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1.  ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7 
Cell Death and Differentiation  2014;21(8):1275-1289.
The process of autophagy has been described in detail at the molecular level in normal cells, but less is known of its regulation in cancer cells. Aplasia Ras homolog member I (ARHI; DIRAS3) is an imprinted tumor suppressor gene that is downregulated in multiple malignancies including ovarian cancer. Re-expression of ARHI slows proliferation, inhibits motility, induces autophagy and produces tumor dormancy. Our previous studies have implicated autophagy in the survival of dormant ovarian cancer cells and have shown that ARHI is required for autophagy induced by starvation or rapamycin treatment. Re-expression of ARHI in ovarian cancer cells blocks signaling through the PI3K and Ras/MAP pathways, which, in turn, downregulates mTOR and initiates autophagy. Here we show that ARHI is required for autophagy-meditated cancer cell arrest and ARHI inhibits signaling through PI3K/AKT and Ras/MAP by enhancing internalization and degradation of the epidermal growth factor receptor. ARHI-mediated downregulation of PI3K/AKT and Ras/ERK signaling also decreases phosphorylation of FOXo3a, which sequesters this transcription factor in the nucleus. Nuclear retention of FOXo3a induces ATG4 and MAP-LC3-I, required for maturation of autophagosomes, and also increases the expression of Rab7, required for fusion of autophagosomes with lysosomes. Following the knockdown of FOXo3a or Rab7, autophagolysosome formation was observed but was markedly inhibited, resulting in numerous enlarged autophagosomes. ARHI expression correlates with LC3 expression and FOXo3a nuclear localization in surgical specimens of ovarian cancer. Thus, ARHI contributes to the induction of autophagy through multiple mechanisms in ovarian cancer cells.
doi:10.1038/cdd.2014.48
PMCID: PMC4085535  PMID: 24769729
2.  Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis 
JIMD Reports  2015;19:59-66.
Variants in the SLC25A3 gene, which codes for the mitochondrial phosphate transporter (PiC), lead to a failure of inorganic phosphate (Pi) transport across the mitochondrial membrane, which is required in the final step of oxidative phosphorylation. The literature described two affected sibships with variants in SLC25A3; all cases had skeletal myopathy and cardiomyopathy (OMIM 610773). We report here two new patients who had neonatal cardiomyopathy; one of whom did not have skeletal myopathy nor elevated lactate. Patient 1 had a homozygous splice site variant, c.158-9A>G, which has been previously reported in a Turkish family. Patient 2 was found to be a compound heterozygote for two novel variants, c.599T>G (p.Leu200Trp) and c. 886_898delGGTAGCAGTGCTTinsCAGATAC (p.Gly296_Ser300delinsGlnIlePro). Protein structure analysis indicated that both variants are likely to be pathogenic. Sequencing of SLC25A3 should be considered in patients with isolated cardiomyopathy, even those without generalized skeletal myopathy or lactic acidosis.
doi:10.1007/8904_2014_364
PMCID: PMC4501241  PMID: 25681081
3.  Evaluation of swabbing methods for estimating the prevalence of bacterial carriage in the upper respiratory tract: a cross sectional study 
BMJ Open  2014;4(10):e005341.
Objectives
Bacterial carriage in the upper respiratory tract is usually asymptomatic but can lead to respiratory tract infection (RTI), meningitis and septicaemia. We aimed to provide a baseline measure of Streptococcus pneumoniae, Moraxella catarrhalis, Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae and Neisseria meningitidis carriage within the community. Self-swabbing and healthcare professional (HCP) swabbing were compared.
Design
Cross-sectional study.
Setting
Individuals registered at 20 general practitioner practices within the Wessex Primary Care Research Network South West, UK.
Participants
10 448 individuals were invited to participate; 5394 within a self-swabbing group and 5054 within a HCP swabbing group. Self-swabbing invitees included 2405 individuals aged 0–4 years and 3349 individuals aged ≥5 years. HCP swabbing invitees included 1908 individuals aged 0–4 years and 3146 individuals aged ≥5 years.
Results
1574 (15.1%) individuals participated, 1260 (23.4%, 95% CI 22.3% to 24.5%) undertaking self-swabbing and 314 (6.2%, 95% CI 5.5% to 6.9%) undertaking HCP-led swabbing. Participation was lower in young children and more deprived practice locations. Swab positivity rates were 34.8% (95% CI 32.2% to 37.4%) for self-taken nose swabs (NS), 19% (95% CI 16.8% to 21.2%) for self-taken whole mouth swabs (WMS), 25.2% (95% CI 20.4% to 30%) for nasopharyngeal swabs (NPS) and 33.4% (95% CI 28.2% to 38.6%) for HCP-taken WMS. Carriage rates of S. aureus were highest in NS (21.3%). S. pneumoniae carriage was highest in NS (11%) and NPS (7.4%). M. catarrhalis carriage was highest in HCP-taken WMS (28.8%). H. influenzae and P. aeruginosa carriage were similar between swab types. N. meningitidis was not detected in any swab. Age and recent RTI affected carriage of S. pneumoniae and H. influenzae. Participant costs were lower for self-swabbing (£41.21) versus HCP swabbing (£69.66).
Conclusions
Higher participation and lower costs of self-swabbing as well as sensitivity of self-swabbing favour this method for use in large population-based respiratory carriage studies.
doi:10.1136/bmjopen-2014-005341
PMCID: PMC4216860  PMID: 25358677
Epidemiology < INFECTIOUS DISEASES; MICROBIOLOGY; Respiratory infections < THORACIC MEDICINE; PRIMARY CARE
4.  Risk of lymphoma subtypes after solid organ transplantation in the United States 
British Journal of Cancer  2013;109(1):280-288.
Background:
Solid organ transplant recipients have high risk of lymphomas, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). A gap in our understanding of post-transplant lymphomas involves the spectrum and associated risks of their many histologic subtypes.
Methods:
We linked nationwide data on solid organ transplants from the US Scientific Registry of Transplant Recipients (1987–2008) to 14 state and regional cancer registries, yielding 791 281 person-years of follow-up for 19 distinct NHL subtypes and HL. We calculated standardised incidence ratios (SIRs) and used Poisson regression to compare SIRs by recipient age, transplanted organ, and time since transplantation.
Results:
The risk varied widely across subtypes, with strong elevations (SIRs 10–100) for hepatosplenic T-cell lymphoma, Burkitt's lymphoma, NK/T-cell lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (both systemic and primary cutaneous forms). Moderate elevations (SIRs 2–4) were observed for HL and lymphoplasmacytic, peripheral T-cell, and marginal zone lymphomas, but SIRs for indolent lymphoma subtypes were not elevated. Generally, SIRs were highest for younger recipients (<20 years) and those receiving organs other than kidneys.
Conclusion:
Transplant recipients experience markedly elevated risk of a distinct spectrum of lymphoma subtypes. These findings support the aetiologic relevance of immunosuppression for certain subtypes and underscore the importance of detailed haematopathologic workup for transplant recipients with suspected lymphoma.
doi:10.1038/bjc.2013.294
PMCID: PMC3708563  PMID: 23756857
non-Hodgkin's lymphoma; Hodgkin's lymphoma; transplantation; immunosuppression; Burkitt's lymphoma; T-cell lymphoma
5.  Hydroxylation of demethoxy-Q6 constitutes a control point in yeast coenzyme Q6 biosynthesis 
Coenzyme Q is a lipid molecule required for respiration and antioxidant protection. Q biosynthesis in Saccharomyces cerevisiae requires nine proteins (Coq1p–Coq9p). We demonstrate in this study that Q levels are modulated during growth by its conversion from demethoxy-Q (DMQ), a late intermediate. Similar conversion was produced when cells were subjected to oxidative stress conditions. Changes in Q6/DMQ6 ratio were accompanied by changes in COQ7 gene mRNA levels encoding the protein responsible for the DMQ hydroxylation, the penultimate step in Q biosynthesis pathway. Yeast coq null mutant failed to accumulate any Q late biosynthetic intermediate. However, in coq7 mutants the addition of exogenous Q produces the DMQ synthesis. Similar effect was produced by over-expressing ABC1/COQ8. These results support the existence of a biosynthetic complex that allows the DMQ6 accumulation and suggest that Coq7p is a control point for the Q biosynthesis regulation in yeast.
doi:10.1007/s00018-008-8547-7
PMCID: PMC3070445  PMID: 19002377
Ubiquinone; coenzyme Q; mitochondria; yeast regulation
6.  Demystifying basal‐like breast carcinomas 
Journal of Clinical Pathology  2007;60(12):1328-1332.
“Basal” breast cancers are dominating the breast research literature at present and pathologists are under increasing pressure to evaluate for such a phenotype by their surgical and oncological colleagues. There is also much confusion about how to assess cancers, which immunohistochemical markers to use, what meaning and benefit this provides, and what the surgeons and oncologists will do with the information. Much remains to be done to answer all these questions but here we try to shed light on some of the issues and suggest what is still to come.
doi:10.1136/jcp.2006.041731
PMCID: PMC2095578  PMID: 17496191
8.  Parkinson's disease 
BMJ : British Medical Journal  2007;335(7617):441-445.
doi:10.1136/bmj.39289.437454.AD
PMCID: PMC1962892  PMID: 17762036
9.  Temporal Analysis of Invasive Pneumococcal Clones from Scotland Illustrates Fluctuations in Diversity of Serotype and Genotype in the Absence of Pneumococcal Conjugate Vaccine▿  
In September 2006, the seven-valent pneumococcal conjugate vaccine (PCV7; Prevenar) was introduced into the childhood vaccination schedule in the United Kingdom. We monitored the population of invasive pneumococci in Scotland in the 5 years preceding the introduction of PCV7 by using serogrouping, multilocus sequence typing (MLST), and eBURST analysis. Here, we present a unique analysis of a complete national data set of invasive pneumococci over this time. We observed an increase in invasive pneumococcal disease (IPD) caused by serotypes 1, 4, and 6 and a decrease in serogroup 14-, 19-, and 23-associated disease. Analysis of sequence type (ST) data shows a significant increase in ST306, associated with serotype 1, and a decrease in ST124, associated with serotype 14. There have also been increases in the amounts of IPD caused by ST227 (serotype 1) and ST53 (serotype 8), although these increases were not found to reach significance (P = 0.08 and 0.06, respectively). In the course of the study period preceding the introduction of PCV7, we observed considerable and significant changes in serogroup and clonal distribution over time.
doi:10.1128/JCM.01485-09
PMCID: PMC2812259  PMID: 19923488
10.  Family history of haematopoietic malignancies and non-Hodgkin's lymphoma risk in the California Teachers Study 
British Journal of Cancer  2009;100(3):524-526.
Family history of haematopoietic malignancies appears to be a risk factor for non-Hodgkin's lymphoma (NHL), but whether risk varies by family member's gender is unclear. Among 121 216 women participating in the prospective California Teachers Study, NHL risk varied by type of haematopoietic malignancy and gender of the relative.
doi:10.1038/sj.bjc.6604881
PMCID: PMC2658543  PMID: 19156148
non-Hodgkin's lymphoma; family history; haematopoietic malignancy; lymphoma; leukaemia
11.  Acute mountain sickness: medical problems associated with acute and subacute exposure to hypobaric hypoxia 
Postgraduate Medical Journal  2006;82(973):748-753.
This article summarises the medical problems of travel to altitudes above 3000 m. These are caused by chronic hypoxia. Acute mountain sickness (AMS), a self limiting common illness is almost part of normal acclimatisation—a transient condition lasting for several days. However, in <2% of people staying above 4000 m, serious illnesses related to hypoxia develop – high altitude pulmonary oedema and cerebral oedema. These are potentially fatal but can be largely avoided by gradual ascent. Short vacations, pressure from travel companies and peer groups often encourage ascent to 4000 m more rapidly than is prudent. Sensible guidelines for ascent are outlined, clinical features, management and treatment of these conditions.
doi:10.1136/pgmj.2006.047662
PMCID: PMC2660503  PMID: 17099095
12.  Side Chain and Backbone Dynamics of Phospholamban in Phospholipid Bilayers Utilizing 2H and 15N Solid-State NMR Spectroscopy† 
Biochemistry  2007;46(42):11695-11706.
2H and 15N solid-state NMR spectroscopic techniques were used to investigate both the side chain and backbone dynamics of wild-type phospholamban (WT-PLB) and its phosphorylated form (P-PLB) incorporated into 1-palmitoyl-2-oleoyl-sn-glycerophosphocholine (POPC) phospholipid bilayers. 2H NMR spectra of site-specific CD3-labeled WT-PLB (at Leu51, Ala24, and Ala15) in POPC bilayers were similar under frozen conditions (-25 °C). However, significant differences in the line shapes of the 2H NMR spectra were observed in the liquid crystalline phase at and above 0 °C. The 2H NMR spectra indicate that Leu51, located toward the lower end of the transmembrane (TM) helix, shows restricted side chain motion, implying that it is embedded inside the POPC lipid bilayer. Additionally, the line shape of the 2H NMR spectrum of CD3-Ala24 reveals more side chain dynamics, indicating that this residue (located in the upper end of the TM helix) has additional backbone and internal side chain motions. 2H NMR spectra of both WT-PLB and P-PLB with CD3-Ala15 exhibit strong isotropic spectral line shapes. The dynamic isotropic nature of the 2H peak can be attributed to side chain and backbone motions to residues located in an aqueous environment outside the membrane. Also, the spectra of 15N-labeled amide WT-PLB at Leu51 and Leu42 residues showed only a single powder pattern component indicating that these two 15N-labeled residues located in the TM helix are motionally restricted at 25 °C. Conversely, 15N-labeled amide WT-PLB at Ala11 located in the cytoplasmic domain showed both powder and isotropic components at 25 °C. Upon phosphorylation, the mobile component contribution increases at Ala11. The 2H and 15N NMR data indicate significant backbone motion for the cytoplasmic domain of WT-PLB when compared to the transmembrane section.
doi:10.1021/bi700749q
PMCID: PMC2756648  PMID: 17910421
13.  Lidocaine infusion as a rescue analgesic in the perioperative setting 
In the present case series, three patients for whom regional anesthesia may have been the optimum technique for controlling postoperative pain are discussed. However, due to prevailing circumstances, regional anesthesia could not be provided. An intravenous infusion of lidocaine at 4 mg/min was administered perioperatively as an alternative ‘rescue’ analgesic technique. This infusion rate, based on previous extensive pharmacokinetic studies, is widely considered to be safe. Postoperative pain was lower than expected for the type of surgery. Anecdotal experience suggests that hospital length of stay may also be reduced, with both patient and economic benefits.
PMCID: PMC2799267  PMID: 18958315
Analgesia; Lidocaine; Postoperative pain
14.  Identification of a region in the TASK3 two pore domain potassium channel that is critical for its blockade by methanandamide 
British Journal of Pharmacology  2007;152(5):778-786.
Background and purpose:
The TASK subfamily of two pore domain potassium channels (K2P) encodes for leak K currents, contributing to the resting membrane potential of many neurons and regulating their excitability. TASK1 and TASK3 channels are regulated by a number of pharmacological and physiological mediators including cannabinoids such as methanandamide. In this study, we investigate how methanandamide blocks these channels.
Experimental approach:
Currents through wild type and mutated TASK1 and TASK3 channels expressed in modified HEK-293 cells were measured using whole-cell electrophysiological recordings in the presence and absence of methanandamide.
Key results:
Methanandamide (3 μM) produced substantial block of hTASK1, hTASK3 and mTASK3 channels but was most potent at blocking hTASK3 channels. Block of these channels was irreversible unless cells were washed with buffer containing bovine serum albumin. Mutation of the distal six amino acids of TASK1 did not alter methanandamide inhibition, whilst C terminal truncation of TASK3 channels caused a small but significant reduction of inhibition. However, deletion of six amino acids (VLRFLT) at the interface between the final transmembrane domain and cytoplasmic C terminus of TASK3 channels gave functional currents that were no longer inhibited by methanandamide or by activation of GPCRs.
Conclusions and implications:
Methanandamide potently blocked TASK3 and TASK1 channels and both methanandamide and G protein-mediated inhibition converged on the same intracellular gating pathway. Physiologically, methanandamide block of TASK1 and TASK3 channels may underpin a number of CNS effects of cannabinoids that are not mediated through activation of CB1 or CB2 receptors.
doi:10.1038/sj.bjp.0707436
PMCID: PMC2190017  PMID: 17828294
two-pore domain potassium channels; TASK1; TASK3; methanandamide; muscarinic receptor; PKA; PKC
15.  Ability of a nurse specialist to diagnose simple headache disorders compared with consultant neurologists 
Methods: An experienced neurology ward sister was trained in the differential diagnosis of headache disorders. Over six months, patients with non-acute headache disorders and role players trained to present with benign or sinister headaches were seen by both the nurse and a consultant neurologist. Both reached independent diagnoses of various headache disorders.
Results: Consultants diagnosed 239 patients with tension-type headache (47%), migraine (39%), or other headache disorders (14%). The nurse agreed with the consultant in 92% of cases of tension-type headache, 91% of migraine, and 61% of other diagnoses. Where the nurse did not agree with the diagnosis, most would have been referred for a consultant opinion. Both the nurse and the doctors misdiagnosed the same three of 13 role players. The investigation rate of the consultants varied between 18% and 59%. Only one clinically relevant abnormality was found on head scans and this was strongly suspected clinically.
Conclusions: A headache nurse specialist can be trained to diagnose tension-type headache and migraine. A nationwide nurse led diagnostic headache service could lead to substantial reduction in neurology waiting times.
doi:10.1136/jnnp.2004.057968
PMCID: PMC1739753  PMID: 16024902
16.  Views of bereaved relatives about quality of survival after radiotherapy for malignant cerebral glioma 
Objective: To explore the views of bereaved relatives about quality of survival after radiotherapy for malignant cerebral glioma.
Design: Semistructured interviews with the bereaved relatives of 56 previously studied patients with glioma.
Setting: Patients treated at six London hospitals from 1990 to 1992 surviving between one and 46 months (median, eight).
Subjects: Fifty six relatives (44 spouses, 12 others) seen four to six months after bereavement and 20 again at 13 months.
Main outcome measures: Views about quality of life and satisfaction with radiotherapy.
Results: Relatives described quality of life as "good or acceptable" when patients carried on some normal activities or enjoyed social relationships. They described restricted and dependent states, constant deterioration, or loss of social interaction as giving "poor or unacceptable" quality of life. Length of time lived in such states also appeared important. Relatives' views of good or acceptable quality of life were independently related to low initial cognitive or personality change or low distress in the patient after diagnosis, and to their subsequent survival free from physical disability for at least one month. Satisfaction with radiotherapy was related to low initial distress, some degree of surgical resection, and overall length of survival longer than six months.
Conclusions: Carefully exploring the views of bereaved relatives can bring a useful perspective to difficult treatment decisions. Their values support including disability and distress in quality of life measures, but cast doubt on the QALY-type approach of using full years of survival or time free from disability to judge whether treatments are worthwhile.
doi:10.1136/jnnp.2004.035931
PMCID: PMC1739608  PMID: 15774445
17.  Mapping loss of heterozygosity in normal human breast cells from BRCA1/2 carriers 
British Journal of Cancer  2006;95(4):515-519.
We have studied loss of heterozygosity at the BRCA1 and BRCA2 loci in 992 normal cell clones derived from topographically defined areas of normal tissue in four samples from BRCA1/BRCA2 mutation carriers. The frequency of loss of heterozygosity in the clones was low (1.01%), but it was found in all four samples, whether or not a tumour was present. Topographical mapping revealed that the genetic changes were clustered in some breast samples. Our study confirms the previous finding that a field of genetic instability can exist around a tumour, suggesting that sufficient tissue must be removed at surgery to avoid local recurrence. We also demonstrate that such a field of genetic change can exist in morphologically normal tissue before a tumour develops and, for the first time, we demonstrate that the field is of a size greater than one terminal duct-lobular unit. The genetic changes are not identical, however, which suggests that genetic instability in these regions may play an early role in tumour development. We also confirm and extend our original observation of loss of the wild-type BRCA1 allele in some clones, and loss of the mutant allele in others, demonstrating that loss of either allele is a stochastic event.
doi:10.1038/sj.bjc.6603298
PMCID: PMC2360661  PMID: 16880780
normal breast; loss of heterozygosity; BRCA1; BRCA2
18.  Early symptoms of brain tumours 
doi:10.1136/jnnp.2003.033308
PMCID: PMC1739177  PMID: 15258238
22.  Histopathologic indicators of breast cancer biology: insights from population mammographic screening 
British Journal of Cancer  2005;92(8):1366-1371.
Histopathologic features of breast cancer such as tumour size, grade and axillary lymph node (LN) status variably reflect tumour biology and time. Recent evidence suggests that the biological character of breast cancer is established at an early stage and has a major impact on clinical course. The aim of this study was to distinguish the impact of biology on breast cancer histopathology by comparing features of breast cancers diagnosed following population mammographic screening with prevalent vs incident detection and screening interval. Central histopathology review data from 1147 cases of ductal in situ and/or invasive breast cancer were examined. Size, grade and LN status of invasive cancers were positively correlated (P<0.001). Prevalent invasive cancers were larger (P<0.001) and more likely to be LN positive (P=0.02) than incident cases, but grade was not associated with screening episode (P=0.7). Screening interval for incident cancers was positively associated with invasive cancer size (P=0.05) and LN status (P=0.002) but not grade (P=0.1). Together, these data indicate that biology and time both impact on size and LN status of invasive breast cancer, but grade reflects biology alone. In view of the clinical importance of breast cancer biology, grade as its most direct indicator assumes particular significance.
doi:10.1038/sj.bjc.6602501
PMCID: PMC2362010  PMID: 15812557
breast cancer; histopathology; mammographic screening
25.  Brachial plexus injury as an unusual complication of coronary artery bypass graft surgery 
Postgraduate Medical Journal  2003;79(928):84-86.
Brachial plexus injury is an unusual and under-recognised complication of coronary artery bypass grafting especially when internal mammary artery harvesting takes place. It is believed to be due to sternal retraction resulting in compression of the brachial plexus. Although the majority of cases are transient, there are cases where the injury is permanent and may have severe implications as illustrated in the accompanying case history.
doi:10.1136/pmj.79.928.84
PMCID: PMC1742608  PMID: 12612322

Results 1-25 (248)