We aimed to evaluate the association of serum C-reactive protein (crp) with prognosis in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy.
We retrospectively reviewed 79 patients with locoregionally advanced nasopharyngeal carcinoma (cT3–4N0–3M0) treated with chemoradiotherapy. Chemoradiotherapy consisted of external-beam radiotherapy to the nasopharynx (70–80 Gy), the lymph node–positive area (60–70 Gy), and the lymph node–negative area (50–60 Gy) combined with 3 cycles of various platinum-based regimens delivered at 3-week intervals. Elevated crp was defined as more than 8 mg/L. The survival rate was calculated using the Kaplan–Meier method, and univariate and multivariate analyses (Cox proportional hazards model) were used to identify factors significantly associated with prognosis.
During the median follow-up of 3.9 years (range: 1–5.5 years), 23 patients died from nasopharyngeal cancer. The 5-year cancer-specific survival (css) rate was 62.90%. Before chemoradiotherapy, 18 patients had high serum crp; the css rate in that subgroup was significantly worse than the rate in the remaining patients (p = 0.0002). Multivariate analysis showed that crp was an independent prognostic indicator of css, with a hazard ratio of 3.04 (95% confidence interval: 1.22 to 7.55; p = 0.017). Among the 18 patients with elevated serum crp, 9 achieved normal serum crp after chemoradiotherapy, of whom 5 remained living with no evidence of recurrence or metastasis during follow-up. By contrast, the remaining 9 patients in whom serum crp did not normalize after chemoradiotherapy died within 4.2 years.
Elevated serum crp before treatment predicts poor prognosis in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy.
Nasopharyngeal carcinoma; C-reactive protein; chemoradiotherapy; cancer-specific survival
Administration or expression of growth factors, as well as implantation of autologous
bone marrow cells, promote in vivo angiogenesis. This study
investigated the angiogenic potential of combining both approaches through the
allogenic transplantation of bone marrow-derived mesenchymal stem cells (MSCs)
expressing human basic fibroblast growth factor (hbFGF). After establishing a hind
limb ischemia model in Sprague Dawley rats, the animals were randomly divided into
four treatment groups: MSCs expressing green fluorescent protein (GFP-MSC), MSCs
expressing hbFGF (hbFGF-MSC), MSC controls, and phosphate-buffered saline (PBS)
controls. After 2 weeks, MSC survival and differentiation, hbFGF and vascular
endothelial growth factor (VEGF) expression, and microvessel density of ischemic
muscles were determined. Stable hbFGF expression was observed in the hbFGF-MSC group
after 2 weeks. More hbFGF-MSCs than GFP-MSCs survived and differentiated into
vascular endothelial cells (P<0.001); however, their differentiation rates were
similar. Moreover, allogenic transplantation of hbFGF-MSCs increased VEGF expression
(P=0.008) and microvessel density (P<0.001). Transplantation of hbFGF-expressing
MSCs promoted angiogenesis in an in vivo hind limb ischemia model by
increasing the survival of transplanted cells that subsequently differentiated into
vascular endothelial cells. This study showed the therapeutic potential of combining
cell-based therapy with gene therapy to treat ischemic disease.
Angiogenesis; Basic fibroblast growth factor; Bone marrow mesenchymal stem cells; Gene transfection; Ischemia
In the present study, we aimed to investigate the effects of chemotherapy-induced peripheral neurotoxicity (cipn) on psychological distress and sleep quality in cancer patients.
A total of 706 cancer patients were interviewed for the study. In the 4th week of treatment, patient cipn was measured using the Patient Neurotoxicity Questionnaire (pnq). The sleep quality and psychological distress of patients were measured using the Pittsburgh Sleep Quality Index (psqi), the Distress Thermometer (dt), and the Hospital Anxiety and Depression Scale (hads). Multiple logistic regression was applied to determine the independent effects of cipn on psychological distress and sleep disturbance in the patients.
These correlation coefficients were obtained: 0.387 (p < 0.0001) between the pnq total score and the dt score, 0.386 (p < 0.0001) between the pnq total score and the hads Depression score, 0.379 (p < 0.0001) between the pnq total score and the hads Anxiety score, and 0.399 (p < 0.0001) between the pnq total score and the psqi global score. The prevalence rates of distress, depression, anxiety, and poor sleep quality in the five pnq grades were statistically significantly different (p < 0.0001). After controlling for age, sex, education level, social supports, fatigue, disease stage, and tumour site, the pnq grades were found to be associated with depression (p < 0.0001), anxiety (p < 0.0001), and poor sleep quality (p < 0.0001).
Chemotherapy-induced peripheral neurotoxicity negatively affects psychological distress and sleep quality in cancer patients treated with chemotherapy. High pnq grades were significantly associated with poor psychological status and sleep quality. Our results emphasize the importance of assessing peripheral neuropathies during chemotherapy and of adjusting treatment plans based on assessment results.
Neuropathy; chemotherapy; anxiety; depression; sleep quality
We report here a novel strategy to redirect oncolytic adenoviruses to CD123 by carry a soluble coxsackie-adenovirus receptor (sCAR)-IL3 expression cassette in the viral genome to form Ad.IL3, which sustainably infected acute myeloid leukemia (AML) cells through CD123. Ad.IL3 was further engineered to harbor gene encoding manganese superoxide dismutase (MnSOD) or mannose-binding plant lectin Pinellia pedatisecta agglutinin (PPA), forming Ad.IL3-MnSOD and Ad.IL3-PPA. As compared with Ad.IL3 or Ad.sp-E1A control, Ad.IL3-MnSOD and Ad.IL3-PPA significantly suppressed in vitro proliferation of HL60 and KG-1 cells. Elevated apoptosis was detected in HL60 and KG-1 cells treated with either Ad.IL3-MnSOD or Ad.IL3-PPA. The caspase-9–caspase-7 pathway was determined to be activated by Ad.IL3-MnSOD as well as by Ad.IL3-PPA in HL60 cells. In an HL60/Luc xenograft nonobese diabetic/severe-combined immunodeficiency mice model, Ad.IL3-MnSOD and Ad.IL3-PPA suppressed cancer cell growth as compared with Ad.IL3. A significant difference of cancer cell burden was detected between Ad.IL3 and Ad.IL3-PPA groups at day 9 after treatment. Furthermore, Ad.IL3-MnSOD significantly prolonged mouse survival as compared with Ad.sp-E1A. These findings demonstrated that Ad.IL3-gene could serve as a novel agent for AML therapy. Harboring sCAR-ligand expression cassette in the viral genome may provide a universal method to redirect oncolytic adenoviruses to various membrane receptors on cancer cells resisting serotype 5 adenovirus infection.
By screening a collection of one hundred combinations of thiazolidinone compounds, we identified one combination (M4) that synergistically inhibited the growth of H460 and H460/TaxR cells and tumor growth in H460/TaxR xenograft mice. A whole genome microarray assay showed that genes involved in negative regulation of microtubule polymerization or depolymerization, intracellular protein kinase cascade, positive regulation of histone acetylation, cell cycle arrest and apoptosis were upregulated. Further analysis proved that the four compounds act as either microtubule polymerization inhibitors or histone deacetylase inhibitors. They act synergistically targeting multiple proteins and leading to the regulation of cell cycle checkpoint proteins, including p53, p21, cdc25C and cdc2, the activation of caspases, JNK, p38 cascades and the inactivation of Akt. These events resulted in the G2/M cell cycle arrest and cell apoptosis. These data provide a new strategy for discovering anticancer drugs and drug combinations for drug-resistant cancers.
thiazolidinone; combination therapy; synergistic effect; histone deacetylase inhibitor; P-glycoprotein; apoptosis
Regulator of Cullins-1 (ROC1) or RING box protein-1 (RBX1) is an essential RING component of Cullin-RING ligase (CRL). Our previous studies showed that ROC1 is required for the growth of several cancer cell lines while ROC1 siRNA silencing inactivates CRL, leading to cell cycle arrest, cell senescence and/or apoptosis. However, it is completely unknown whether ROC1 knockdown triggers autophagic response by inactivating CRL. Moreover, the role of ROC1 in liver cancer remains elusive. In this study, we reported that ROC1 knockdown significantly inhibited the growth of liver cancer cells by sequentially and independently inducing autophagy and p21-dependent cell senescence. Mechanism analysis revealed that ROC1 silencing triggered autophagy by inhibition of mammalian target of rapamycin (mTOR) activity due to accumulation of mTOR-inhibitory protein Deptor, a substrate of CRL. Consistently, Deptor knockdown significantly blocked autophagy response upon ROC1 silencing. Biologically, autophagy response upon ROC1 silencing was a survival signal, and blockage of autophagy pathway sensitized cancer cells to apoptosis. Finally, we demonstrated that ROC1 was overexpressed in hepatocellular carcinomas, which is associated with poor prognosis of liver cancer patients. These findings suggest that ROC1 is an appealing drug target for liver cancer and provide a proof-of-concept evidence for a novel drug combination of ROC1 inhibitor and an autophagy inhibitor for effective treatment of liver cancer by enhancing apoptosis.
ROC1; Cullin-RING ligase; autophagy; senescence; Deptor
Androgen receptor (AR) has essential roles during prostate cancer progression. With genome-wide AR-binding sites mapped to high resolution, studies have recently reported AR as a transcriptional repressor. How AR inhibits gene expression and how this contributes to prostate cancer, however, are incompletely understood. Through meta-analysis of microarray data, here we nominate nephroblastoma overexpressed (NOV) as a top androgen-repressed gene. We show that NOV is directly suppressed by androgen through the AR. AR occupies the NOV enhancer and communicates with the NOV promoter through DNA looping. AR activation recruits the polycomb group protein EZH2, which subsequently catalyzes histone H3 lysine 27 tri-methylation around the NOV promoter, thus leading to repressive chromatin remodeling and epigenetic silencing. Concordantly, AR and EZH2 inhibition synergistically restored NOV expression. NOV is downregulated in human prostate cancer wherein AR and EZH2 are upregulated. Functionally, NOV inhibits prostate cancer cell growth in vitro and in vivo. NOV reconstitution reverses androgen-induced cell growth and NOV knockdown drives androgen-independent cell growth. In addition, NOV expression is restored by hormone-deprivation therapies in mice and prostate cancer patients. Therefore, using NOV as a model gene we gained further understanding of the mechanisms underlying AR-mediated transcriptional repression. Our findings establish a tumor-suppressive role of NOV in prostate cancer and suggest that one important, but previously underestimated, manner by which AR contributes to prostate cancer progression is through inhibition of key tumor-suppressor genes.
androgen receptor; polycomb EZH2; NOV; CCN3
Silicon nanoarray hybrid solar cells benefit from the ease of fabrication and the cost-effectiveness of the hybrid structure, and represent a new research focus towards the utilization of solar energy. However, hybrid solar cells composed of both inorganic and organic components suffer from the notorious stability issue, which has to be tackled before the hybrid solar cells could become a viable alternative for harvesting solar energy. Here we show that Si nanoarray/PEDOT:PSS hybrid solar cells with improved stability can be fabricated via eliminating the water inclusion in the initial formation of the heterojunction between Si nanoarray and PEDOT:PSS. The Si nanoarray hybrid solar cells are stable against rapid degradation in the atmosphere environment for several months without encapsulation. This finding paves the way towards the real-world applications of Si nanoarray hybrid solar cells.
The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50<200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.
multiple myeloma (MM); selective inhibitors of nuclear export (SINEs) against CRM1/XPO1; osteoclasts (OC); nuclear factor-κB (NF-κB) activation; nuclear export protein; tumor suppressors
The aim of this study was to prospectively evaluate the initial application and value of prospective electrocardiogram (ECG)-triggered dual-source CT coronary angiography (DSCTCA) in the diagnosis of infants and children with coronary artery aneurysms due to Kawasaki disease.
19 children [12 males; mean age 13.47 months, range 3 months to 5 years; mean heart rate 112 beats per minute (bpm), range 83–141 bpm] underwent prospective ECG-triggered DSCTCA with free breathing. Subjective image quality was assessed on a five-point scale (1, excellent; 5, non-diagnostic) by two blinded observers. The location, number and size of each aneurysm were observed and compared with those of transthoracic echocardiography (TTE) performed within 1 week. Interobserver agreement concerning the subjective image quality was evaluated with Cohen's κ-test. Bland–Altman analysis was used to evaluate the agreement on measurements (diameter and length of aneurysms) between DSCTCA and TTE. The average effective dose required for DSCTCA was calculated for all children.
All interobserver agreement for subjective image quality assessment was excellent (κ=0.87). The mean±standard deviation (SD) aneurysm diameter with DSCTCA was 0.76±0.36 cm and with TTE was 0.76±0.39 cm. The mean±SD aneurysm length with DSCTCA was 2.06±1.35 cm and with TTE was 2.00±1.22 cm. The Bland–Altman plot for agreement between DSCTCA and TTE measurements showed good agreement. The mean effective dose was 0.36±0.06 mSv.
As an alternative diagnostic modality, prospective ECG-triggered DSCTCA with excellent image quality and low radiation exposure has been proved useful for diagnosing infants and children with coronary artery aneurysms due to Kawasaki disease.
Advances in knowledge
Prospective ECG–triggered DSCTCA for infants and children allows rapid, accurate assessment of coronary aneurysms due to Kawasaki diseases, compared with TTE.
The authors analyzed data from the Women’s Health Initiative (WHI) Calcium and Vitamin D Supplementation Trial (CaD) to learn more about factors affecting adherence to clinical trial study pills (both active and placebo). Most participants (36,282 postmenopausal women aged 50–79 years) enrolled in CaD 1 year after joining either a hormone trial or the dietary modification trial of WHI. The WHI researchers measured adherence to study pills by weighing the amount of remaining pills at an annual study visit; adherence was primarily defined as taking ≥ 80% of the pills. The authors in this study examined a number of behavioral, demographic, procedural, and treatment variables for association with study pill adherence. They found that relatively simple procedures (ie, phone contact early in the study [4 weeks post randomization] and direct social contact) later in the trial may improve adherence. Also, at baseline, past pill-use experiences, personal supplement use, and relevant symptoms may be predictive of adherence in a supplement trial.
adherence; calcium supplementation; clinical trial; women
Macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, plays an
important role in the pathogenesis of atrial fibrillation; however, the upstream
regulation of MIF in atrial myocytes remains unclear. In the present study, we
investigated whether and how MIF is regulated in response to the
renin-angiotensin system and oxidative stress in atrium myocytes (HL-1 cells).
MIF protein and mRNA levels in HL-1 cells were assayed using immunofluorescence,
real-time PCR, and Western blot. The result indicated that MIF was expressed in
the cytoplasm of HL-1 cells. Hydrogen peroxide (H2O2), but
not angiotensin II, stimulated MIF expression in HL-1 cells.
H2O2-induced MIF protein and gene levels increased in
a dose-dependent manner and were completely abolished in the presence of
catalase. H2O2-induced MIF production was completely
inhibited by tyrosine kinase inhibitors genistein and PP1, as well as by protein
kinase C (PKC) inhibitor GF109203X, suggesting that redox-sensitive MIF
production is mediated through tyrosine kinase and PKC-dependent mechanisms in
HL-1 cells. These results suggest that MIF is upregulated by HL-1 cells in
response to redox stress, probably by the activation of Src and PKC.
Macrophage migration inhibitory factor; HL-1 cells; Hydrogen peroxide; Atrial fibrillation; Protein kinases
The formulation of quercetin nanoliposomes (QUE-NLs) has been shown to enhance QUE antitumor activity in C6 glioma cells. At high concentrations, QUE-NLs induce necrotic cell death. In this study, we probed the molecular mechanisms of QUE-NL-induced C6 glioma cell death and examined whether QUE-NL-induced programmed cell death involved Bcl-2 family and mitochondrial pathway through STAT3 signal transduction pathway. Downregulation of Bcl-2 and the overexpression of Bax by QUE-NL supported the involvement of Bcl-2 family proteins upstream of C6 glioma cell death. In addition, the activation of JAK2 and STAT3 were altered following exposure to QUE-NLs in C6 glioma cells, suggesting that QUE-NLs downregulated Bcl-2 mRNAs expression and enhanced the expression of mitochondrial mRNAs through STAT3-mediated signaling pathways either via direct or indirect mechanisms. There are several components such as ROS, mitochondrial, and Bcl-2 family shared by the necrotic and apoptotic pathways. Our studies indicate that the signaling cross point of the mitochondrial pathway and the JAK2/STAT3 signaling pathway in C6 glioma cell death is modulated by QUE-NLs. In conclusion, regulation of JAK2/STAT3 and ROS-mediated mitochondrial pathway agonists alone or in combination with treatment by QUE-NLs could be a more effective method of treating chemical-resistant glioma.
quercetin nanoliposomes; programmed cell death; JAK2/STAT3; mitochondrial pathway
Close homologue of L1 (CHL1) is a transmembrane cell adhesion molecule that is critical for brain development and for the maintenance of neural circuits in adults. Recent studies revealed that CHL1 has diverse roles and is involved in the regulation of recovery after spinal cord injury. CHL1 expression was downregulated in the cerebral cortex, hypothalamus, and brain stem after the induction of acute hypoxia (AH). In the current study, we sought to address the role of CHL1 in regulating homeostasis responses to hypoxia using CHL1-knockout (CHL1−/−) mice. We found that, compared with wild-type littermates, CHL1−/− mice showed a dramatically lower mortality rate and an augmented ventilatory response after they were subjected to AH. Immunofluorescence staining revealed that CHL1 was expressed in the carotid body (CB), the key oxygen sensor in rodents, and CHL1 expression level in the CB as assayed by western blot was decreased after hypoxic exposure. The number of glomus cells and the expression of tyrosine hydroxylase (a marker for glomus cells) in the CB of CHL1−/− mice appeared to be increased compared with CHL1+/+ mice. In addition, in the ex vivo CB preparation, hypoxia induced a significantly greater afferent nerve discharge in CHL1−/− mice compared with CHL1+/+ mice. Furthermore, the arterial blood pressure and plasma catecholamine levels of CHL1−/− mice were also significantly higher than those of CHL1+/+ mice. Our findings first demonstrate that CHL1 is a novel intrinsic factor that is involved in CB function and in the ventilatory response to AH.
CHL1; acute hypoxia; homeostatic adaptation; survival
Cancer stem cells (CSCs) paradigm suggests that CSCs might have important clinical implications in cancer therapy. Previously, we reported that accumulation efficiency of CSCs is different post low- and high-LET irradiation in 48 h.
Cancer stem cells and non-stem cancer cells (NSCCs) were sorted and functionally identified through a variety of assays such as antigen profiles and sphere formation. Inter-conversion between CSCs and NSCCs were in situ visualised. Cancer stem cells proportions were assayed over multiple generations under normal and irradiation surroundings. Supplement and inhibition of TGF-β1, as well as immunofluorescence assay of E-cadherin and Vimentin, were performed.
Surface antigen markers of CSCs and NSCCs exist in an intrinsic homoeostasis state with spontaneous and in situ visualisable inter-conversions, irrespective of prior radiations. Supplement with TGF-β1 accelerates the equilibrium, whereas inhibition of TGF-β signalling disturbs the equilibrium and significantly decreases CSC proportion. Epithelial mesenchymal transition (EMT) might be activated during the process.
Our results indicate that the intrinsic inter-conversion and dynamic equilibrium between CSCs and NSCCs exist under normal and irradiation surroundings, and TGF-β might have important roles in the equilibrium through activating EMT.
cancer stem cells; inter-conversion; dynamic equilibrium; radiation; epithelial mesenchymal transition
Subgroups of patients with oral pre-malignant lesions (OPLs) are at extremely high risk for developing invasive cancer in spite of surgical excision. The objective of this study was to evaluate the utility of specific genes and their associated centromeres as markers to stratify OPLs for their cancer risk. Samples used in this study included 35 oral dysplasia with known outcome and 20 normal oral mucosa. Of the dysplasias, 20 were from an ongoing longitudinal study showing progression. The remaining 15 cases (2 of which progressed) were chosen from the population-based, provincial BC Oral Biopsy Service (OBS). Copy number alterations at EGFR, CEP7, CCND1, and CEP11 were evaluated by fluorescent in situ hybridization (FISH). There was no significant difference in demographics between progressors and non-progressors. Specific FISH profiles at these genes and their corresponding centromeres were associated with progression. High gene gain of CCND1 was associated with an 8-fold elevated risk of progression compared with those with no gain in time-to-progression analysis. Numerical alterations of EGFR and CCND1 and their centromeres might be an effective means for identifying OPLs at risk. Future studies will expand on this analysis and set the stage for application of this approach in routine clinical practice.
oral dysplasia; progression; EGFR; CCND1; fluorescent in situ hybridization; chromosomal instability
Spinae are tubular surface appendages broadly found in Gram-negative bacteria. Little is known about their architecture, function or origin. Here, we report structural characterization of the spinae from marine bacteria Roseobacter sp. YSCB. Electron cryo-tomography revealed that a single filament winds into a hollow flared base with progressive change to a cylinder. Proteinase K unwound the spinae into proteolysis-resistant filaments. Thermal treatment ripped the spinae into ribbons that were melted with prolonged heating. Circular dichroism spectroscopy revealed a dominant beta-structure of the spinae. Differential scanning calorimetry analyses showed three endothermic transformations at 50–85°C, 98°C and 123°C, respectively. The heating almost completely disintegrated the spinae, abolished the 98°C transition and destroyed the beta-structure. Infrared spectroscopy identified the amide I spectrum maximum at a position similar to that of amyloid fibrils. Therefore, the spinae distinguish from other bacterial appendages, e.g. flagella and stalks, in both the structure and mechanism of assembly.
Dendritic cells (DCs) are immune cells specialized to capture, process and present antigen to T cells in order to initiate an appropriate adaptive immune response. The study of mouse DC has revealed a heterogeneous population of cells that differ in their development, surface phenotype and function. The study of human blood and spleen has shown the presence of two subsets of conventional DC including the CD1b/c+ and CD141+CLEC9A+ conventional DC (cDC) and a plasmacytoid DC (pDC) that is CD304+CD123+. Studies on these subpopulations have revealed phenotypic and functional differences that are similar to those described in the mouse. In this study, the three DC subsets have been generated in vitro from human CD34+ precursors in the presence of fms-like tyrosine kinase 3 ligand (Flt3L) and thrombopoietin (TPO). The DC subsets so generated, including the CD1b/c+ and CLEC9A+ cDCs and CD123+ pDCs, were largely similar to their blood and spleen counterparts with respect to surface phenotype, toll-like receptor and transcription factor expression, capacity to stimulate T cells, cytokine secretion and cross-presentation of antigens. This system may be utilized to study aspects of DC development and function not possible in vivo.
dendritic cells; fms-like tyrosine kinase 3 ligand; thrombopoietin
For the emerging DSM-V, it has been recommended that dimensional and categorical methods be used simultaneously in diagnostic classification; however, little is known about this combined approach for abuse and dependence.
Using data (n=37 708) from the 2007 National Survey on Drug Use and Health (NSDUH), DSM-IV criteria for prescription opioid abuse and dependence among non-prescribed opioid users (n=3037) were examined using factor analysis (FA), latent class analysis (LCA, categorical), item response theory (IRT, dimensional), and factor mixture (hybrid) approaches.
A two-class factor mixture model (FMM) combining features of categorical latent classes and dimensional IRT estimates empirically fitted more parsimoniously to abuse and dependence criteria data than models from FA, LCA and IRT procedures respectively. This mixture model included a severely affected group (7%) with a comparatively moderate to high probability (0.32–0.88) of endorsing all abuse and dependence criteria items, and a less severely affected group (93%) with a low probability (0.003–0.16) of endorsing all criteria. The two empirically defined groups differed significantly in the pattern of non-prescribed opioid use, co-morbid major depression, and substance abuse treatment use.
A factor mixture model integrating categorical and dimensional features of classification fits better to DSM-IV criteria for prescription opioid abuse and dependence in adults than a categorical or dimensional approach. Research is needed to examine the utility of this mixture classification for substance use disorders and treatment response.
DSM-IV; factor mixture model; item response theory; latent class analyses; nosology; prescription opioid use disorders
We have earlier reported that γ-hydroxybutyric acid (GHB) disrupts the acquisition of spatial learning and memory in adolescent rats. GHB is known to interact with several neurotransmitter systems that have been implicated in cognitive functioning. The N-methyl-D-aspartate receptor (NR) -type of glutamate receptor is considered to be an important target for spatial learning and memory. Molecular mechanisms governing the neuroadptations following repeated GHB treatment in adolecent rats remain unknown. We examined the role of NMDA receptor in adolescent GHB-induced cognitive deficit. Adolescent rats were administered with GHB on 6 consecutive days, and surface-expressed NMDA receptor subunits levels were measured. GHB significantly decreased NR1 levels in the frontal cortex. Adolescent GHB also significantly reduced cortical NR2A subunit levels. Our findings support the hypothesis that adolescent GHB-induced cogntive deficits are associated with neuroadaptations in glutamatergic transmission, particulaly NR functioning in the frontal cortex.
Addiction; juvenile; cognitive function; glutamatergic; radioligand binding; western blot; NR subunit; GHB.
Aberrant electrophysiological and hemodynamic processing of auditory oddball stimuli is among the most robustly documented findings in patients with schizophrenia. However, no study to date has directly examined linked patterns of electrical and hemodynamic differences in patients and controls.
In a recent paper we demonstrated a data-driven approach, joint independent component analysis (jICA) to fuse together functional magnetic resonance imaging (fMRI) and event-related potential (ERP) data and elucidated the chronometry of auditory oddball target detection in healthy control subjects. In this paper we extend our fusion method to identify specific differences in the neuronal chronometry of target detection for chronic schizophrenia patients compared to healthy controls.
We found one linked source, consistent with the N2 response, known to be related to cognitive processing of deviant stimuli, spatially localized to bilateral fronto-temporal regions. This source showed significant between-group differences both in amplitude response and in the fMRI/ERP distribution pattern. These findings are consistent with previous work showing N2 amplitude and latency abnormalities in schizophrenia, and provide new information about the linkage between the two.
In summary, we use a novel approach to isolate and identify a linked fMRI/ERP component which shows marked differences in chronic schizophrenia patients. We also demonstrate that jointly using both fMRI and ERP measures provides a fully picture of the underlying hemodynamic and electrical changes which are present in patients. Our approach also has broad applicability to other diseases such as autism, Alzheimer’s disease, or bipolar disorder.
schizophrenia; fMRI; ERP; data fusion; independent component analysis; N2
The deprivation gap for breast cancer survival remains unexplained by stage at presentation, treatment, or co-morbidities. We hypothesised that p53 mutation might contribute to the impaired outcome observed in patients from deprived communities.
p53 mutation status was determined using the Roche Amplichip research test in 246 women with primary breast cancer attending a single cancer centre and related to deprivation, pathology, overall, and disease-free survival.
p53 mutation, identified in 64/246 (26%) of cancers, was most common in 10 out of 17 (58.8%) of the lowest (10th) deprivation decile. Those patients with p53 mutation in the 10th decile had a significantly worse disease-free survival of only 20% at 5 years (Kaplan–Meier logrank χ2=6.050, P=0.014) and worse overall survival of 24% at 5 years (Kaplan–Meier logrank χ2=6.791, P=0.009) than women of deciles 1–9 with p53 mutation (c.f. 56% and 72%, respectively) or patients in the 10th decile with wild-type p53 (no disease relapse or deaths).
p53 mutation in breast cancer is associated with socio-economic deprivation and may provide a molecular basis, with therapeutic implications, for the poorer outcome in women from deprived communities.
p53; primary breast cancer; socio-economic deprivation; overall survival; disease-free survival
DNA methylation is an epigenetic event involved in a variety array of processes that may be the foundation of genetic phenomena and diseases. DNA methyltransferase is a key enzyme for cytosine methylation in DNA, and can be divided into two functional families (Dnmt1 and Dnmt3) in mammals. All mammalian DNA methyltransferases are encoded by their own single gene, and consisted of catalytic and regulatory regions (except Dnmt2). Via interactions between functional domains in the regulatory or catalytic regions and other adaptors or cofactors, DNA methyltransferases can be localized at selective areas (specific DNA/nucleotide sequence) and linked to specific chromosome status (euchromatin/heterochromatin, various histone modification status). With assistance from UHRF1 and Dnmt3L or other factors in Dnmt1 and Dnmt3a/Dnmt3b, mammalian DNA methyltransferases can be recruited, and then specifically bind to hemimethylated and unmethylated double-stranded DNA sequence to maintain and de novo setup patterns for DNA methylation. Complicated enzymatic steps catalyzed by DNA methyltransferases include methyl group transferred from cofactor Ado-Met to C5 position of the flipped-out cytosine in targeted DNA duplex. In the light of the fact that different DNA methyltransferases are divergent in both structures and functions, and use unique reprogrammed or distorted routines in development of diseases, design of new drugs targeting specific mammalian DNA methyltransferases or their adaptors in the control of key steps in either maintenance or de novo DNA methylation processes will contribute to individually treating diseases related to DNA methyltransferases.
DNA methyltransferase; epigenetics; enzyme catalysis; protein-DNA interactions