Cell line models suggest that activation of NFκB is associated with progression of prostate cancer. This pathway may be a therapeutic target if these observations translate to clinical specimens.
Immunohistochemistry measured NFκBp65 (p65), NFκBp65 nuclear localisation signal (NLS), NFκBp65 phosphorylated at ser 276 (p65ser276), NFκBp65 phosphorylated at ser 536 (p65ser536), IκBα phosphorylated at ser 32/36 (pIκBαser32/36) and MMP-9 protein expression in 61 matched hormone naive prostate cancer (HNPC) and castrate-resistant prostate cancer (CRPC) tumours. Animal and cell models were used to investigate the role of NFκB inhibition in prostate carcinogenesis.
In HNPC tumours, NLS expression significantly associated with a shorter time to disease recurrence and disease-specific death. In CRPC tumours p65, pIκBαser32/36 and MMP-9 expression significantly associated with shorter time to death from disease recurrence and shorter disease-specific death. MMP-9 and pIκBαser32/36 expression significantly associated with metastases at recurrence and were independent of Gleason sum and prostate-specific antigen at recurrence. Expression of phosphorylated Akt was associated with increased p65 activation in mouse models and inhibition of NFκB in LNCaP cells significantly reduced cellular proliferation and induced apoptosis.
These results provide further evidence that the NFκB pathway could be exploited as a target for CRPC.
MMP-9; pIκBα; NFκB; hormone naïve prostate cancer
In the United States, the 2009 pandemic influenza A (H1N1) virus (pH1N1) infected almost 20% of the population and caused >200,000 hospitalizations and >10,000 deaths from April 2009 to April 2010. On 24 April 2009, the CDC posted interim guidance on infection control measures in health care settings explicitly for pH1N1 and recommended using filtering face respirators (FFRs) when in close contact with a suspected- or confirmed-to-be-infected individual, particularly when performing aerosol-generating procedures. The persistence and infectivity of pH1N1 were evaluated on FFRs, specifically N95 respirators, under various conditions of absolute humidity (AH) (4.1 × 105 mPa, 6.5 × 105 mPa, and 14.6 × 105 mPa), sample matrices (2% fetal bovine serum [FBS], 5 mg/ml mucin, and viral medium), and times (4, 12, 24, 48, 72, and 144 h). pH1N1 was distributed onto N95 coupons (3.8 to 4.2 cm2) and extracted by a vortex-centrifugation-filtration process, and the ability of the remaining virus to replicate was quantified using an enzyme-linked immunosorbent assay (ELISA) to determine the log10 concentration of the infectious virus per coupon. Overall, pH1N1 remained infectious for 6 days, with an approximately 1-log10 loss of virus concentrations over this time period. Time and AH both affected virus survival. We found significantly higher (P ≤ 0.01) reductions in virus concentrations at time points beyond 24 to 72 h (−0.52-log10 reduction) and 144 h (−0.74) at AHs of 6.5 × 105 mPa (−0.53) and 14.6 × 105 mPa (−0.47). This research supports discarding respirators after close contact with a person with suspected or confirmed influenza infection due to the virus's demonstrated ability to persist and remain infectious.
The aim of this study was to determine whether Src family kinases (SFK) are expressed in renal cell cancer and to assess their prognostic significance.
mRNA expression levels were investigated for the 8 SFK members by quantitative real-time PCR in 19 clear cell cancer tissue samples. Immunohistochemical staining was utilised to assess expression of Src kinase, dephosphorylated Src kinase at Y530 (SrcY530), phosphorylated Src at Y419 (SrcY419) and the downstream focal adhesion kinase (FAK) marker at the Y861 site (FAK Y861) in a cohort of 57 clear cell renal cancer specimens. Expression was assessed using the weighted histoscore method.
Src, Lyn, Hck, Fgr and Fyn were the most highly expressed in renal cancer. All members were more highly expressed in T2 disease, and furthermore expression levels between T2 and T3 disease showed a significant decrease for Lck, Lyn, Fyn, Blk and Yes (P=0.032). Assessment of membrane, cytoplasm and nuclear expression of Src kinase, SrcY530 and SrcY419 were not significantly associated with cancer-specific survival. High expression of cytoplasmic FAK Y861 was associated with decreased cancer-specific survival (P=0.001). On multivariate analysis, cytoplasmic FAK Y861 was independently associated with cancer-specific survival (hazard ratio 3.35, 95% CI 1.40–7.98, P=0.006).
We have reported that all SFK members are expressed in renal cell carcinoma. The SFK members had their highest levels of expression before the disease no longer being organ confined. We hypothesise that these SFK members are upregulated before the cancer spreading out-with the organ and given that Src itself is not associated with cancer-specific survival but the presence of FAK Y861, a downstream marker for SFK member activity is associated with decreased cancer-specific survival, we hypothesise that another SFK member is associated with decreased cancer-specific survival in renal cell cancer.
Src kinase; Src; FAK; renal cancer
The importance of the components of host local inflammatory response in determining outcome in primary operable ductal invasive breast cancer is not clear. The aim of this study was to examine the relationship between components of the tumour inflammatory cell infiltrate and standard clinicopathological factors including hormone status (oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER)-2), Ki-67 and survival in patients with primary operable invasive ductal breast cancer.
Tumour inflammatory cell infiltrate, hormone status (ER, PR and HER-2), Ki-67 and standard clinicopathological factors were determined using routine pathological and immuno-histochemical techniques in 468 patients.
The large majority (94%) of ductal tumours had evidence of inflammatory cell infiltrate. The general inflammatory cell infiltrate was positively associated with high grade (P<0.001), the absence of ER (P<0.001), the absence of PR (P<0.01), the presence of vascular invasion (P<0.05) and high lymphocytic infiltrate, plasma cell infiltrate, other inflammatory cell infiltrate and macrophage infiltrate (all P<0.001). The median follow-up of the survivors was 165 months. During this period, 93 patients died of their cancer. On univariate analysis, stratified for ER status, tumour size (P<0.01), lymph node involvement (P<0.001), tumour plasma cell infiltrate (P<0.001), other inflammatory cell infiltrate (P<0.05) and treatment (P<0.05) were associated with poorer cancer-specific survival whereas lymphocyte infiltrate (P<0.001) was associated with improved cancer-specific survival. On multivariate analysis, stratified for ER status, lymph node involvement (P<0.05) was independently associated with poorer cancer-specific survival whereas increased tumour lymphocyte infiltrate (P<0.001) was independently associated with improved cancer-specific survival.
The results of this study show that, using routine histology, the general inflammatory cell infiltrate was a common feature and was positively associated with high grade, the absence of ER, the absence of PR, the presence of vascular invasion and high-grade infiltration of lymphocytes, plasma cells, other inflammatory cells and macrophages. Also, that within a mature cohort of patients, a high lymphocytic infiltrate was associated with improved survival, independent of clinicopathological characteristics including ER status, in primary operable ductal invasive breast cancer. These results rationalise previous work and provide a sound basis for future studies in this important area of breast cancer research.
primary ductal invasive breast cancer; hormone status; tumour inflammatory cell infiltrate; lymphocytes; plasma cells; survival
Although child abuse is widespread and has been associated with cardiovascular disease (CVD) risk factors, its association with CVD events is not established.
Methods and Results
We examined associations of child abuse with CVD events among 66,798 women in the Nurses’ Health Study 2. Proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for myocardial infarction (n=262), stroke (n=251), and total CVD (n=513). Severe physical abuse was reported by 9% and forced sex by 11% of participants. Adjusting for age, race, childhood body type, parental education and family CVD history, the HR for CVD events was 0.91 (95% CI: 0.70–1.17) for mild physical abuse, 1.02 (0.82–1.26) for moderate physical abuse, and 1.46 (1.11–1.92) for severe physical abuse compared to none. Compared to women without childhood sexual abuse, the HR was 1.10 (0.88–1.35) for unwanted sexual touching, and 1.56 (1.23–1.99) for forced sex. After adjustment for adult lifestyle and medical risk factors, the HR for severe physical abuse was 1.13 (0.85–1.51) and that for forced sex was 1.25 (0.98–1.60); these intermediates accounted for much of the association of severe child abuse with CVD. Associations were similar for retrospectively and prospectively reported events. Women with abuse were less likely to release medical records. The associations were stronger for unconfirmed self-reported events than endpoints which were corroborated with additional information or medical record review.
Severe child abuse is a prevalent risk for early adult CVD that is partially mediated by preventable risk factors.
myocardial infarction; stroke; women; epidemiology; violence
We previously reported that sphingosine 1-phosphate receptor 4 (S1P4) is expressed and stimulates the ERK-1/2 pathway via a human epidermal growth factor receptor 2 (HER2)-dependent mechanism in oestrogen receptor-negative (ER−) MDA-MB-453 breast cancer cells.
Clinical relevance of S1P4 and sphingosine kinase 1 (SK1, which catalyses the formation of S1P) was assessed in a cohort of 140 ER− breast tumours by immunohistochemistry (IHC) and the weighted histoscore method. Additional evidence for a functional interaction between S1P4 and SK1 and between HER2 and SK1 was obtained using MDA-MB-453 cells.
High S1P4 expression is associated with shorter disease-free (P=0.014) and disease-specific survival (P=0.004), and was independent on multivariate analysis. In addition, patients with tumours that contain high and low levels of SK1 and S1P4, respectively, have a significantly shorter disease-free survival (P=0.043) and disease-specific survival (P=0.033) compared with patients whose tumours contain both low S1P4 and SK1 levels. In addition, high tumour expression of SK1 was significantly associated with shorter disease-specific survival (P=0.0001) in patients with HER2-positive tumours. Treatment of MDA-MB-453 cells with the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) reduced the basal and S1P/S1P4-induced activation of ERK-1/2 and altered HER2 trafficking in these cells.
These findings highlight an important role for S1P4 and SK1 in ER− breast cancer progression.
sphingosine 1-phosphate; sphingosine kinase; oestrogen receptor; HER2; sphingosine 1-phosphate receptor 4; extracellular signal regulated kinase
The aim of this current study was to assess the expression and activity of Src family kinases, focal adhesion kinase (FAK), caveolin (Cav-1) and RhoGD12 in bladder cancer.
Fifty-eight patients with a new diagnosis of bladder cancer undergoing transurethral resection were included. Immunohistochemical staining was utilised to assess expression of c-Src, dephosphorylated (SrcY530), phosphorylated Src (Y419), phosphorylated FAK (FAK Y861), Cav-1 and RhoGD12. Expression was assessed using the weighted histoscore method.
High expression of dephosphorylated Y527, phosphorylated Y416 and phosphorylated FAK Y861 in the membrane were associated with increased cancer-specific survival (P=0. 01, P=0.001, P=0.008, respectively) and expression of Y416 in the membrane was an independent factor on multivariate analysis when combined with known clinical parameters (P=0.008, HR 0.288, 95% CI 0.11–0.72).
These results demonstrate that in contrast to other solid tumours, activation of the Src family members and downstream signalling proteins are associated with a good prognosis in transitional cell carcinoma of the bladder, and activated Src has a positive relationship with RhoGD12.
Src kinase; Cav-1; RhoGD12; bladder cancer; survival
There is increasing evidence that the local and systemic inflammatory responses are associated with survival in oesophageal cancer. The aim of this study was to examine the relationship between tumour necrosis, tumour proliferation, local and systemic inflammation and microvessel density and survival in patients undergoing potentially curative resection of oesophageal adenocarcinoma.
The interrelationship between tumour necrosis, tumour proliferation, local inflammatory response (Klintrup–Makinen criteria, intra-tumoural CD8+ lymphocyte and macrophage infiltration), systemic inflammatory response (modified Glasgow Prognostic score (mGPS)), and microvessel density was examined in 121 patients undergoing potentially curative resection for oesophageal adenocarcinoma (including type I and II tumours of the gastro-oesophageal junction).
Tumour necrosis was not significantly associated with any tumour measure other than the degree of differentiation. On multivariate analysis, only age (HR 1.93, 95% CI 1.23–3.04, P=0.004), mGPS (HR 2.91, 95% CI 1.51–5.62, P=0.001), positive to total lymph node ratio (HR 2.38, 95% CI 1.60–3.52, P<0.001) and macrophage infiltration (HR 1.49, 95% CI 1.02–2.18, P=0.041) were independently associated with cancer-specific survival in oesophageal adenocarcinoma. Intra-tumoural macrophages were associated with tumour proliferation (P<0.001) and CD8+ lymphocytes infiltration (P<0.01).
The results of this study suggest that tumour necrosis does not link local and systemic inflammatory responses and is not significantly associated with survival. In contrast, tumour macrophage infiltration appears to have a central role in the proliferative activity and the coordination of the inflammatory cell infiltrate and is independently associated with poorer survival in patients with oesophageal adenocarcinoma.
oesophageal cancer; C-reactive protein; tumour inflammatory infiltrate; microvessel; necrosis; survival
Immunohistochemistry of Ki-67 protein is widely used to assess tumour proliferation, and is an established prognostic factor in breast cancer. There is interest in automating the assessment of Ki-67 labelling index (LI) with possible benefits in handling increased workload, with improved accuracy and precision.
Patients and methods:
Visual and automated assessment of Ki-67 LI and survival were examined in patients with primary operable invasive ductal breast cancer. Tissue microarrays (n=379 patients) immunostained for Ki-67 were scored visually and automatically with the Slidepath Tissue IA system.
Visual and automated Ki-67 LI were in excellent agreement (ICCC=0.96, P<0.001). On univariate analysis, visual (P<0.001) and automated Ki67 LI (P<0.05) were associated with cancer-specific survival in patients with invasive ductal breast cancer overall and in patients who received endocrine therapy (Tamoxifen) (P<0.01 for visual and P<0.05 for automated scoring).
Automated assessment of Ki-67 LI would appear to be comparable to visual Ki-67 LI. However, automated Ki-67 LI assessment was inferior in predicting cancer survival in patients with breast cancer, including patients who received Tamoxifen.
primary invasive breast cancer; visual counting method; automated counting method; survival
Prostate cancer (PC) represents a global health issue. Treatment for locally advanced and metastatic PC remains unsatisfactory. The androgen receptor (AR) has been validated in having a key role in both naïve and castrate-resistant PC (CRPC). However, the significance of other signalling pathways in CRPC is less well validated.
To gain a better insight into the molecular signalling cascades involved in clinical CRPC, we performed gene expression profiling using the Illumina DASL assay and studied matched hormone-naive (HN) and CR prostate tumours (n=10 pairs). Ingenuity Pathways Analysis (IPA) was used to identify potential networks involved, and further validation was performed in in vitro cell models and clinical tumours.
Expression of 50 genes was significantly different between HN and CRPC. IPA revealed two networks of particular interest, including AR and FGFR1, respectively. FGFR1 expression was confirmed to be significantly upregulated in CRPC (P⩽0.005), and abnormal FGFR1 expression was associated with shorter time to biochemical relapse in HNPC (P=0.006) and less favourable disease-specific survival in CRPC (P=0.018).
For the first time, our gene expression profiling experiment on archival tumour materials has identified upregulated FGFR1 expression to be associated with PC progression to the CR state.
prostate cancer; formalin-fixed, paraffin-embedded samples; gene expression analysis; hormone-naive and castrate-resistant prostate cancer; fibroblast growth factor receptor 1
Chewing of regurgitated food elicits in baboons life-long gastro-esophageal reflux (GER). The acid reflux transforms the multilayered squamous cell epithelium of the esophagus into columnar-lined mucosa with mucus-producing accessory glands. The function of this mucous gland metaplasia (MGM), which mimics Barrett’s mucosa with MGM in humans, is to buffer the gastric acid entering the esophagus during regurgitation. In a previous study of entire esophagi, the majority of baboons showed MGM. The gastric mucosa was not investigated.
Materials and Methods
Hematoxylin-eosin-stained sections from the esophagus, from the lesser gastric curvature and from the greater gastric curvature were collected separately from 50 adult baboons. The presence of MGM was assessed in each one of these locations.
MGM was demonstrated in 92% (46/50) of blocks from the esophagus, in 98% (49/50) of blocks from the lesser curvature and in 90% (45/50) of those of the greater curvature (fundus).
The majority of the animals had MGM, not only in the esophagus but also in the proximal gastric mucosa. Rationally, MGM in baboons starts in the distal esophagus and proceeds downwards, towards the proximal stomach. The histogenesis of the MGM in Barrett’s mucosa in humans (that is Barrett’s mucosa type 2) remains elusive. Therefore the baboon might be an important animal model for studying the histogenesis of Barrett’s mucosa with MGM in humans, a recognized pre-cancerous lesion.
Esophagus; baboon; gastric reflux; mucus metaplasia
Recent evidence has implicated the MAP kinase (MAPK) pathway with the development of castrate-resistant prostate cancer (CRPC). We have previously reported gene amplification of critical members of this pathway with the development of castrate-resistant disease. In addition, we have shown that rising Raf-1 expression, with the development of CRPC, influences time to biochemical relapse. We therefore sought to further analyse the role of both Raf-1 and its downstream target MAPK in the molecular pathogenesis of CRPC.
Protein expression of Raf-1 and MAPK, including their activation status, was analysed using immunohistochemistry in a database of 65 paired tumour specimens obtained before and after the development of CRPC and correlated with other members of the pathway.
Patients whose nuclear expression of MAPK rose with the development of CRPC had a significantly shorter median time to death following biochemical relapse (1.40 vs 3.00 years, P=0.0255) as well as reduced disease-specific survival when compared with those whose expression fell or remained unchanged (1.16 vs 2.62 years, P=0.0005). Significant correlations were observed between protein expression of Raf-1 and MAPK with the type 1 receptor tyrosine kinases, Her2 and epidermal growth factor receptor, as well as the transcription factor AP-1 in CRPC tumours.
We conclude that the Her2/Raf-1/MAPK/AP-1 axis may promote the development of CRPC, leading to early relapse, and reduced disease-specific survival. In addition, members of the pathway may act as novel therapeutic and/or diagnostic targets for prostate cancer.
MAP kinase pathway; castrate-resistant prostate cancer; prostate cancer; Her2; AP-1; Raf
Four different genera of diaporthalean coelomycetous fungi associated with leaf spots of tree hosts are morphologically treated and phylogenetically compared based on the DNA sequence data of the large subunit nuclear ribosomal DNA gene (LSU) and the internal transcribed spacers and 5.8S rRNA gene of the nrDNA operon. These include two new Australian genera, namely Auratiopycnidiella, proposed for a leaf spotting fungus occurring on Tristaniopsis laurina in New South Wales, and Disculoides, proposed for two species occurring on leaf spots of Eucalyptus leaves in Victoria. Two new species are described in Aurantiosacculus, a hitherto monotypic genus associated with leaf spots of Eucalyptus in Australia, namely A. acutatus on E. viminalis, and A. eucalyptorum on E. globulus, both occurring in Tasmania. Lastly, an epitype specimen is designated for Erythrogloeum hymenaeae, the type species of the genus Erythrogloeum, and causal agent of a prominent leaf spot disease on Hymenaea courbaril in South America. All four genera are shown to be allied to Diaporthales, although only Aurantiosacculus (Cryphonectriaceae) could be resolved to family level, the rest being incertae sedis.
leaf spot disease; molecular phylogeny; systematics
Several studies have shown that stressful life events are associated with a subsequent significant increase in risk of multiple sclerosis (MS) exacerbations. We wanted to study prospectively whether stress can increase the risk of developing the disease itself.
We studied 2 cohorts of female nurses: the Nurses' Health Study (NHS) (n = 121,700) followed from 1976 and the Nurses' Health Study II (NHS II) (n = 116,671) followed from 1989. The risk of MS after self-report on general stress at home and at work in the NHS in 1982 was studied prospectively using Cox regression. Logistic regression was used to retrospectively estimate the effects of physical and sexual abuse in childhood and adolescence collected in the NHS II 2001. We identified 77 cases of MS in the NHS by 2005 and 292 in the NHS II by 2004. All analyses were adjusted for age, ethnicity, latitude of birth, body mass index at age 18, and smoking.
We found no increased risk of MS associated with severe stress at home in the NHS (hazard ratio 0.85 [95% confidence interval (CI)] 0.32–2.26). No significantly increased risk of MS was found among those who reported severe physical abuse during childhood (odds ratio [OR] 0.68, 95% CI 0.41–1.14) or adolescence (OR 0.77, 95% CI 0.46–1.28) or those having been repeatedly forced into sexual activity in childhood (OR 1.47, 95% CI 0.87–2.48) or adolescence (OR 1.21, 95% CI 0.68–2.17).
These results do not support a major role of stress in the development of the disease, but repeated and more focused measures of stress are needed to firmly exclude stress as a potential risk factor for MS. Neurology® 2011;76:1866–1871
Recent work has demonstrated that c-Src and fully activated Y419Src expression was associated with poor clinical outcome of breast cancer patients. It is unknown whether different activation stages of c-Src equally influence disease-specific survival of breast cancer patients.
Immunohistochemistry was performed on 165 resected breast cancers using antibodies to phosphorylated and dephosphorylated Src kinase tyrosine site 530. Expression was assessed using the weighted histoscore method.
Majority of phosphorylated and dephosphorylated Y530Src expression was observed in the nucleus and cytoplasm. Only 3.6% of phosphorylated Y530Src (pY530Src) expression was detected in the membrane, compared with 53% with dephosphorylated Y530Src. Nuclear expression of pY530Src correlated negatively with oestrogen receptor (ER) status (χ2 P<0.001), whereas cytoplasmic phosphorylated and dephosphorylated Y530Src expression correlated negatively with membrane c-Src expression (χ2 P=0.008, χ2 P<0.001). On univariate and multivariate analysis, no significant association was noticed between phosphorylated or dephosphorylated Y530Src expression and disease-specific survival at any cellular location.
ER-negative breast cancer patients were more likely to express pY530Src in the nucleus. Breast cancer patients with higher cytoplasmic expression of phosphorylated or dephosphorylated Y530Src were more likely not to express c-Src at the membrane. Phosphorylated and dephosphorylated Y530Src expression is not associated with survival of patients.
Src kinase; breast cancer; immunohistochemistry; disease-specific survival
This study determined mRNA expression levels for Src kinase family (SFK) members in breast tissue specimens and assessed protein expression levels of prominent SFK members in invasive breast cancer to establish associations with clinical outcome. Ki67 was investigated to determine association between SFK members and proliferation.
The mRNA expression levels were assessed for eight SFK members by quantitative real-time PCR. Immunohistochemistry was performed for c-Src, Lyn, Lck and Ki67.
mRNA expression was quantified in all tissue samples. SRC and LYN were the most highly expressed in malignant tissue. LCK was more highly expressed in oestrogen receptor (ER)-negative, compared with ER-positive tumours. High cytoplasmic Src kinase protein expression was significantly associated with decreased disease-specific survival. Lyn was not associated with survival at any cellular location. High membrane Lck expression was significantly associated with improved survival. Ki67 expression correlated with tumour grade and nuclear c-Src, but was not associated with survival.
All eight SFK members were expressed in different breast tissues. Src kinase was highest expressed in breast cancer and had a negative impact on disease-specific survival. Membrane expression of Lck was associated with improved clinical outcome. High expression of Src kinase correlated with high proliferation.
Src kinase family members; breast cancer; quantitative real-time PCR; immunohistochemistry; disease-specific survival
Pharmacological studies of narcoleptic canines indicate that exaggerated pontine cholinergic transmission promotes cataplexy. Since disruption of orexin (hypocretin) signaling is a primary defect in narcolepsy with cataplexy, we investigated whether markers of cholinergic synaptic transmission might be altered in mice constitutively lacking orexin receptors (double receptor knockout; DKO). We found that choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT) and the high-affinity choline transporter (CHT1) but not acetylcholinesterase (AChE) were significantly higher in samples from DKO compared to wild-type (WT) mice. This was region-specific since levels were elevated in samples from the laterodorsal tegmental nucleus (LDT) and the fifth motor nucleus (Mo5) but not in whole brainstem samples. Consistent with region-specific changes, we were unable to detect significant differences in Western blots for ChAT and CHT1 in isolates from brainstem, thalamus and cortex or in ChAT enzymatic activity in the pons. However, using ChAT immunocytochemistry, we found that while the number of cholinergic neurons in the LDT and Mo5 were not different, the intensity of somatic ChAT immunostaining was significantly greater in the LDT, but not Mo5, from DKOs compared to WTs. We also found that ChAT activity was significantly reduced in cortical samples from DKOs compared to WTs. Collectively, these findings suggest that the orexins can regulate neurotransmitter expression and that the constitutive absence of orexin signaling results in an up-regulation of the machinery necessary for cholinergic neurotransmission in a mesopontine population of neurons that have been associated with both normal REM sleep and cataplexy.
acetylcholine; narcolepsy; ChAT; VAChT; CHT1
Novel species of microfungi described in the present study include the following from Australia: Bagadiella victoriae and Bagadiella koalae on Eucalyptus spp., Catenulostroma eucalyptorum on Eucalyptus laevopinea, Cercospora eremochloae on Eremochloa bimaculata, Devriesia queenslandica on Scaevola taccada, Diaporthe musigena on Musa sp., Diaporthe acaciigena on Acacia retinodes, Leptoxyphium kurandae on Eucalyptus sp., Neofusicoccum grevilleae on Grevillea aurea, Phytophthora fluvialis from water in native bushland, Pseudocercospora cyathicola on Cyathea australis, and Teratosphaeria mareebensis on Eucalyptus sp. Other species include Passalora leptophlebiae on Eucalyptus leptophlebia (Brazil), Exophiala tremulae on Populus tremuloides and Dictyosporium stellatum from submerged wood (Canada), Mycosphaerella valgourgensis on Yucca sp. (France), Sclerostagonospora cycadis on Cycas revoluta (Japan), Rachicladosporium pini on Pinus monophylla (Netherlands), Mycosphaerella wachendorfiae on Wachendorfia thyrsifolia and Diaporthe rhusicola on Rhus pendulina (South Africa). Novel genera of hyphomycetes include Noosia banksiae on Banksia aemula (Australia), Utrechtiana cibiessia on Phragmites australis (Netherlands), and Funbolia dimorpha on blackened stem bark of an unidentified tree (USA). Morphological and culture characteristics along with ITS DNA barcodes are provided for all taxa.
ITS DNA barcodes; LSU; novel fungal species; systematics
For over two decades, the Nottingham Prognostic Index (NPI) has been used in the United Kingdom to calculate risk scores and inform management about breast cancer patients. It is derived using just three clinical variables – nodal involvement, tumour size and grade. New scientific methods now make cost-effective measurement of many biological characteristics of tumour tissue from breast cancer biopsy samples possible. However, the number of potential explanatory variables to be considered presents a statistical challenge. The aim of this study was to investigate whether in ER+ tamoxifen-treated breast cancer patients, biological variables can add value to NPI predictors, to provide improved prognostic stratification in terms of overall recurrence-free survival (RFS) and also in terms of remaining recurrence free while on tamoxifen treatment (RFoT). A particular goal was to enable the discrimination of patients with a very low risk of recurrence.
Tissue samples of 401 cases were analysed by microarray technology, providing biomarker data for 72 variables in total, from AKT, BAD, HER, MTOR, PgR, MAPK and RAS families. Only biomarkers screened as potentially informative (i.e., exhibiting univariate association with recurrence) were offered to the multivariate model. The multiple imputation method was used to deal with missing values, and bootstrap sampling was used to assess internal validity and refine the model.
Neither the RFS nor RFoT models derived included Grade, but both had better predictive and discrimination ability than NPI. A slight difference was observed between models in terms of biomarkers included, and, in particular, the RFoT model alone included HER2. The estimated 7-year RFS rates in the lowest-risk groups by RFS and RFoT models were 95 and 97%, respectively, whereas the corresponding rate for the lowest-risk group of NPI was 89%.
The findings demonstrate considerable potential for improved prognostic modelling by incorporation of biological variables into risk prediction. In particular, the ability to identify a low-risk group with minimal risk of recurrence is likely to have clinical appeal. With larger data sets and longer follow-up, this modelling approach has the potential to enhance an understanding of the interplay of biological characteristics, treatment and cancer recurrence.
breast cancer; tamoxifen resistance; statistical model; HER2 signalling
Here we report the results of a pilot study investigating the relative and combined effects of a 12 week course of clozapine and CBT in first-episode psychosis patients with prominent ongoing positive symptoms following their initial treatment. Patients from our early psychosis service who met the inclusion criteria (n = 48) were randomized to one of four treatment groups: clozapine, clozapine plus CBT, thioridazine, or thioridazine plus CBT. The degree of psychopathology and functionality of all participants was measured at baseline then again at 6, 12 and 24 weeks, and the treatment outcomes for each group determined by statistical analysis. A substantial proportion (52%) of those treated with clozapine achieved symptomatic remission, as compared to 35% of those who were treated with thioridazine. Overall, those who received clozapine responded more rapidly to treatment than those receiving the alternative treatments. Interestingly, during the early treatment phase CBT appeared to reduce the intensity of both positive and negative symptoms and thus the time taken to respond to treatment, as well having as a stabilizing effect over time.
Multidetector row computed tomography (MDCT) with its high spatial and temporal resolution has now become an established and complementary method for cardiac imaging. It can now be used reliably to exclude significant coronary artery disease and delineate complex coronary artery anomalies, and has become a valuable problem-solving tool. Our experience with MDCT imaging suggests that it is clinically useful for imaging the pericardium. It is important to be aware of the normal anatomy of the pericardium and not mistake normal variations for pathology. The pericardial recesses are visible in up to 44% of non-electrocardiogram (ECG)-gated MDCT images. Abnormalities of the pericardium can now be identified with increasing certainty on 64-detector row CT; they may be the key to diagnosis and therefore must not be overlooked. This educational review of the pericardium will cover different imaging techniques, with a significant emphasis on MDCT. We have a large research and clinical experience of ECG-gated cardiac CT and will demonstrate examples of pericardial recesses, their variations and a wide variety of pericardial abnormalities and systemic conditions affecting the pericardium. We give a brief relevant background of the conditions and reinforce the key imaging features. We aim to provide a pictorial demonstration of the wide variety of abnormalities of the pericardium and the pitfalls in the diagnosis of pericardial disease.
To determine the association between age and analgesia for emergency department (ED) patients with abdominal or back pain.
Using a fully electronic medical record, we performed a retrospective cohort study of adults presenting with abdominal or back pain to two urban EDs. To assess differences in analgesia administration and time to analgesia between age groups, we used chi-square and Kruskal-Wallis test respectively. To adjust for potential confounders, we used a generalized linear model with log link and Gaussian error.
Of 24,752 subjects (mean age 42 years, 65% female, 69% black, mean triage pain score 7.5), the majority (76%) had abdominal pain and 61% received analgesia. The ≥80 years group (n=722; 3%), compared to the 65–79 years group (n=2,080; 8%) and to the <65 years group (n=21,950; 89%), was more often female (71 vs. 61 vs. 65%), black (72 vs. 65 vs. 69%), and had a lower mean pain score (6.6 vs. 7.1 vs. 7.6). Both older groups were less likely to receive any analgesia (48 vs. 59 vs. 62%, p<0.0001) and the oldest group less likely to receive opiates (35 vs. 47 vs. 44%, p<0.0001). Of those who received analgesia, both older groups waited longer for their medication (123 vs. 113 vs. 94 minutes; p<0.0001). After controlling for potential confounders, patients ≥80 years were 17% less likely than the <65 years group to receive analgesia (95% CI 14–20%).
Older adults who present to the ED for abdominal or back pain are less likely to receive analgesia and wait significantly longer for pain medication compared to younger adults.