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1.  Effect of a YAG laser iridotomy on intraocular pressure in pigmentary glaucoma 
The British Journal of Ophthalmology  2002;86(12):1443-1444.
PMCID: PMC1771416  PMID: 12446385
YAG laser iridotomy; intraocular pressure; pigmentary glaucoma
2.  Quantitative analysis of contrast-enhanced ultrasonography: differentiating focal nodular hyperplasia from hepatocellular carcinoma 
The British Journal of Radiology  2013;86(1023):20120536.
To explore the potential of quantitative analysis of contrast-enhanced ultrasonography (CEUS) in differentiating focal nodular hyperplasia (FNH) from hepatocellular carcinoma (HCC).
34 cases of FNH and 66 cases of HCC (all lesions <5 cm) were studied using CEUS to evaluate enhancement patterns and using analytic software Sonoliver® (Image-Arena™ v.4.0, TomTec Imaging Systems, Munich, Germany) to obtain quantitative features of CEUS in the region of interest. The quantitative features of maximum of intensity (IMAX), rise slope (RS), rise time (RT) and time to peak (TTP) were compared between the two groups and applied to further characterise both FNH and HCC with hypoenhancing patterns in the late phase on CEUS.
The sensitivity and specificity of CEUS for diagnosis of FNH were 67.6% and 93.9%, respectively. For quantitative analysis, IMAX and RS in FNHs were significantly higher than those in HCCs (p<0.05), while RT and TTP in FNHs were significantly shorter (p<0.05). Both the 11 FNHs and 62 HCCs with hypo-enhancing patterns in the late phase were further characterised with their quantitative features, and the sensitivity and specificity of IMAX for diagnosis of FNH were 90.9% and 43.5%, RS 81.8% and 80.6%, RT 90.9% and 71.0%, and TTP 90.9% and 71.0%, respectively.
The quantitative features of CEUS in FNH and HCC were significantly different, and they could further differentiate FNH from HCC following conventional CEUS.
Advances in knowledge:
Our findings suggest that quantitative analysis of CEUS can improve the accuracy of differentiating FNH from HCC.
PMCID: PMC3608056  PMID: 23392189
3.  Inducement of mitosis delay by cucurbitacin E, a novel tetracyclic triterpene from climbing stem of Cucumis melo L., through GADD45γ in human brain malignant glioma (GBM) 8401 cells 
Cell Death & Disease  2014;5(2):e1087-.
Cucurbitacin E (CuE) is a natural compound previously shown to have anti-feedant, antioxidant and antitumor activities as well as a potent chemo-preventive action against cancer. The present study investigates its anti-proliferative property using MTT assay; CuE demonstrated cytotoxic activity against malignant glioma GBM 8401 cells and induced cell cycle G2/M arrest in these cells. CuE-treated cells accumulated in metaphase (CuE 2.5–10 μM) as determined using MPM-2 by flow cytometry. We attempted to characterize the molecular pathways responsible for cytotoxic effects of CuE in GBM 8401 cells. We studied the genome-wide gene expression profile on microarrays and molecular networks by using pathway analysis tools of bioinformatics. The CuE reduced the expression of 558 genes and elevated the levels of 1354 genes, suggesting an existence of the common pathways involved in induction of G2/M arrest. We identified the RB (GADD45β and GADD45γ) and the p53 (GADD45α) signaling pathways as the common pathways, serving as key molecules that regulate cell cycle. Results indicate that CuE produced G2/M arrest as well as the upregulation of GADD45 γ and binding with CDC2. Both effects increased proportionally with the dose of CuE, suggesting that the CuE-induced mitosis delay is regulated by GADD45γ overexpression. Our findings suggest that, in addition to the known effects on cancer prevention, CuE may have antitumor activity in glioma therapy.
PMCID: PMC3944240  PMID: 24577085
cucurbitacin E (CuE); malignant glioma; G2/M arrest; growth arrest and DNA damage 45 (GADD45)
4.  Corrigendum 
Li, J | Sima, W | Ouyang, B | Wang, T | Ziaf, K | Luo, Z | Liu, L | Li, H | Chen, M | Huang, Y | Feng, Y | Hao, Y | Ye, Z
PMCID: PMC3873127
5.  No increased mortality from donor or recipient hepatitis B- and/or hepatitis C-positive serostatus after related-donor allogeneic hematopoietic cell transplantation 
Limited data exist on allogeneic transplant outcomes in recipients receiving hematopoietic cells from donors with prior or current hepatitis B (HBV) or C (HCV) infection (seropositive donors) or for recipients with prior or current HBV or HCV infection (seropositive recipients). Transplant outcomes are reported for 416 recipients from 121 centers who received a human leukocyte antigen-identical related-donor allogeneic transplant for hematologic malignancies between 1995 and 2003. Of these, 33 seronegative recipients received grafts from seropositive donors and 128 recipients were seropositive. The remaining 256 patients served as controls. With comparable median follow-up (cases, 5.9 years; controls, 6.7 years), the incidence of treatment-related mortality, survival, graft-versus-host disease, and hepatic toxicity appears similar in all cohorts. The frequencies of hepatic toxicities as well as causes of death between cases and controls were similar. Prior exposure to HBV or HCV in either the donor or the recipient should not be considered an absolute contraindication to transplant.
PMCID: PMC3481161  PMID: 22548788
allogeneic transplantation; hepatitis B; hepatitis C
6.  WWOX suppresses autophagy for inducing apoptosis in methotrexate-treated human squamous cell carcinoma 
Cell Death & Disease  2013;4(9):e792-.
Squamous cell carcinoma (SCC) cells refractory to initial chemotherapy frequently develop disease relapse and distant metastasis. We show here that tumor suppressor WW domain-containing oxidoreductase (WWOX) (also named FOR or WOX1) regulates the susceptibility of SCC to methotrexate (MTX) in vitro and cure of SCC in MTX therapy. MTX increased WWOX expression, accompanied by caspase activation and apoptosis, in MTX-sensitive SCC cell lines and tumor biopsies. Suppression by a dominant-negative or small interfering RNA targeting WWOX blocked MTX-mediated cell death in sensitive SCC-15 cells that highly expressed WWOX. In stark contrast, SCC-9 cells expressed minimum amount of WWOX protein and resisted MTX-induced apoptosis. Transiently overexpressed WWOX sensitized SCC-9 cells to apoptosis by MTX. MTX significantly downregulated autophagy-related Beclin-1, Atg12–Atg5 and LC3-II protein expression and autophagosome formation in the sensitive SCC-15, whereas autophagy remained robust in the resistant SCC-9. Mechanistically, WWOX physically interacted with mammalian target of rapamycin (mTOR), which potentiated MTX-increased phosphorylation of mTOR and its downstream substrate p70 S6 kinase, along with dramatic downregulation of the aforementioned proteins in autophagy, in SCC-15. When WWOX was knocked down in SCC-15, MTX-induced mTOR signaling and autophagy inhibition were blocked. Thus, WWOX renders SCC cells susceptible to MTX-induced apoptosis by dampening autophagy, and the failure in inducing WWOX expression leads to chemotherapeutic drug resistance.
PMCID: PMC3789168  PMID: 24008736
tumor suppressor; methotrexate; chemotherapy; autophagy; apoptosis
7.  The HDAC inhibitor, MPT0E028, enhances erlotinib-induced cell death in EGFR-TKI-resistant NSCLC cells 
Cell Death & Disease  2013;4(9):e810-.
Epidermal growth factor receptor (EGFR), which promotes cell survival and division, is found at abnormally high levels on the surface of many cancer cell types, including many cases of non-small cell lung cancer. Erlotinib (Tarceva), an oral small-molecule tyrosine kinase inhibitor, is a so-called targeted drug that inhibits the tyrosine kinase domain of EGFR, and thus targets cancer cells with some specificity while doing less damage to normal cells. However, erlotinib resistance can occur, reducing the efficacy of this treatment. To develop more effective therapeutic interventions by overcoming this resistance problem, we combined the histone deacetylase inhibitor, MPT0E028, with erlotinib in an effort to increase their antitumor effects in erlotinib-resistant lung adenocarcinoma cells. This combined treatment yielded significant growth inhibition, induced the expression of apoptotic proteins (PARP, γH2AX, and caspase-3), increased the levels of acetylated histone H3, and showed synergistic effects in vitro and in vivo. These effects were independent of the mutation status of the genes encoding EGFR or K-Ras. MPT0E028 synergistically blocked key regulators of the EGFR/HER2 signaling pathways, attenuating multiple compensatory pathways (e.g., AKT, extracellular signal-regulated kinase, and c-MET). Our results indicate that this combination therapy might be a promising strategy for facilitating the effects of erlotinib monotherapy by activating various networks. Taken together, our data provide compelling evidence that MPT0E028 has the potential to improve the treatment of heterogeneous and drug-resistant tumors that cannot be controlled with single-target agents.
PMCID: PMC3789188  PMID: 24052078
lung cancer; HDAC; synergistic; EGFR; apoptosis; erlotinib
8.  Defective jejunal and colonic salt absorption and altered Na+/H+ exchanger 3 (NHE3) activity in NHE regulatory factor 1 (NHERF1) adaptor protein-deficient mice 
We investigated the role of the Na+/H+ exchanger regulatory factor 1 (NHERF1) on intestinal salt and water absorption, brush border membrane (BBM) morphology, and on the NHE3 mRNA expression, protein abundance, and transport activity in the murine intestine. NHERF1-deficient mice displayed reduced jejunal fluid absorption in vivo, as well as an attenuated in vitro Na+ absorption in isolated jejunal and colonic, but not of ileal, mucosa. However, cAMP-mediated inhibition of both parameters remained intact. Acid-activated NHE3 transport rate was reduced in surface colonocytes, while its inhibition by cAMP and cGMP was normal. Immunodetection of NHE3 revealed normal NHE3 localization in the BBM of NHERF1 null mice, but NHE3 abundance, as measured by Western blot, was significantly reduced in isolated BBM from the small and large intestines. Furthermore, the microvilli in the proximal colon, but not in the small intestine, were significantly shorter in NHERF1 null mice. Additional knockout of PDZK1 (NHERF3), another member of the NHERF family of adaptor proteins, which binds to both NHE3 and NHERF1, further reduced basal NHE3 activity and caused complete loss of cAMP-mediated NHE3 inhibition. An activator of the exchange protein activated by cAMP (EPAC) had no effect on jejunal fluid absorption in vivo, but slightly inhibited NHE3 activity in surface colonocytes in vitro. In conclusion, NHERF1 has segment-specific effects on intestinal salt absorption, NHE3 transport rates, and NHE3 membrane abundance without affecting mRNA levels. However, unlike PDZK1, NHERF1 is not required for NHE3 regulation by cyclic nucleotides.
PMCID: PMC3746809  PMID: 18758809
PDZ domain proteins; Intestinal electrolyte transport; PDZK1; NHERF1; EPAC; Knockout mice
9.  Intensity-modulated radiotherapy for nasopharyngeal carcinoma: improvement of the therapeutic ratio with helical tomotherapy vs segmental multileaf collimator-based techniques 
The British Journal of Radiology  2012;85(1016):e537-e543.
The aim of the study was to compare differences in dosimetric, clinical and quality-of-life end points among patients treated with helical tomotherapy (HT) and segmental multileaf collimator (SMLC)-based intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma.
From June 2005 to August 2009, 30 consecutive patients were treated with IMRT for nasopharyngeal carcinoma to a dose of 70 Gy. 14 patients (47%) were treated using HT and 16 (53%) were treated using SMLC-based IMRT. 28 patients (93%) received concurrent chemotherapy. The patients were evenly balanced between the two radiotherapy groups with respect to clinical and pathological characteristics. Median follow-up was 30 months (range, 6–62 months).
The 2-year estimates of overall survival, local–regional control and progression-free survival were 81%, 87% and 82%, respectively. There were no significant differences in any of these end points with respect to IMRT technique (p>0.05 for all). Dosimetric analysis revealed that patients treated by HT had significantly improved salivary sparing with respect to mean dose (27.3 vs 34.1 Gy, p=0.03) and volume receiving greater than or equal to 30 Gy (31.7% vs 47.3%, p=0.01) to the contralateral (spared) parotid gland. The incidence of Grade 3+ late xerostomia was 13 and 7% among patients treated with SMLC-based IMRT and HT, respectively (p=0.62). The corresponding proportion of patients who subjectively reported “too little” or “no” saliva at final follow-up was 38% and 7%, respectively (p=0.04).
The superior dosimetric outcome observed with HT appeared to translate into moderately improved clinical outcomes with respect to salivary sparing. Prospective trials are needed to validate this gain in the therapeutic ratio.
PMCID: PMC3587075  PMID: 22253350
10.  Controllable Disorder in a Hybrid Nanoelectronic System: Realization of a Superconducting Diode 
Scientific Reports  2013;3:2274.
We have studied a hybrid nanoelectronic system which consists of an AlGaAs/GaAs two-dimensional electron gas (2DEG) in close proximity (~70 nm) to an Al superconducting nanofilm. By tuning the current through the Al film, we can change the conductance of the 2DEG and furthermore vary the effective disorder in the Al superconducting film in a controllable way. When a high current is injected into the film, screening which couples the Al film and the 2DEG results in a collapse of anti-symmetric behavior in the current-voltage characteristics, V(I) ~ -V(-I), which holds true in a conventional superconductor. Our results may open a new avenue of experimentally realizing a superconducting diode.
PMCID: PMC3721077  PMID: 23881449
11.  Proteomic profiling of human retinal pigment epithelium exposed to an advanced glycation-modified substrate 
The retinal pigment epithelium (RPE) and underlying Bruch’s membrane undergo significant modulation during ageing. Progressive, age-related modifications of lipids and proteins by advanced glycation end products (AGEs) at this cell–substrate interface have been implicated in RPE dysfunction and the progression to age-related macular degeneration (AMD). The pathogenic nature of these adducts in Bruch’s membrane and their influence on the overlying RPE remains unclear. This study aimed to identify alterations in RPE protein expression in cells exposed to AGE-modified basement membrane (AGE-BM), to determine how this “aged” substrate impacts RPE function and to map the localisation of identified proteins in ageing retina.
Confluent ARPE-19 monolayers were cultured on AGE-BM and native, non-modified BM (BM). Following 28-day incubation, the proteome was profiled using 2-dimensional gel electrophoresis (2D), densitometry and image analysis was employed to map proteins of interest that were identified by electrospray ionisation mass spectrometry (ESI MS/MS). Immunocytochemistry was employed to localise identified proteins in ARPE-19 monolayers cultured on unmodified and AGE-BM and to analyze aged human retina.
Image analysis detected altered protein spot densities between treatment groups, and proteins of interest were identified by LC ESI MS/MS which included heat-shock proteins, cytoskeletal and metabolic regulators. Immunocytochemistry revealed deubiquitinating enzyme ubiquitin carboxyterminal hydrolase-1 (UCH-L1), which was upregulated in AGE-exposed RPE and was also localised to RPE in human retinal sections.
This study has demonstrated that AGE-modification of basement membrane alters the RPE proteome. Many proteins are changed in this ageing model, including UCHL-1, which could impact upon RPE degradative capacity. Accumulation of AGEs at Bruch”s membrane could play a significant role in age-related dysfunction of the RPE.
PMCID: PMC3673018  PMID: 22081232
Bruch’s membrane; RPE; Advanced glycation endproducts; Ubiquitin carboxyterminal hydrolase-1
12.  64-slice CT angiography for the detection of functionally significant coronary stenoses: comparison with stress myocardial perfusion imaging 
The British Journal of Radiology  2012;85(1012):368-376.
To evaluate the accuracy of 64-slice CT angiography (CTA) compared with single photon emission CT (SPECT) myocardial perfusion imaging (MPI), which served as the reference standard, for the detection of functionally significant coronary artery disease (CAD).
141 consecutive patients (60±10 years, 101 men) were investigated with 64-slice CTA and SPECT MPI; a subset of 35 patients had additional invasive coronary angiography (ICA). The data from CTA and ICA were compared with those from MPI for both cut-offs of ≥50% and ≥70% stenosis, respectively.
The sensitivity, specificity, positive and negative predictive values, and accuracy of CTA, using a cut-off of ≥50% for significant stenosis, in detecting inducible perfusion defects on MPI were 96% [95% confidence interval (CI) 88–100%], 61% (95% CI 52–70%), 37% (95% CI 23–49%), 99% (95% CI 97–100%) and 68%, respectively, in patient-based analysis and 97% (95% CI 91–100%), 86% (95% CI 83–89%), 33% (95% CI 24–42%), 100% (95% CI 99–100%) and 87%, respectively, in vessel-based analysis. Applying a cut-off of ≥70% for significant stenosis, CTA yielded the following sensitivity, specificity, positive and negative predictive values, and accuracy for the detection of inducible MPI defects: by patient, 65% (95% CI 46–84%), 95% (95% CI 91–99%), 74% (95% CI 50–92%), 92% (95% CI 87–97%) and 89%, respectively; by vessel, 58% (95% CI 42–74%), 97% (95% CI 95–99%), 62% (95% CI 45–79%), 97% (95% CI 95–99%) and 95%, respectively.
64-slice CTA is a reliable tool to exclude functionally significant CAD when using a cut-off of ≥50% diameter stenosis. By contrast, a cut-off of ≥70% diameter narrowing is a strong predictor of ischaemia.
PMCID: PMC3486657  PMID: 21224298
13.  Minimizing shoulder syndrome with intra-operative spinal accessory nerve monitoring for neck dissection 
The objective of this study was to analyze the safety and results of intra-operative SAN (spinal accessary nerve) monitoring during selective neck dissection, with emphasis on shoulder syndrome. Twenty-five consecutive patients with head and neck cancer were studied. Selective neck dissection was performed by a single clinical fellow under the supervision of the department chief using an intra-operative SAN monitor. Electrophysiological data were recorded after initial identification of the SAN and continued until just before closure. Electromyographic evaluation was carried out to assess SAN function one month postoperatively. Shoulder disability was also evaluated at this time using a questionnaire for shoulder syndrome (shrug, flexion, abduction, winging, and pain). No patients had postoperative shoulder syndrome involving shrug, flexion, abduction, or winging. Twenty-two of the 25 (88%) patients had shoulder pain, but the average pain score was low (2.3 ± 1.3). No patients had neck recurrence during at least 1 year of follow up. By using nerve monitoring during selective neck dissection, no patient developed significant "shoulder syndrome", with the exception of slight pain.
PMCID: PMC3665377  PMID: 23853398
Head and neck; Selective neck dissection; Axonal injury; Spinal accessory nerve; Electrophysiology
14.  Retinopathy in a patient with Fanconi anemia and vitamin B12 deficiency 
Eye  2011;26(2):331.
PMCID: PMC3272190  PMID: 22056860
15.  Identification and Quantification of Dimethylamylamine in Geranium by Liquid Chromatography Tandem Mass Spectrometry 
A sensitive and reliable method of liquid chromatography–electrospray ionization/tandem mass spectrometry (LC-ESI/MS/ MS) was developed and validated for determining 1,3-dimethylamylamine (1,3-DMAA) and 1,4-dimethylamylamine (1,4-DMAA) in geranium plants (Pelargonium graveolens). The sample was extracted with 0.5 M HCl and purified by liquid-liquid partition with hexane. The parameters for reverse-phase (C18) LC and positive ESI/MS/MS were optimized. The matrix effect, specificity, linearity, precision, accuracy and reproducibility of the method were determined and evaluated. The method was linear over a range of 0.10–10.00 ng/mL examined, with R2 of 0.99 for both 1,3-DMAA and 1,4-DMAA. The recoveries from spiked concentrations between 5.00–40.00 ng/g were 85.1%–104.9% for 1,3-DMAA, with relative standard deviation (RSD) of 2.9%–11.0%, and 82.9%–101.8% for 1,4-DMAA, with RSD of 3.2%–11.7%. The instrument detection limit was 1–2 pg for both DMAAs. The quantification limit was estimated to be 1–2 ng/g for the plant sample. This method was successfully applied to the quantitative determination of 1,3- and 1,4-DMAA in both geranium plant and geranium oil.
PMCID: PMC3422085  PMID: 22915838
1,3-dimethylamylamine; 1,4-dimethylamylamine; geranium (Pelargonium graveolens); liquid chromatography-tandem mass spectrometry (LC/MS/MS)
17.  Differing Neisseria gonorrhoeae Bacterial Loads in the Pharynx and Rectum in Men Who Have Sex with Men: Implications for Gonococcal Detection, Transmission, and Control ▿  
Journal of Clinical Microbiology  2011;49(12):4304-4306.
The bacterial loads for gonococcal infections of the pharynx and rectum were determined among men with male sexual partners. The median bacterial load for rectal infections (18,960 copies/swab) was significantly higher than the load for pharyngeal infections (2,100 copies/swab; P = 0.001). Bacterial loads among men with symptomatic proctitis were strikingly high (median, 278,000 copies/swab).
PMCID: PMC3232985  PMID: 21956992
18.  Ciliary Blood Flow and Aqueous Humor Production 
Aqueous humor production is a metabolically active process sustained by the delivery of oxygen and nutrients and removal of metabolic waste by the ciliary circulation. This article describes our investigations into the relationship between ciliary blood flow and aqueous humor production. The results presented indicate that there is a dynamic relationship between ciliary blood flow and aqueous humor production, with production being blood flow independent above a critical level of perfusion, and blood flow dependent below it. The results also show that the plateau portion of the relationship shifts up or down depending on the level of secretory stimulation or inhibition, and that oxygen is one critical factor provided by ciliary blood flow. Also presented is a theoretical model of ocular hydrodynamics incorporating these new findings.
PMCID: PMC3010334  PMID: 20801226
Ciliary blood flow; Aqueous humor production; Aqueous humor dynamics; Intraocular pressure
19.  Sprouty 2 Binds ESCRT-II Factor Eap20 and Facilitates HIV-1 Gag Release ▿  
Journal of Virology  2011;85(14):7353-7362.
The four ESCRT (endocytic sorting complexes required for transport) complexes (ESCRT-0, -I, -II, and -III) normally operate sequentially in the trafficking of cellular cargo. HIV-1 Gag trafficking and release as virus-like particles (VLPs) require the participation of ESCRTs; however, its use of ESCRTs is selective and nonsequential. Specifically, Gag trafficking to release sites on the plasma membrane does not require ESCRT-0 or -II. It is known that a bypass of ESCRT-0 is achieved by the direct linkage of the ESCRT-I component, Tsg101, to the primary L domain motif (PTAP) in Gag and that bypass of ESCRT-II is achieved by the linkage of Gag to ESCRT-III through the adaptor protein Alix. However, the mechanism by which Gag suppresses the interaction of bound ESCRT-I with ESCRT-II is unknown. Here we show (i) that VLP release requires the steady-state level of Sprouty 2 (Spry2) in COS-1 cells, (ii) that Spry2 binds the ESCRT-II component Eap20, (iii) that binding Eap20 permits Spry2 to disrupt ESCRT-I interaction with ESCRT-II, and (iv) that coexpression of Gag with a Spry2 fragment that binds Eap20 increases VLP release. Spry2 also facilitated release of P7L-Gag (i.e., release in the absence of Tsg101 binding). In this case, rescue required the secondary L domain (YPXnL) in HIV-1 Gag that binds Alix and the region in Spry2 that binds Eap20. The results identify Spry2 as a novel cellular factor that facilitates release driven by the primary and secondary HIV-1 Gag L domains.
PMCID: PMC3126580  PMID: 21543492
20.  Intensity-modulated radiotherapy increases dose to the brachial plexus compared with conventional radiotherapy for head and neck cancer 
The British Journal of Radiology  2011;84(997):58-63.
The preferential use of intensity-modulated radiotherapy (IMRT) over conventional radiotherapy (CRT) in the treatment of head and neck cancer has raised concerns regarding dose to non-target tissue. The purpose of this study was to compare dose-volume characteristics with the brachial plexus between treatment plans generated by IMRT and CRT using several common treatment scenarios.
The brachial plexus was delineated on radiation treatment planning CT scans from 10 patients undergoing IMRT for locally advanced head and neck cancer using a Radiation Therapy Oncology Group-endorsed atlas. No brachial plexus constraint was used. For each patient, a conventional three-g0ield shrinking-g0ield plan was generated and the dose-volume histogram (DVH) for the brachial plexus was compared with that of the IMRT plan.
The mean irradiated volumes of the brachial plexus using the IMRT vs the CRT plan, respectively, were as follows: V50 (18±5 ml) vs (11±6 ml), p = 0.01; V60 (6±4 ml) vs (3±3 ml), p = 0.02; V66 (3±1 ml) vs (1±1 ml), p = 0.04, V70 (0±1 ml) vs (0±1 ml), p = 0.68. The maximum point dose to the brachial plexus was 68.9 Gy (range 62.3–78.7 Gy) and 66.1 Gy (range 60.2–75.6 Gy) for the IMRT and CRT plans, respectively (p = 0.01).
Dose to the brachial plexus is significantly increased among patients undergoing IMRT compared with CRT for head and neck cancer. Preliminary studies on brachial plexus-sparing IMRT are in progress.
PMCID: PMC3473798  PMID: 20858665
21.  Overstaging of cartilage invasion by multidetector CT scan for laryngeal cancer and its potential effect on the use of organ preservation with chemoradiation 
The British Journal of Radiology  2011;84(997):64-69.
The two currently acceptable treatment options for locally advanced laryngeal cancer are total laryngectomy and organ preservation using chemoradiation. To facilitate therapeutic decision making, the accurate pre-treatment evaluation of cartilage invasion is of paramount importance. The purpose of this study was to evaluate the positive predictive value (PPV) and negative predictive value (NPV) of detecting neoplastic cartilage invasion in laryngeal cancer patients using fast-speed multidetector CT (MDCT).
61 consecutive patients with clinically staged T3 or T4 squamous cell carcinoma of the larynx or hypopharynx who underwent total laryngectomy were analysed. All patients had MDCT of the neck within 2 weeks prior to surgery. Central radiographic and pathological review was performed in an attempt to correlate findings. MDCT invasion of cartilage was graded based on objective criteria.
MDCT scan was found to have a PPV of 78% and an NPV of 100% for detection of invasion through cartilage, with sensitivity being 100% and specificity 96%. For detection of any cartilage invasion (minor, major or through cartilage invasion), PPV and NPV were 63% and 92%, respectively. The sensitivity was 85% and specificity was 75%. For the detection of tumour invasion through cartilage or major cartilage invasion, MDCT scan had a PPV of 53% and an NPV of 95%. 47% (9/19) patients were down-staged from T4 to T3 after central pathology review.
The low PPV for cartilage destruction using MDCT suggests that a significant proportion of patients who were treated by total laryngectomy could have been appropriately offered organ preservation if more accurately staged at initial diagnosis.
PMCID: PMC3473799  PMID: 20858661
22.  A flow cytometry based assay to assess RSV specific neutralizing antibody is reproducible, efficient and accurate 
Journal of immunological methods  2010;362(1-2):180-184.
Respiratory syncytial virus (RSV) is an important cause of respiratory infection in people of all ages, and is the leading cause of hospitalization in infants. Although commercially available monoclonal antibody is available for passive prophylaxis of neonates at risk of severe disease, there is no available vaccine to prevent RSV. Measurement of neutralizing activity will be a key endpoint for vaccine evaluation. Assessment of neutralizing antibody against RSV has been limited to traditional plaque reduction, which is time consuming and inherently operator dependent and highly variable. Here, we describe a flow cytometry-based RSV-specific neutralization assay which is more rapid than traditional methods, highly sensitive and highly reproducible.
PMCID: PMC2964415  PMID: 20727896
23.  Detection of p53 Phosphorylation and Oligomerization Using Proximity Ligation Assay 
The tumor suppressor protein p53 is one of the most studied architects of transcription control in cells. Recent reports detail crucial tertiary structural requirements for p53 influence in transcription regulation complexes. These findings indicate the tetrameric assembly of p53 protein is essential for stabilization and localization of the protein. This event is critical for DNA binding and transcriptional activation. Post-translational modifications (PTM) have been linked to activation of p53 function in response to genotoxic stress. In particular, phosphorylation of the p53 Ser-15 is a critical event in the genotoxic pathway cascade. We investigate the interconnection between this PTM and p53 higher order structure formation. We employ a novel antibody binding assay scheme to elucidate details of the multimeric status of p53 in both recombinant p53 protein experiments and in cells undergoing genotoxic responses. This approach utilizes the Proximity Ligation Assay (PLA) to simultaneously query the role of Ser-15 phosphorylation and the multimeric state of p53. By use of a phospho-Ser-15 specific monoclonal antibody PLA probe, we quantify proximity of two individual phospho-Ser-15 motifs in experimental samples. Our results demonstrate that phospho-Ser15 promotes multimerization of p53 protein both in vitro and in cells responding to genotoxic stress. Further studies using PLA to explore the p53 protein-protein interactome should reveal a more complete view of the downstream interplay facilitated by the tetrameric conformation.
PMCID: PMC3186609
24.  Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol 
Diabetologia  2011;54(10):2506-2514.
Type 2 diabetes is regarded as inevitably progressive, with irreversible beta cell failure. The hypothesis was tested that both beta cell failure and insulin resistance can be reversed by dietary restriction of energy intake.
Eleven people with type 2 diabetes (49.5 ± 2.5 years, BMI 33.6 ± 1.2 kg/m2, nine male and two female) were studied before and after 1, 4 and 8 weeks of a 2.5 MJ (600 kcal)/day diet. Basal hepatic glucose output, hepatic and peripheral insulin sensitivity and beta cell function were measured. Pancreas and liver triacylglycerol content was measured using three-point Dixon magnetic resonance imaging. An age-, sex- and weight-matched group of eight non-diabetic participants was studied.
After 1 week of restricted energy intake, fasting plasma glucose normalised in the diabetic group (from 9.2 ± 0.4 to 5.9 ± 0.4 mmol/l; p = 0.003). Insulin suppression of hepatic glucose output improved from 43 ± 4% to 74 ± 5% (p = 0.003 vs baseline; controls 68 ± 5%). Hepatic triacylglycerol content fell from 12.8 ± 2.4% in the diabetic group to 2.9 ± 0.2% by week 8 (p = 0.003). The first-phase insulin response increased during the study period (0.19 ± 0.02 to 0.46 ± 0.07 nmol min−1 m−2; p < 0.001) and approached control values (0.62 ± 0.15 nmol min−1 m−2; p = 0.42). Maximal insulin response became supranormal at 8 weeks (1.37 ± 0.27 vs controls 1.15 ± 0.18 nmol min−1 m−2). Pancreatic triacylglycerol decreased from 8.0 ± 1.6% to 6.2 ± 1.1% (p = 0.03).
Normalisation of both beta cell function and hepatic insulin sensitivity in type 2 diabetes was achieved by dietary energy restriction alone. This was associated with decreased pancreatic and liver triacylglycerol stores. The abnormalities underlying type 2 diabetes are reversible by reducing dietary energy intake.
PMCID: PMC3168743  PMID: 21656330
Insulin secretion; Liver fat; Low energy diet; Pancreatic fat; Type 2 diabetes
25.  Perinatal choline supplementation improves cognitive functioning and emotion regulation in the Ts65Dn mouse model of Down syndrome 
Behavioral neuroscience  2010;124(3):346-361.
In addition to mental retardation, individuals with Down syndrome (DS) also develop the neuropathological changes typical of Alzheimer’s disease (AD) and the majority of these individuals become demented. The Ts65Dn mouse model of DS exhibits key features of these disorders, including early degeneration of cholinergic basal forebrain (CBF) neurons and impairments in functions dependent on the two CBF projection systems; namely, attention and explicit memory. Herein, we demonstrate that supplementing the maternal diet with excess choline during pregnancy and lactation dramatically improved attentional function of the adult trisomic offspring. Specifically, the adult offspring of choline-supplemented Ts65Dn dams performed significantly better than unsupplemented Ts65Dn mice on a series of five visual attention tasks, and in fact, on some tasks did not differ from the normosomic (2N) controls. A second area of dysfunction in the trisomic animals, heightened reactivity to committing an error, was partially normalized by the early choline supplementation. The 2N littermates also benefited from increased maternal choline intake on one attention task. These findings collectively suggest that perinatal choline supplementation might significantly lessen cognitive dysfunction in DS and reduce cognitive decline in related neurodegenerative disorders such as AD.
PMCID: PMC2955960  PMID: 20528079
Down syndrome; choline-early exposure delayed effects; Alzheimer’s Disease; Attention; Emotion regulation; Arousal

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