Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy followed by minimally invasive esophagectomy for locally advanced esophageal squamous cell carcinoma: a prospective multicenter randomized clinical trial.

BACKGROUND: Neoadjuvant therapy is recommended for locally advanced esophageal cancer, but the optimal strategy remains unclear. We aimed to evaluate the safety and efficacy of neoadjuvant chemoradiotherapy (nCRT) versus neoadjuvant chemotherapy (nCT) followed by minimally invasive esophagectomy (MIE) for locally advanced esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Eligible patients staged as cT3-4aN0-1M0 ESCC were randomly assigned (1 : 1) to the nCRT or nCT group stratified by age, cN stage, and centers. The chemotherapy, based on paclitaxel and cisplatin, was administered to both groups, while concurrent radiotherapy was added for the nCRT group; then MIE was carried out. The primary endpoint was 3-year overall survival. This study is registered with ClinicalTrials.gov (NCT03001596). RESULTS: A total of 264 patients were eligible for the intention-to-treat analysis. By 30 November 2021, 121 deaths had occurred. The median follow-up was 43.9 months (interquartile range 36.6-49.3 months). The overall survival in the intention-to-treat population was comparable between the nCRT and nCT strategies [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.58-1.18; P = 0.28], with a 3-year survival rate of 64.1% (95% CI 56.4% to 72.9%) versus 54.9% (95% CI 47.0% to 64.2%), respectively. There were also no differences in progression-free survival (HR 0.83, 95% CI 0.59-1.16; P = 0.27) and recurrence-free survival (HR 1.07, 95% CI 0.71-1.60; P = 0.75), although the pathological complete response in the nCRT group (31/112, 27.7%) was significantly higher than that in the nCT group (3/104, 2.9%; P < 0.001). Besides, a trend of lower risk of recurrence was observed in the nCRT group (P = 0.063), while the recurrence pattern was similar (P = 0.802). CONCLUSIONS: NCRT followed by MIE was not associated with significantly better overall survival than nCT among patients with cT3-4aN0-1M0 ESCC. The results underscore the pending issue of the best strategy of neoadjuvant therapy for locally advanced bulky ESCC.

Exosome-mediated transfer of MIF confers temozolomide resistance by regulating TIMP3/PI3K/AKT axis in gliomas.

Temozolomide (TMZ) resistance is an important cause of clinical treatment failure and poor prognosis in gliomas. Increasing evidence indicates that cancer-derived exosomes contribute to chemoresistance; however, the specific contribution of glioma-derived exosomes remains unclear. The aim of this study was to explore the role and underlying mechanisms of exosomal macrophage migration inhibitory factor (MIF) on TMZ resistance in gliomas. We first demonstrated that MIF was upregulated in the exosomes of TMZ-resistant cells, engendering the transfer of TMZ resistance to sensitive cells. Our results indicated that exosomal MIF conferred TMZ resistance to sensitive cells through the enhancement of cell proliferation and the repression of cell apoptosis upon TMZ exposure. MIF knockdown enhanced TMZ sensitivity in resistant glioma cells by upregulating Metalloproteinase Inhibitor 3 (TIMP3) and subsequently suppressing the PI3K/AKT signaling pathway. Additionally, exosomal MIF promoted tumor growth and TMZ resistance of glioma cells in vivo, while IOS-1 (MIF inhibitor) promotes glioma TMZ sensitive in vivo. Taken together, our study demonstrated that exosome-mediated transfer of MIF enhanced TMZ resistance in glioma through downregulating TIMP3 and further activating the PI3K/AKT signaling pathway, highlighting a prognostic biomarker and promising therapeutic target for TMZ treatment in gliomas.

De novo subacute cutaneous lupus erythematosus-like eruptions in the setting of programmed death-1 or programmed death ligand-1 inhibitor therapy: clinicopathological correlation.

Immune checkpoint inhibitors (ICI) may cause eruptions resembling cutaneous autoimmune diseases. There are six cases of immunotherapy-associated subacute cutaneous lupus erythematosus (SCLE) in the literature. We present details of five patients referred to the Skin Toxicity Program at the Dana-Farber Cancer Institute/Brigham and Women's Cancer Center who developed de novo immunotherapy-associated SCLE-like eruptions, along with clinicopathological correlation and highlight potential mechanistic features and important diagnostic points. Two patients were maintained on topical corticosteroids, antihistamines and photoprotection. One had complete clearance and two had improvement with addition of hydroxychloroquine. Four patients continued their immunotherapy uninterrupted, while one had immunotherapy suspended for a month before restarting at full dose. Histopathologically, this series illustrates the temporal evolution of ICI-induced immune cutaneous reactions with SCLE subtype. Looking beyond the universally present lichenoid infiltrate, features of evolving SCLE were evident. We hypothesize that programmed death-1 blockade may induce immunological recognition of previously immunologically tolerated drug antigens, leading to epitope spreading and the SCLE phenotype.

Pityriasis rubra pilaris-like erythroderma secondary to phosphoinositide 3-kinase inhibition.

BACKGROUND: Phosphoinositide 3-kinase (PI3K) inhibitors are a class of small-molecule inhibitors approved for the treatment of certain leukaemias and lymphomas. Their dermatological adverse event profile is poorly described. AIM: To characterize a rare cutaneous adverse event from PI3K inhibitors in order to help dermatologists and oncologists identify and effectively manage such eruptions. METHODS: This was a retrospective analysis of patients receiving PI3K inhibitors referred to the Skin Toxicities Program in The Center for Cutaneous Oncology. RESULTS: Three patients on PI3K inhibitors for treatment of malignancy developed diffuse erythroderma and keratoderma. Clinical and histopathological findings were consistent with pityriasis rubra pilaris (PRP)-like reactions. All patients improved with topical and oral corticosteroids, oral acitretin, and drug discontinuation. CONCLUSIONS: PRP-like cutaneous eruptions may develop secondary to PI3K inhibition. Early dermatological evaluation of cutaneous toxicities to PI3K inhibitors as well as rapid initiation of disease-specific treatments may help keep patients on life-prolonging anti-cancer therapies.

Human Umbilical Cord Mesenchymal Stem Cells: Subpopulations and Their Difference in Cell Biology and Effects on Retinal Degeneration in RCS Rats.

BACKGROUND: Human umbilical cord mesenchymal stem cells (hUC-MSCs) are potential candidates for treating retinal degeneration (RD). OBJECTIVE: To further study the biology and therapeutic effects of the hUC-MSCs on retinal degeneration. METHODS: Two hUC-MSC subpopulations, termed hUC-MSC1 and hUC-MSC2, were isolated by single-cell cloning method and their therapeutic functions were compared in RCS rat, a RD model. RESULTS: Although both subsets satisfied the basic requirements for hUC-MSCs, they were significantly different in morphology, proliferation rate, differentiation capacity, phenotype and gene expression. Furthermore, only the smaller, fibroblast-like, faster growing subset hUC-MSC1 displayed stronger colony forming potential as well as adipogenic and osteogenic differentiation capacities. When the two subsets were respectively transplanted into the subretinal spaces of RCS rats, both subsets survived, but only hUC-MSC1 expressed RPE cell markers Bestrophin and RPE65. More importantly, hUC-MSC1 showed stronger rescue effect on the retinal function as indicated by the higher b-wave amplitude on ERG examination, thicker retinal nuclear layer, and decreased apoptotic photoreceptors. When both subsets were treated with interleukin-6, mimicking the inflammatory environment when the cells were transplanted into the eyes with degenerated retina, hUC-MSC1 expressed much higher levels of trophic factors in comparison with hUC-MSC2. CONCLUSION: The data here, in addition to prove the heterogeneity of hUC-MSCs, confirmed that the stronger therapeutic effects of hUC-MSC1 were attributed to its stronger anti-apoptotic effect, paracrine of trophic factors and potential RPE cell differentiation capacity. Thus, the subset hUC-MSC1, not the other subset or the ungrouped hUC-MSCs should be used for effective treatment of RD.

Influence and significance of intervening diabetes microRNA expression profile of NOD mice with exendin-4.

OBJECTIVE: To provide selectable microRNA for intervening diabetes mellitus diseases, NOD mice's expression of microRNA in pancreas tissues and blood under the exendin-4 intervention of was observed and the difference of microRNA target gene was screened. MATERIALS AND METHODS: Forty clean NOD mice were randomly divided into four groups (in each group, n = 10): One is blank control group D which is intervened with normal saline, and the other three groups were divided into low-dose group A, middle-dose group B, and high-dose group C according to the different exendin-4 dosage 2, 4, and 8 µg/kg·d. After the 8-week intervention, these four groups were killed, and the pancreatic tissue and blood were left to prepare specimens for morphology and molecular biology analysis. The specimen with differential expression microRNA in pancreas tissue and blood should be screened out after detected with the locked nucleic acid array system (LNATM) microRNA expression profile chip. The primers should be designed, and the ABI7500 real-time fluorescent quantitative PCR should be applied to amplify, analyze, and verify according to the screen results of the microRNA chip in order to screen out the significant differentially expressed microRNA. RESULTS: Histological detection showed that the pancreas of the mice in control group D was fibrosis gradually and the islet frame was relatively disordered and significantly atrophied. Groups A, B, and C have no islet hypertrophy or atrophy and the degree of fibrosis of the pancreas has reduced. According to the gene chip detection, there are four significantly differently expressed microRNAs in pancreas tissue and blood among the group A, B, and C, among which miR-19a, miR-19b, and miR-22 were downregulated expressed while the miRNA-1 was upregulated expressed. Bioinformatics analysis showed that the target genes of 4 differentially regulated microRNA genes were related to cell proliferation, apoptosis, glucose metabolism, and angiogenesis. The expression of microRNA in pancreatic tissue and blood of NOD rats was highly consistent. CONCLUSIONS: MicroRNA expression file of pancreatic tissue and blood can be changed during the intervention of the NOD rat model with exendin-4. MicroRNA that indicates the differential expression may take part in the recovering process of the NOD pancreatic trauma. At the same time, the administration of exendin-4 can protect NOD mice, reduce its pancreatic tissue fibrosis, and regulate molecular markers of pancreatic cells in size and pancreatic mast cells. This may be one of the main mechanisms of pancreatic injury in diabetes prevention.

Subpopulations of Bone Marrow Mesenchymal Stem Cells Exhibit Differential Effects in Delaying Retinal Degeneration.

Bone marrow mesenchymal stem cells (BMSCs) have a therapeutic role in retinal degeneration (RD). However, heterogeneity of BMSCs may be associated with differential therapeutic effects in RD. In order to confirm this hypothesis, two subsets of rat BMSCs, termed rBMSC1 and rBMSC2, were obtained, characterized and functionally evaluated in the treatment of RD of Royal College of Surgeons (RCS) rats. Both subpopulations expressed mesenchymal stem cells (MSC) markers CD29 and CD90, but were negative for hemacyte antigen CD11b and CD45 expression. In comparison with rBMSC2, rBMSC1 showed higher rate of proliferation, stronger colony formation, and increased adipogenic potential, whereas rBMSC2 exhibited higher osteogenic potential. Microarray analysis showed differential gene expression patterns between rBMSC1 and rBMSC2, including functions related to proliferation, differentiation, immunoregulation, stem cell maintenance and division, survival and antiapoptosis. After subretinal transplantation in RCS rats, rBMSC1 showed stronger rescue effect than rBMSC2, including increased b-wave amplitude, restored retinal nuclear layer thickness, and decreased number of apoptotic photoreceptors, whereas the rescue function of rBMSC2 was essentially not better than the control. Histological analysis also demonstrated that rBMSC1 possessed a higher survival rate than rBMSC2 in subretinal space. In addition, treatment of basic fibroblast growth factor, an accompanying event in subretinal injection, triggered more robust increase in secretion of growth factors by rBMSC1 as compared to rBMSC2. Taken together, these results have suggested that the different therapeutic functions of BMSC subpopulations are attributed to their distinct survival capabilities and paracrine functions. The underlying mechanisms responsible for the different functions of BMSC subpopulation may lead to a new strategy for the treatment of RD.

Human Adipose-Derived Stem Cells Delay Retinal Degeneration in Royal College of Surgeons Rats Through Anti-Apoptotic and VEGF-Mediated Neuroprotective Effects.

UNLABELLED: Stem cell therapy is a promising therapeutic approach for retinal degeneration (RD). Our study investigated the effects of human adipose derived stem cell (hADSCs) on Royal College of Surgeons (RCS) rats. METHODS: Green fluorescent protein (GFP)-labeled hADSCs were transplanted subretinally into RCS rats at postnatal (PN) 21 days to explore potential therapeutic effects, while adeno-associated viral vector (AAV2)-vascular endothelial growth factor (VEGF) and siVEGF-hADSCs were used to aid the mechanistic dissections. Visual function was evaluated by Electroretinogram (ERG) recording. Potential transdifferentiations were examined by Immunofluorescence (IF) and gene expressions were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Apoptotic retinal cells were detected by Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) assay and the cytokines secreted by hADSCs were measured by Enzyme-linked Immunosorbent Assay (ELISA). RESULTS: The visual function of RCS rats began to decrease one week after their eyes opened at PN week 3 and almost lost in PN 5 weeks, accompanied by the loss of retinal outer nuclear layer (ONL). Subretinal transplantation of hADSCs significantly improved the visual function 2 weeks after the transplantation and such therapeutic effect persisted up to 8 weeks after the treatment (PN 11 weeks), with 3-4 rows of photoreceptors remained in the ONL and reduced apoptosis. Consistent with these phenotypic changes, the gene expression of rod photoreceptor markers Rhodopsin (Rho), Crx and Opsin (Opn1) in RCS rats showed obvious decreasing trends over time after PN 3 weeks, but were elevated with hADSC treatment. hADSC transplantation also repressed the expressions of Bax, Bak and Caspase 3, but not the expression of anti-apoptotic genes, including Bcl-2 and Bcl-XL. Finally, substantial VEGF, hepatocyte growth factor (HGF) and pigment epithelium-derived factor (PEDF) secretions from hADSCs were detected, while endogenous Vegf expression level decreased over time in RCS rats. The treatment of AAV2-VEGF showed comparable therapeutic effects as hADSCs but siRNA knockdown of VEGF in hADSCs essentially abolished the therapeutic effects. CONCLUSIONS: Subretinal transplantation of hADSCs in RCS rats effectively delayed the retinal degeneration, enhanced the retinal cell survival and improved the visual function. Mechanistically this was mainly due to hADSC dependent anti-apoptotic and neuroprotective effects through its secretion of growth and neurotrophic factors including VEGF. Clinical application of hADSCs merits further investigation.

Codominant Role of Interferon-γ- and Interleukin-17-Producing T Cells During Rejection in Full Facial Transplant Recipients.

Facial transplantation is a life-changing procedure for patients with severe composite facial defects. However, skin is the most immunogenic of all transplants, and better understanding of the immunological processes after facial transplantation is of paramount importance. Here, we describe six patients who underwent full facial transplantation at our institution, with a mean follow-up of 2.7 years. Seum, peripheral blood mononuclear cells, and skin biopsy specimens were collected prospectively, and a detailed characterization of their immune response (51 time points) was performed, defining 47 immune cell subsets, 24 serum cytokines, anti-HLA antibodies, and donor alloreactivity on each sample, producing 4269 data points. In a nonrejecting state, patients had a predominant T helper 2 cell phenotype in the blood. All patients developed at least one episode of acute cellular rejection, which was characterized by increases in interferon-γ/interleukin-17-producing cells in peripheral blood and in the allograft's skin. Serum monocyte chemotactic protein-1 level was significantly increased during rejection compared with prerejection time points. None of the patients developed de novo donor-specific antibodies, despite a fourfold expansion in T follicular helper cells at 1 year posttransplantation. In sum, facial transplantation is frequently complicated by a codominant interferon-γ/interleukin-17-mediated acute cellular rejection process. Despite that, medium-term outcomes are promising with no evidence of de novo donor-specific antibody development.

Oscillation in tissue oxygen index during recovery from exercise.

It was hypothesized that an oscillation of tissue oxygen index (TOI) determined by near-infrared spectroscopy during recovery from exercise occurs due to feedback control of adenosine triphosphate and that frequency of the oscillation is affected by blood pH. In order to examine these hypotheses, we aimed 1) to determine whether there is an oscillation of TOI during recovery from exercise and 2) to determine the effect of blood pH on frequency of the oscillation of TOI. Three exercises were performed with exercise intensities of 30 % and 70 % peak oxygen uptake (V(.)o(2)peak) for 12 min and with exercise intensity of 70 % V(.)o(2)peak for 30 s. TOI during recovery from the exercise was analyzed by fast Fourier transform in order to obtain power spectra density (PSD). There was a significant difference in the frequency at which maximal PSD of TOI appeared (Fmax) between the exercises with 70 % V(.)o(2)peak for 12 min (0.0039+/-0 Hz) and for 30 s (0.0061+/-0.0028 Hz). However, there was no significant difference in Fmax between the exercises with 30 % (0.0043+/-0.0013 Hz) and with 70 % V(.)o(2)peak for 12 min despite differences in blood pH and blood lactate from the warmed fingertips. It is concluded that there was an oscillation in TOI during recovery from the three exercises. It was not clearly shown that there was an effect of blood pH on Fmax.

Targeting heat-shock protein 90 with ganetespib for molecularly targeted therapy of gastric cancer.

Gastric cancer (GC) remains the fifth most common cancer worldwide. Heat-shock protein 90 (HSP90) has become an attractive therapeutic target in treating cancers, because of its abnormally high expression in cancers. Several successful cases of HSP90 inhibitors capable of inhibiting GC inspired us to try ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor in GC treatment. In our study, we show that ganetespib markedly reduced the growth of MGC-803 and also significantly inhibited the growth of SGC-7901 and MKN-28 in a dose-dependent manner. It induced G2/M cell-cycle arrest and apoptosis in all three cell lines, together with the related markers affected significantly. Mechanistically, ganetespib caused pronounced decrease of expression of classic HSP90 client proteins. Specifically, it greatly affected epidermal growth factor receptor (EGFR) signaling cascades by markedly decreasing the levels of total EGFR and EGFR on cell membranes. EGFR knockdown also induced cell-cycle arrest and apoptosis accompanied with a decrease of several EGFR downstream proteins. These results strongly support that EGFR signaling greatly contributes to the ganetespib inhibitory effects. Besides, we found that the responses of GC cell lines to ganetespib correlated well with their EGFR expression levels: MGC-803, as well as AGS and BGC-803, with higher EGFR expression responded to ganetespib better, whereas SGC-7901 and MKN-28 with lower EGFR levels were much less sensitive to ganetespib. Although SGC-7901 and MKN-28 were not very sensitive to ganetespib, ganetespib worked synergistically with radiation and cisplatin in killing them. Importantly, ganetespib significantly inhibited the growth of xenograft tumors in vivo as a single agent or in combination with cisplatin. Results of hematoxylin/eosin staining, TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assays, and immunohistochemistry staining of phosphorylated cyclin-dependent kinase 1 (pCDK1), EGFR and Ki-67 revealed significant differences in ganetespib-treated tumors. Collectively, our data suggest that ganetespib, as a new potent treatment option, can be used for the molecularly targeted therapy of GC patients according to their expression profiles of EGFR.

The management of antibody-mediated rejection in the first presensitized recipient of a full-face allotransplant.

We report on the management of the first full-face transplantation in a sensitized recipient with a positive preoperative crossmatch and subsequent antibody-mediated rejection (AMR). The recipient is a 45-year-old female who sustained extensive chemical burns, with residual poor function and high levels of circulating anti-HLA antibodies. With a clear immunosuppression plan and salvage options in place, a full-face allotransplant was performed using a crossmatch positive donor. Despite plasmapheresis alongside a standard induction regimen, clinical signs of rejection were noted on postoperative day 5 (POD5). Donor-specific antibody (DSA) titers rose with evidence of C4d deposits on biopsy. By POD19, biopsies showed Banff Grade III rejection. Combination therapy consisting of plasmapheresis, eculizumab, bortezomib and alemtuzumab decreased DSA levels, improved clinical exam, and by 6 months postop she had no histological signs of rejection. This case is the first to demonstrate evidence and management of AMR in face allotransplantation. Our findings lend support to the call for an update to the Banff classification of rejection in vascularized composite tissue allotransplantation (VCA) to include AMR, and for further studies to better classify the histology and mechanism of action of AMR in VCA.

Long-term dietary sodium restriction increases adiponectin expression and ameliorates the proinflammatory adipokine profile in obesity.

BACKGROUND/AIM: Obesity is associated with changes in adiponectin and pro-inflammatory adipokines. Sodium intake can affect adipokine secretion suggesting a role in cardiovascular dysfunction. We tested if long-term dietary sodium restriction modifies the expression of adiponectin and ameliorates the pro-inflammatory profile of obese, diabetic mice. METHODS/RESULTS: Db/db mice were randomized to high sodium (HS 1.6% Na+, n = 6) or low sodium (LS 0.03% Na+, n = 8) diet for 16 weeks and compared with lean, db/+ mice on HS diet (n = 8). Insulin levels were 50% lower in the db/db mice on LS diet when compared with HS db/db (p < 0.05). LS diet increased cardiac adiponectin mRNA levels in db/db mice by 5-fold when compared with db/db mice on HS diet and by 2-fold when compared with HS lean mice (both p < 0.01). LS diet increased adiponectin in adipose tissue compared with db/db mice on HS diet, achieving levels similar to those of lean mice. MCP-1, IL-6 and TNF-α expression were reduced more than 50% in adipose tissue of db/db mice on LS diet when compared with HS db/db mice (all p < 0.05), to levels observed in the HS lean mice. Further, LS db/db mice had significantly reduced circulating MCP-1 and IL-6 levels when compared with HS db/db mice (both p < 0.01). CONCLUSION: In obese-diabetic mice, long-term LS diet increases adiponectin in heart and adipose tissue and reduces pro-inflammatory factors in adipose tissue and plasma. These additive mechanisms may contribute to the potential cardioprotective benefits of LS diet in obesity-related metabolic disorders.

Functional single nucleotide polymorphism in C20orf54 modifies susceptibility to esophageal squamous cell carcinoma.

The aim of this study was to explore the association of C20orf54 functional single nucleotide polymorphism (SNP) with the susceptibility to esophageal squamous cell carcinoma (ESCC) in a northern China population. The C20orf54 SNP was genotyped by direct sequencing in 240 cancer patients and 198 controls in northern China. The results showed that drinking status, family history of ESCC, and body mass index have great influence on the risk of developing ESCC. The overall genotype frequencies of C20orf54 in ESCC patients have a significant difference with healthy controls (χ(2) = 8.06, P = 0.018). By using C/C genotype as the reference, the C/T genotype showed a significantly decreased risk to the development of ESCC. Thus, compared with the C/C genotype, smokers, drinkers with C/T genotype significantly decreased the risk of developing ESCC. A positive family history of ESCC with C/T and T/T genotype both increased the risk of developing ESCC. Body mass index between 18.5 and 24 with C/T genotype significantly decreased the risk of developing ESCC. The present study suggests that the C20orf54 functional SNP might be associated with a risk of development in ESCC.

Monte Carlo study of the energy response and depth dose water equivalence of the MOSkin radiation dosimeter at clinical kilovoltage photon energies.

Skin dose is often the quantity of interest for radiological protection, as the skin is the organ that receives maximum dose during kilovoltage X-ray irradiations. The purpose of this study was to simulate the energy response and the depth dose water equivalence of the MOSkin radiation detector (Centre for Medical Radiation Physics (CMRP), University of Wollongong, Australia), a MOSFET-based radiation sensor with a novel packaging design, at clinical kilovoltage photon energies typically used for superficial/orthovoltage therapy and X-ray CT imaging. Monte Carlo simulations by means of the Geant4 toolkit were employed to investigate the energy response of the CMRP MOSkin dosimeter on the surface of the phantom, and at various depths ranging from 0 to 6 cm in a 30 × 30 × 20 cm water phantom. By varying the thickness of the tissue-equivalent packaging, and by adding thin metallic foils to the existing design, the dose enhancement effect of the MOSkin dosimeter at low photon energies was successfully quantified. For a 5 mm diameter photon source, it was found that the MOSkin was water equivalent to within 3% at shallow depths less than 15 mm. It is recommended that for depths larger than 15 mm, the appropriate depth dose water equivalent correction factors be applied to the MOSkin at the relevant depths if this detector is to be used for depth dose assessments. This study has shown that the Geant4 Monte Carlo toolkit is useful for characterising the surface energy response and depth dose behaviour of the MOSkin.

A mutation in SART3 gene in a Chinese pedigree with disseminated superficial actinic porokeratosis.

BACKGROUND: Disseminated superficial actinic porokeratosis (DSAP) is an uncommon autosomal dominant chronic disorder of keratinization, characterized by multiple superficial keratotic lesions surrounded by a slightly raised keratotic border. Thus far, although two loci for DSAP have been identified, and the genetic basis and pathogenesis of this disorder have not been elucidated. OBJECTIVES: To determine the locus of DSAP and identify the candidate gene(s) of the disease. METHODS: Genome-wide scan and linkage analysis were performed in a six-generation Chinese family with DSAP. The coding exons of the candidate genes were sequenced to analyse and detect the nucleotide variations. RESULTS: Linkage analysis showed that the maximum two-point lod score of 5.56 was obtained with the marker D12S79 at a recombination fraction theta of 0.00. Haplotype analysis defined the critical region for DSAP between D12S330 and D12S1612 on 12q24.1-24.2. By sequence analysis, we found a Val591Met mutation in SART3 in all affected individuals of the family. CONCLUSION: SART3 is a candidate gene for DSAP, and is possibly involved in the pathogenesis of DSAP.

Satisfaction of orthognathic surgical patients in a Malaysian population.

Thirty-one patients treated at the Faculty of Dentistry, University of Malaya, were assessed for their satisfaction following orthognathic surgery. The female to male ratio was 22:9 with an age range of 17 to 36. Almost all patients (97%) listed appearance as one of their rationales for surgery. More males (78%) than females (59%) wanted functional improvement, while more females (91%) than males (33%) hoped for improvement in self-confidence. All patients reported esthetic improvement while 68% each reported improvement in mastication and self-confidence. Slightly more than half (52%) chose esthetic improvement as the single most important factor resulting in satisfaction. Almost ninety percent of male patients claimed satisfaction with functional improvement, while 68% of those who found satisfaction in improved self-confidence were females. Eighty-seven percent rated their post-surgical changes as being well accepted by their family. The impact of these findings on the success of the surgery and the need to reinforce verbal communication with printed pamphlets are emphasized.

Orthognathic surgery in the University of Malaya.

This is the first review on orthognathic surgery in Malaysia. The records of a total of 84 patients seen between 1977 and 1999 in the Department of Oral and Maxillofacial Surgery of the Faculty of Dentistry, University of Malaya were analysed. Skeletal III deformity formed 85% of the sample with a female dominance of 2 to 1. The patients' age ranged from 17 to 36 years, with a mean of 25.3 years. The common surgical techniques used were combined bilateral sagittal split and Le Fort I osteotomy. The predominant ethnic group was Chinese (n = 58, 69%); followed by Malay (n = 14, 17%) and Indian (n = 12, 14%).