM are intertwined both clinically and pathologically. Apolipoprotein (apo) A-I, the main apolipoprotein of HDL, plays an important role in lipid metabolism in the cerebrospinal fluid and is known to suppress pro-inflammatory cytokines generated by activated T cells in some autoimmune diseases as an immune regulator. However, the differences in the levels of serum apoA-I between NMO and ATM patients are unclear.
In the present study, serum apo A-I levels were measured in 53 NMO patients, 45 ATM patients and 49 healthy subjects. We tested serum apoA-I levels in all participants and investigated EDSS scores of patients with NMO and ATM. Statistical analyses were performed by using SPSS statistical software.
We found that serum apoA-I levels in patients with NMO were significantly lower in comparison to those with ATM. We also found that serum levels of apoA-I was lower in male subjects in comparison to the female subjects in all groups although these differences were not statistically significant in patients with NMO or ATM. It is also shown in our study that serum apoA-I levels in patients with NMO were significantly elevated after receiving a high dosage of intravenous corticosteroids over a period of one week. However, we did not find any correlation between the apoA-I levels and disease disability.
From this study, we concluded that serum levels of apoA-I were lower in NMO patients compared to patients with ATM. Serum apoA-I studies might provide some useful clues to differentiate NMO cases from ATM cases.
Apolipoprotein(apo) A-I; Neuromyelitis optica; Acute ransverse myelitis
Background and Aims
Previous studies have shown impaired cerebral autoregulation (CA) in carotid and middle cerebral artery (MCA) stenosis/occlusion. Little is known about CA in patients with basilar artery (BA) stenosis. We therefore investigated dynamic CA patterns in BA stenosis using transfer function analysis (TFA).
We measured spontaneous oscillations of blood flow velocity (CBFV) in the right posterior cerebral artery (PCA), and left MCA and mean arterial pressure (ABP) continuously in 25 patients with BA stenosis (moderate n=16 with 50-69% occlusion and severe n=9 with ≥70% occlusion) and 22 healthy volunteers in supine position during 6 circles per minute deep breath. Analysis was based on the ‘black-box’ model of transfer function deriving phase and gain in both PCA and MCA.
Though changes of phase shift and gain between the patients and healthy controls were observed in MCA, the differences are however not significant. Phase shift in PCA was significantly decreased in severe stenosis when comparing with healthy controls and moderate stenosis (4.2±34.2° VS 41.1±40.4°, 4.2±34.2° VS 34.2±27.2°, both p<0.05), whilst the gain in PCA is increased for moderate BA stenosis and decreased for severe BA stenosis. Furthermore, we found that phase shift were almost abolished in patients with ischemic stroke who developed unfavorable clinical outcome (mRs>2) on the 90 days after stroke onset.
Dynamic CA in PCA reduces in patients with severe BA stenosis and those with ischemic stroke who present poor outcome in 90 days after stroke onset. Phase shift might be a sensitive index prompting impaired CA in posterior circulation.
Peroxiredoxin 4 (PRDX4), a member of Peroxiredoxin (PRDX) family, is a typical 2-Cys PRDX. PRDX4 monitors the oxidative burden within cellular compartment and reduces hydrogen peroxide and alkyl hydroperoxide related to oxidative stress and apoptosis. Antioxidant, like PRDX4, may promote follicle development and participate in the pathophysiology of PCOS. In our previous study, we found that PRDX4 was expressed in mice oocyte cumulus oophorus complex, and that PRDX4 could be associated with follicle development. In this study, we explored the expression of PRDX4 in human follicles and possible role of PRDX4 in PCOS pathophysiology. Our data showed that PRDX4 was mainly expressed in granulosa cells in human ovaries. When compared to control group, both PRDX4 mRNA level and protein level decreased in PCOS group. The lowered levels of PRDX4 may relate to oxidative stress in the pathophysiologic progress of PCOS. Furthermore, expression of PRDX4 in the granulosa cells of in vivo or in vitro matured follicles was higher than that in immatured follicles, which suggested that PRDX4 may have a close relationship with follicular development. Altogether, our findings may provide new clues of the pathophysiologic mechanism of PCOS and potential therapeutic strategy using antioxidant, like PRDX4.
Environmental exposure to arsenic, especially the trivalent inorganic form (As3+), has been linked to human cancers in addition to a number of other diseases including skin lesions, cardiovascular disorders, neuropathy, and internal organ injury. In the present study, we describe a novel signaling axis of the c-Jun NH2 kinase (JNK) and signal transducer and activator of transcription 3 (Stat3) and its involvement in As3+-induced Akt activation in human bronchial epithelial cells. As3+ activates JNK and induces phosphorylation of the Stat3 at serine 727 (S727) in a dose- and time-dependent manner, which occurred concomitantly with Akt activation. Disruption of the JNK signaling pathway by treatment with the JNK inhibitor SP600125, siRNA knockdown of JNK, or genetic deficiency of the JNK1 or JNK2 gene abrogated As3+-induced S727 phosphorylation of Stat3, Akt activation, and the consequent release of vascular endothelial growth factor (VEGF) and migration of the cells. Similarly, pretreatment of the cells with Stat3 inhibitor or Stat3 siRNA prevented Akt activation and VEGF release from the cells in response to As3+ treatment. Taken together, these data revealed a new signaling mechanism that might be pivotal in As3+-induced malignant transformation of the cells by linking the key stress signaling pathway, JNK, to the activation of Stat3 and the carcinogenic kinase, Akt.
In some areas of cultivation, a lack of salt tolerance severely affects plant productivity. Apple, Malus x domestica Borkh., is sensitive to salt, and, as a perennial woody plant the mechanism of salt stress adaption will be different from that of annual herbal model plants, such as Arabidopsis. Malus zumi is a salt tolerant apple rootstock, which survives high salinity (up to 0.6% NaCl). To examine the mechanism underlying this tolerance, a genome-wide expression analysis was performed, using a cDNA library constructed from salt-treated seedlings of Malus zumi. A total of 15,000 cDNA clones were selected for microarray analysis. In total a group of 576 cDNAs, of which expression changed more than four-fold, were sequenced and 18 genes were selected to verify their expression pattern under salt stress by semi-quantitative RT-PCR. Our genome-wide expression analysis resulted in the isolation of 50 novel Malus genes and the elucidation of a new apple-specific mechanism of salt tolerance, including the stabilization of photosynthesis under stress, involvement of phenolic compounds, and sorbitol in ROS scavenging and osmoprotection. The promoter regions of 111 genes were analyzed by PlantCARE, suggesting an intensive cross-talking of abiotic stress in Malus zumi. An interaction network of salt responsive genes was constructed and molecular regulatory pathways of apple were deduced. Our research will contribute to gene function analysis and further the understanding of salt-tolerance mechanisms in fruit trees.
salt stress; Malus zumi; microarray; salt-responsive gene; interaction network
Although available evidence relating to its effectiveness is weak, acupuncture is used as an alternative therapy for stress urinary incontinence. We report a protocol of a randomized controlled trial using electroacupuncture (the passing of a weak current between inserted acupuncture needles) to treat women with pure stress urinary incontinence.
This is a large-scale multicenter subject-blinded randomized controlled trial. A total of 500 women with pure stress urinary incontinence will be randomly assigned to two groups: a treatment group and a control group. The treatment group will receive electroacupuncture with deep needling at acupuncture points BL33 and BL35. The control group will receive sham electroacupuncture with non-penetrating needling at sham locations for the acupuncture points of BL33 and BL35. Participants will be given three sessions a week for 6 weeks. A 24-week-long follow-up will be conducted. The primary outcome will be the change in amount of urine leakage at the sixth week from a baseline measured by a 1-h pad test. The secondary outcomes include: the 72-h incontinence episode frequency based on a 72-h bladder diary; the score of International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form; the degree of urinary incontinence based on a 72-h bladder diary; self-assessment of the therapeutic effect; weekly consumption of pads; application of other treatments for stress urinary incontinence; and subgroup analysis stratified by incontinence severity. The safety of electroacupuncture will also be assessed.
This trial will help to identify whether electroacupuncture is effective for stress urinary incontinence, and, if so, whether it is a therapeutic effect rather than a placebo effect.
Clinical Trials.gov NCT01784172
Electroacupuncture; Pure stress urinary incontinence; Efficacy; RCT; Study protocol
It is difficult in clinical practice to differentiate patients with newly diagnosed diabetes and ketosis. The aim of this study was to investigate the effect of intensive insulin therapy on islet function in patients with new-onset diabetes and concomitant ketosis, and to determine the value of alternation in islet function in the typing of diabetes.
A total of 206 inpatients with new-onset diabetes and ketosis were recruited after intensive insulin therapy and followed for 36 months. Patients were divided into type 1 diabetes group (Group A) and type 2 diabetes group (Group B). Islet function was compared between the 2 groups before and after intensive insulin therapy, and the influence of islet function on the typing of diabetes and the selection of therapeutic strategies is discussed.
In group A, the AUCI, AUCC, HOMA-β cell and HOMA-IR were significantly lower than those in Group B before and after intensive insulin therapy. The sensitivity and accuracy of antibody test were at a low level in Group A. An insulin release test was done after intensive insulin therapy. Results showed that the peaks of insulin and C peptide appeared at 0.5–1 h after glucose administration in Group A, which was earlier than that before therapy, but the maximal levels were no more than 2 times those of baseline levels. In Group B, the peaks appeared at 2 h, and the maximal levels were about 10 times those of baseline levels.
Poor islet function, incomplete recovery of islet function after intensive insulin therapy, and a short “honeymoon” period are characteristics of type 1 diabetes. Detection of diabetes-related antibodies is not reliable.
diabetic ketosis; typing; islet function; honeymoon period
Decrease in endogenous hydrogen sulfide (H2S) was reported to participate in the pathogenesis of diabetic nephropathy (DN). This study is aimed at exploring the relationship between the abnormalities in H2S metabolism, hyperglycemia-induced oxidative stress and the activation of intrarenal renin-angiotensin system (RAS). Cultured renal mesangial cells (MCs) and streptozotocin (STZ) induced diabetic rats were used for the studies. The expressions of angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II (Ang II) type I receptor (AT1), transforming growth factor-β1 (TGF-β1) and collagen IV were measured by real time PCR and Western blot. Reactive oxygen species (ROS) production was assessed by fluorescent probe assays. Cell proliferation was analyzed by 5'-bromo-2'-deoxyuridine incorporation assay. Ang II concentration was measured by an enzyme immunoassay. AGT, ACE and AT1 receptor mRNA levels and Ang II concentration were increased in high glucose (HG) -treated MCs, the cell proliferation rate and the production of TGF-β1 and of collagen IV productions were also increased. The NADPH oxidase inhibitor diphenylenechloride iodonium (DPI) was able to reverse the HG-induced RAS activation and the changes in cell proliferation and collagen synthesis. Supplementation of H2S attenuated HG-induced elevations in ROS and RAS activation. Blockade on H2S biosynthesis from cystathione-γ-lyase (CSE) by DL-propargylglycine (PPG) resulted in effects similar to that of HG treatment. In STZ-induced diabetic rats, the changes in RAS were also reversed by H2S supplementation without affecting blood glucose concentration. These data suggested that the decrease in H2S under hyperglycemic condition leads to an imbalance between oxidative and reductive species. The increased oxidative species results in intrarenal RAS activation, which, in turn, contributes to the pathogenesis of renal dysfunction.
Pulmonary infections frequently occur following hip fracture surgery in aged patients. However, the underlying reasons are not fully understood. The present study investigates the systemic inflammatory response and pulmonary conditions following hip fracture surgery as a means of identifying risk factors for lung infections using an aged rodent model. Aged, male Sprague-Dawley rats (8 animals per group) underwent a sham procedure or hip fracture plus femoral intramedullary pinning. Animals were sacrificed 1, 3, and 7 days after the injury. Markers of systemic inflammation and pulmonary injury were analyzed. Both sham-operated and injured/surgical group animals underwent intratracheal inoculation with Pseudomonas aeruginosa 1, 3, and 7 days after surgery. P. aeruginosa counts in blood and bronchoalveolar lavage (BAL) fluid and survival rates were recorded. Serum TNF-α, IL-6, IL-1β, and IL-10 levels and markers of pulmonary injury were significantly increased at 1 and 3 days following hip fracture and surgery. Animals challenged with P. aeruginosa at 1 and 3 days after injury had a significantly decreased survival rate and more P. aeruginosa recovered from blood and BAL fluid. This study shows that hip fracture and surgery in aged rats induced a systemic inflammatory response and lung injury associated with increased susceptibility to infection during the acute phase after injury and surgery.
Periostin (POSTN), a recently characterised matricellular protein, is frequently dysregulated in various malignant cancers and promotes tumor metastatic growth. POSTN plays a critical role in the crosstalk between murine breast cancer stem cells (CSCs) and their niche to permit metastatic colonization. However, whether pro-metastatic capability of POSTN is associated with multipotent potentials of mesenchymal stem cells (MSCs) has not been documented. Here we demonstrate that POSTN promotes a stem cell-like trait and a mesenchymal phenotype in human mammary epithelial cells and breast cancer cells. Interestingly, ectopic overexpression of POSTN or recombinant POSTN treatment can induce human mammary epithelial cells and breast cancer cells differentiation into multiple cell lineages that recapitulate part of the multilineage differentiation potentials of MSCs. Moreover, POSTN is highly expressed in bone marrow-derived MSCs and their derived adipocytes, chondrocytes, and osteoblasts in vitro. Furthermore, POSTN promotes the growth of xenograft tumors in vivo. POSTN-overexpressing human mammary epithelial cells enhance breast tumor growth and metastasis. These data thus provide evidence of a new role for POSTN in mammary epithelial neoplasia and metastasis, suggesting that epithelial cancer cells might acquire CSC-like traits and a mesenchymal phenotype, as well as the multipotent potentials of MSCs to promote tumorigenesis and metastasis. Therefore, targeting POSTN and other extracellular matrix components of tumor microenvironment may help to develop new therapeutical strategies to inhibit tumor metastasis.
Trust is a vital lubricant that increases the sense of security in social interactions. In this study, we investigated the intergroup trust between the Uyghur and the Han, the two largest ethnic groups in Xinjiang, China, with a Go/No-Go Association Task. Specifically, we instructed Uyghur and Han participants to respond to ethnic faces (Uyghur vs. Han) and trust/distrust words and measured the strength of the automatic associations between the faces and words for both in-group and out-group pairs. As expected, both ethnic groups showed implicit in-group trust and out-group distrust, but the Han group demonstrated stronger in-group trust and out-group distrust toward the Uyghur than the Uyghur group toward the Han. However, the magnitude of distrust of the Han toward the Uyghur was small to medium as compared with that reported by other intergroup relationship research. In addition, participant geographic location was associated with out-group distrust. These findings offer implications for developing effective strategies to encourage trust between conflicting groups.
In order to evaluate the efficacy and tolerability of oxycodone in moderate-severe cancer-related pain, we conducted a systematic review of randomized controlled trials (RCTs). Publications addressing the efficacy and tolerability of oxycodone in moderate-severe cancer-related pain were selected from the Cochrane library, PubMed, Embase and CBM databases. Data were extracted from the studies by two independent reviewers. The meta-analysis was performed by RevMan 5.0.25 and STATA 9.2 software. From these data, odds ratios (ORs) or the standard mean difference (SMD) with 95% confidence intervals (CIs) were calculated. Finally, only seven RCTs were retrieved with a total of 613 cancer patients with moderate-severe pain. The meta-analysis results showed that oxycodone was statistically superior to other strong opioids based on pain intensity scores following intervention [weighted mean difference (WMD), 0.25; 95% CI, 0.05–0.45; P=0.01; WMD, −1.30; 95% CI, −1.55–1.05; P<0.001, respectively]. In addition, there were statistically significant differences between oxycodone and other strong opioids in cancer-related pain on the obvious effective rate and the overall effective rate (OR, 2.03; 95% CI, 1.40–2.95; P=0.0002; OR, 1.94; 95% CI, 1.09–3.44; P=0.02, respectively). Compared with other strong opioids, nausea and constipation occurred significantly less frequently with the use of oxycodone for cancer-related pain (OR=0.52, 95% CI=0.32–0.85, P=0.009; OR= 0.55, 95% CI= 0.35–0.87, P= 0.01; respectively). In conclusion, this meta-analysis confirms that the efficacy and tolerability of oxycodone are superior to those of other strong opioids, including morphine sulfate, codeine and tramadol, supporting its use as an opioid for cancer-related pain.
oxycodone; cancer-related pain; randomized controlled trial; meta-analysis
Retinal hemorrhages occur in a variety of sight-threatening conditions including ocular trauma, high altitude retinopathy, and chronic diseases such as diabetic and hypertensive retinopathies. The goal of this study is to investigate the effects of blood in the vitreous on retinal vascular function in rats.
Intravitreal injections of autologous blood, plasma kallikrein (PK), bradykinin, and collagenase were performed in Sprague-Dawley and Long-Evans rats. Retinal vascular permeability was measured using vitreous fluorophotometry and Evans blue dye permeation. Leukostasis was measured by fluorescein isothiocyanate–coupled concanavalin A lectin and acridine orange labeling. Retinal hemorrhage was examined on retinal flatmounts. Primary cultures of bovine retinal pericytes were cultured in the presence of 25 nM PK for 24 hours. The pericyte-conditioned medium was collected and the collagen proteome was analyzed by tandem mass spectrometry.
Intravitreal injection of autologous blood induced retinal vascular permeability and retinal leukostasis, and these responses were ameliorated by PK inhibition. Intravitreal injections of exogenous PK induced retinal vascular permeability, leukostasis, and retinal hemorrhage. Proteomic analyses showed that PK increased collagen degradation in pericyte-conditioned medium and purified type IV collagen. Intravitreal injection of collagenase mimicked PK's effect on retinal hemorrhage.
Intraocular hemorrhage increases retinal vascular permeability and leukostasis, and these responses are mediated, in part, via PK. Intravitreal injections of either PK or collagenase, but not bradykinin, induce retinal hemorrhage in rats. PK exerts collagenase-like activity that may contribute to blood–retinal barrier dysfunction.
Intravitreal bleeding increases retinal vascular permeability and leukostasis, and these responses are mediated via plasma kallikrein (PK). Intravitreal injections of PK induce retinal hemorrhage in rats. PK exerts collagenase-like activity that may contribute to blood–retinal barrier dysfunction.
The role of preexisting minority drug-resistance mutations in treatment failure has not been fully understood in chronic hepatitis B patients. To understand mechanisms of drug resistance, we analyzed drug-resistance mutations in 46 treatment-failure patients and in 29 treatment-naïve patients and determined linkage patterns of the drug-resistance mutations in individual viral genomes using a highly sensitive parallel allele-specific sequencing (PASS) method. Lamivudine resistance (LAMr) mutations were predominant in treatment-failure patients, irrespective of the inclusion of LAM in the regimen. The primary LAMr mutations M204V and M204I were detected in 100% and 30% of the treatment-failure patients, respectively. Two secondary LAMr mutations (L180M and V173L) were also found in most treatment-failure patients (87% and 78%, respectively). The linkages containing these three mutations dominated the resistant viruses. Importantly, minority LAMr mutations present in <2% of the viral population were detected in 83% of the treatment-naïve patients. Moreover, the low-frequency same linked LAMr mutations (<0.15%) were detected in 24% of the treatment-naïve patients. Our results demonstrate that the selection of preexisting minority linked LAMr mutations may be an important mechanism for the rapid development of LAM resistance, caution the continuous use of LAM to treat drug-experienced and -naïve hepatitis B patients, and underline the importance of the detection of minority single and linked drug-resistance mutations before initiating antiviral therapy.