Dynamic FDG-PET in localization of focal epilepsy: A pilot study.

Epilepsy surgery remains underutilized, in part because non-invasive methods of potential seizure foci localization are inadequate. We used high-resolution, parametric quantification from dynamic 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography (dFDG-PET) imaging to locate hypometabolic foci in patients whose standard clinical static PET images were normal. We obtained dFDG-PET brain images with simultaneous EEG in a one-hour acquisition on seven patients with no MRI evidence of focal epilepsy to record uptake and focal radiation decay. Images were attenuation- and motion-corrected and co-registered with high-resolution T1-weighted patient MRI and segmented into 18 regions of interest (ROI) per hemisphere. Tracer uptake was calibrated with a model corrected blood input function with partial volume (PV) corrections to generate tracer parametric maps compared between mean radiation values between hemispheres with z-scores. We identified ROI with the lowest negative z scores (<-1.65 SD) as hypometabolic. Dynamic 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography ( found focal regions of altered metabolism in all cases in which standard clinical FDG-PET found no abnormalities. This pilot study of dynamic FDG-PET suggests that further research is merited to evaluate whether glucose dynamics offer improved clinical utility for localization of epileptic foci over standard static techniques.

Association of PALB2 sequence variants with the risk of familial and early-onset breast cancer in a South-American population.

BACKGROUND: Germline mutations in PALB2 have been identified in approximately 1% of familial breast cancer (BC) in several populations. Nevertheless its contribution in the South-American population is unknown. The goal of this study was to determine the prevalence of PALB2 mutations in the Chilean population. METHODS: 100 Chilean BRCA1/2-negatives familial BC cases were included for the PALB2 mutation analysis. We use conformational sensitive gel electrophoresis and direct sequencing. Using a case-control design, we studied the identified variants in 436 BC cases and 809 controls to evaluate their possible association with BC risk. RESULTS: No pathogenic mutations were detected. We identified three variants, the variant c.1861C > A not previously described was found in one of the 436 cases and none of the 809 controls. The bioinformatic analyses indicate that this variant probably is not pathogenic. PALB2 c.1676A > G (rs152451A/G) and c.2993C > T (rs45551636C/T) variants were significantly associated with increased BC risk only in cases with a strong family history of BC (OR = 1.9 [CI 95% 1.3-2.8] p < 0.01 and OR = 3.3 [CI 95% 1.4-7.3] p < 0.01, respectively). The rs152451A/G-rs45551636C/T composite genotype produce increase of the BC risk in cases with a strong family history of BC (OR = 3.6 [CI 95% 1.7-8.0] p = 0.003). The rs152451-G/rs45551636-C and rs152451-G/rs45551636-T haplotypes were associated with an increased BC risk only in cases with a strong family history of BC (OR = 1.6 [CI 95% 1.0-2.5] p = 0.05 and OR = 3.7 [CI 95% 1.8-7.5] p < 0.001, respectively). CONCLUSION: Our results suggest that PALB2 c.1676A > G and c.2993C > T play roles in BC risk in women with a strong family history of BC.

Gold as an intruder in ZnO nanowires.

Several techniques for obtaining ZnO nanowires (ZnO NWs) have been reported in the literature. In particular, vapour-liquid-solid (VLS) with Au as a catalyst is widely used. During this process, Au impurities in the ZnO NWs can be incorporated accidentally, and for this reason we named these impurities as intruders. It is thought that these intruders may produce interesting alterations in the electronic characteristics of nanowires. In the experiment, it is not easy to detect either Au atoms in these nanowires, or the modification that intruders produce in different electrical, optical and other properties. For this reason, in this density functional theory investigation, the effect of Au intruders on ZnO NWs is analysed. Au extended (thread) and point defects (atoms replacing Zn or O, or Au interstitials) are used to simulate the presence of gold atoms. Optimised geometries, band-gaps and density of states indicate that the presence of small amounts of Au drastically modifies the electronic states of ZnO NWs. The results reported here clearly indicate that small amounts of Au have a strong impact on the electronic properties of ZnO NWs, introducing states in the band edges that may promote transitions in the visible spectral region. The presence of Au as an intruder in ZnO NWs enhances the potential use of this system for photonic and photovoltaic applications.

Association of genetic variants at TOX3, 2q35 and 8q24 with the risk of familial and early-onset breast cancer in a South-American population.

Recent Genome-Wide Association Studies have identified several single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) among women of Asian, European, and African-American ancestry. Nevertheless, the contribution of these variants in the South American population is unknown. Furthermore, there is little information about the effect of these risk alleles in women with early BC diagnosis. In the present study, we evaluated the association between rs3803662 (TOX3, also known as TNRC9), rs13387042 (2q35), and rs13281615 (8q24) with BC risk in 344 Chilean BRCA1/2-negative BC cases and in 801 controls. Two SNPs, rs3803662 and rs13387042, were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC. The risk of BC increased in a dose-dependent manner with the number of risk alleles (P-trend < 0.0001 and 0.0091, respectively). The odds ratios for BC in familial BC and in early-onset non-familial BC were 3.76 (95%CI 1.02-13.84, P = 0.046) and 8.0 (95%CI 2.20-29.04, P = 0.002), respectively, for the maximum versus minimum number of risk alleles. These results indicate an additive effect of the TOX3 rs3803662 and 2q35 rs13387042 alleles for BC risk. We also evaluated the interaction between rs3803662 and rs13387042 SNPs. We observed an additive interaction only in non-familial early-onset BC cases (AP = 0.72 (0.28-1.16), P = 0.001). No significant association was observed for rs13281615 (8q24) with BC risk in women from the Chilean population. The strongly increased risk associated with the combination of low-penetrance risk alleles supports the polygenic inheritance model of BC.

Genetic variants in FGFR2 and MAP3K1 are associated with the risk of familial and early-onset breast cancer in a South-American population.

Genome-Wide Association Studies have identified several loci associated with breast cancer (BC) in populations of different ethnic origins. One of the strongest associations was found in the FGFR2 gene, and MAP3K1 has been proposed as a low-penetrance BC risk factor. In this study, we evaluated the associations among FGFR2 SNPs rs2981582, rs2420946, and rs1219648; and MAP3K1 rs889312, with BC risk in 351 BRCA1/2-negative Chilean BC cases and 802 controls. All the SNPs studied were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC, in a dose-dependent manner. Subjects with 3 risk alleles were at a significantly increased risk of BC compared with subjects with 0-2 risk alleles, in both familial BC and early-onset non-familial BC (OR = 1.47, 95 % CI 1.04-2.07, P = 0.026 and OR = 2.04 95 % CI 1.32-3.24, P < 0.001, respectively). In the haplotype analysis, the FGFR2 rs2981582 T / rs2420946 T / rs1219648 G haplotype (ht2) was associated with a significantly increased BC risk compared with the rs2981582 C / rs2420946 C / rs1219648 A haplotype in familial BC and in non-familial early-onset BC (OR = 1.32, 95 % CI 1.06-1.65, P = 0.012; OR = 1.46, 95 % CI 1.11-1.91, P = 0.004, respectively). When the FGFR2 ht2 and MAP3K1 rs889312 were evaluated as risk alleles, the risk of BC increased in a dose-dependent manner as the number of risk alleles increased (P trend <0.0001), indicating an additive effect. Nevertheless, there is no evidence of an interaction between FGFR2 ht2 and the MAP3K1 rs889312 C allele. These findings suggest that genetic variants in the FGFR2 and MAP3K1 genes may contribute to genetic susceptibility to BC.

Perioperative outcomes of robotic and open partial nephrectomy for moderately and highly complex renal lesions.

PURPOSE: We compared outcomes in patients undergoing robotic vs open partial nephrectomy stratified by moderately and highly complex tumor nephrometry scores. MATERIALS AND METHODS: Patients treated with partial nephrectomy from 2007 to 2010 were grouped by tumor characteristics into low-nephrotomy score 4 to 6, moderate-7 to 9 and high-10 to 12 anatomical complexity cohorts. Lesions with low complexity were excluded from study. Demographic, surgical and pathological outcomes were compared between patients undergoing robotic vs open partial nephrectomy in the moderately and highly complex cohorts. RESULTS: A total of 281 patients, of whom 63.3% were male, with a mean±SD age of 58.1±11.7 years and a mean followup of 21.3±16.3 months underwent partial nephrectomy. Moderately complex lesions were noted in 81 robotic and 136 open partial nephrectomy cases with a mean tumor size of 3.8±2.2 cm. Highly complex lesions were noted in 10 robotic and 54 open partial nephrectomy cases with a mean tumor size of 4.8±3.0 cm. There were no differences between the groups in patient age, race, gender, body mass index or American Society of Anesthesiologists classification. Cases treated with open partial nephrectomy for moderately or highly complex lesions were of higher pathological stage (p=0.02 and 0.01, respectively). The percent change in creatinine and the glomerular filtration rate were similar for robotic and open partial nephrectomy in the moderately and highly complex tumor groups. In patients undergoing robotic vs open partial nephrectomy for moderately complex lesions we noted differences in pathological tumor size (mean 3.2±1.8 vs 4.1±2.3 cm, p<0.0001) and operative time (205.9±52.5 vs 189.5±52.0 minutes, p<0.01) while decreased estimated blood loss (131.3±127.8 vs 256.5±291.3 ml) and hospital length of stay (3.7±1.6 vs 5.6±3.9 days, each p<0.001) were observed in the robotic group. Comparison of highly complex lesions revealed decreased hospital length of stay (2.9±1.4 vs 6.1±4.1 days, p<0.0001) in the robotic partial nephrectomy group. CONCLUSIONS: In our large institutional series of patients with moderate and highly complex solid renal tumors classified by the nephrometry score robotic partial nephrectomy offered comparable perioperative and functional outcomes with the added benefit of decreased hospital length of stay.

Gunshot wounds to the scrotum: a large single-institutional 20-year experience.

UNLABELLED: Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Penetrating trauma to the scrotum often requires operative intervention, with testicular salvage only possible when enough testicular tissue can be re-approximated in the traumatic setting. The present report represents the largest series of gunshot wound trauma to the scrotum in the literature. Further, it validates recommendations of the European Association of Urology guidelines on urological trauma that advocate operative intervention due to minimal rates of patient morbidity and the inherent limitations of scrotal ultrasonography in discerning testicular compromise. OBJECTIVE: To report our 20-year experience of gunshot wounds (GSWs) to the scrotum and outline the management of this traumatic injury. PATIENTS AND METHODS: We queried our institutional database for patients presenting with GSWs to the scrotum between 1985 and 2006. All patients underwent the standard trauma evaluation upon presentation, including physical examination of the external genitalia. Management was dictated by the presence or absence of a penetrating injury to the scrotum and associated traumatic injuries. Nonoperative and operative management of traumatic injury to the scrotum were used. Testicular salvage was performed when anatomically feasible. If testicular salvage was not feasible, an orchiectomy was performed. RESULTS: Scrotal exploration was performed in 91 (94%) patients while six (6%) patients were treated nonoperatively. Testicular injury was found in 44 (48%) patients undergoing exploration, six (7%) of whom had bilateral testicular injuries, which gave a total of 50 injured testicles. Of the injured testicles, 24 (48%) could not be salvaged and required orchiectomy, while 26 (52%) were debrided and repaired. The most common associated genitourinary (GU) injuries were to the corpora cavernosum (n= 20 [21%]) and urethra (n= 10 [10%]). Soft tissue injury of the extremities occurred in 54 patients (56%), representing the most common non-GU-associated injury. Postoperative complications occurred infrequently: one patient (1%) returned for abscess drainage and one (1%) for haematoma evacuation. CONCLUSIONS: The present report confirms that any patient with a penetrating injury to the scrotum should undergo immediate scrotal exploration. A low clinical suspicion for performing additional studies to rule out associated urethral and/or penile injury is clinically warranted. Testicular loss occurs in ≈50% of injured testicles.

Delayed proximal ureteric stricture formation after complex partial nephrectomy.

OBJECTIVE: • To report and review our incidence of delayed ureteric stricture (US) after complex nephron-sparing surgery (NSS). PATIENTS AND METHODS: • Using our institutional kidney cancer database, we identified 720 patients who underwent NSS from 1 January 2000 until 31 December 2010 and identified eleven (1.5%) patients with a delayed US. • Patient and tumour characteristics were reviewed. RESULTS: • Median (range) tumour size and RENAL nephrometry score was 4.1 (2-7.2) cm and 10p (4-11p), respectively. • There were eight of 10 solitary tumours (80%) located in the lower or mid-pole of the kidney. • There were eight of 11 patients with delayed US (72.7%) who experienced a postoperative urinary leak. • There were two of 11 (18.2%) patients who experienced a postoperative retroperitoneal haemorrhage, with one of these patients requiring selective embolization. • All US were in the upper third of the ureter and were diagnosed at a minimum of 10 weeks postoperatively (median 154 days, range 70-400 days). CONCLUSIONS: • US formation is an uncommon and under-reported event after complex NSS. • Risk factors appear to include tumour complexity, imperative indications, mid- or lower pole location, postoperative urinary leak and haemorrhage. • Although uncommon, postoperative US can occur after NSS for complex renal masses, necessitating patient counselling and diligent postoperative surveillance.

The BARD1 Cys557Ser variant and risk of familial breast cancer in a South-American population.

Since the discovery of the BRCA1 and BRCA2 genes, much work has been carried out to identify further breast cancer (BC) susceptibility genes. BARD1 (BRCA1-associated ring domain) was originally identified as a BRCA1-interacting protein but has also been described in tumor-suppressive functions independent of BRCA1. Some association studies have suggested that the BARD1 Cys557Ser variant might be associated with increased risk of BC, but others have failed to confirm this finding. To date, this variant has not been analyzed in Spanish or South-American populations. In this study, using a case-control design, we analyzed the C-terminal Cys557Ser change in 322 Chilean BC cases with no mutations in BRCA1 or BRCA2 and in 570 controls in order to evaluate its possible association with BC susceptibility. BARD1 Cys557Ser was associated with an increased BC risk (P = 0.04, OR = 3.4 [95 % CI 1.2-10.2]) among cases belonging to families with a strong family history of BC. No difference between single cases affected with age <50 years at diagnosis (n = 117) and controls was observed for carriers of Cys/Ser genotype. It is likely that this variant is not involved in BC risk in this group of women. We also analyzed a possible interaction between BARD1 557Ser/XRCC3 241Met variants considering the role of both genes in the maintenance of genome integrity. The combined genotype Cys/Ser-carrier with the XRCC3 241Met allele was associated with an increased BC risk (P = 0.02, OR = 5.01 [95 % CI 1.36-18.5]) among women belonging to families with at least three BC and/or ovarian cancer cases. Our results suggest that BARD1 557Ser and XRCC3 241Met may play roles in BC risk in women with a strong family history of BC. Nevertheless there is no evidence of an interaction between the two SNPs. These findings should be confirmed by other studies and in other populations.

Current status of robot-assisted partial nephrectomy.

The incidence of incidentally diagnosed small renal masses is rising. Although open partial nephrectomy (OPN) remains the reference standard for clinically localized renal lesions, growing experience with minimally invasive PN has demonstrated equivalent oncologic efficacy and improved short-term perioperative outcomes compared to open techniques. Compared to the technically demanding laparoscopic PN (LPN), robotic PN (RPN) overcomes a number of the technical hurdles of LPN with a shorter learning curve, and now has emerged as an attractive minimally invasive treatment option for amenable tumors. Although experience with RPN has been limited to date, early series have demonstrated short-term oncologic outcomes comparable to OPN and equivalent perioperative outcomes to LPN (all ≤ level III evidence). Although prospective evidence would be ideal, clinical trial comparisons with LPN and OPN will be fraught with accrual challenges and are not expected in the near future. This review summarizes the advantages and indications for a robotic approach, operative principles and emerging technologies, early functional and oncologic outcomes, and expected future advances of RPN for localized renal tumors.

Spectrum of BRCA1/2 point mutations and genomic rearrangements in high-risk breast/ovarian cancer Chilean families.

The distribution of BRCA1/2 germline mutations in breast/ovarian cancer (BC/OC) families varies among different populations. In the Chilean population, there are only two reports of mutation analysis of BRCA1/2, and these included a low number of BC and/or OC patients. Moreover, the prevalence of BRCA1/2 genomic rearrangements in Chilean and in other South American populations is unknown. In this article, we present the mutation-detection data corresponding to a set of 326 high-risk families analyzed by conformation-sensitive gel electrophoresis and heteroduplex analysis. To determine the contribution of BRCA1/2 LGRs in Chilean BC patients, we analyzed 56 high-risk subjects with no pathogenic BRCA1/2 point mutations. Germline BRCA1/2 point mutations were found in 23 (7.1%) of the 326 Chilean families. Families which had at least three BC and/or OC cases showed the highest frequency of mutations (15.9%). We identified 14 point pathogenic mutations. Three recurrent mutations in BRCA1 (c.187_188delAG, c.2605_2606delTT, and c.3450_3453delCAAG) and three in BRCA2 (c.4969_4970insTG, c.5374_5377delTATG, and c.6503_6504delTT) contributed to 63.6 and 66.7% of all the deleterious mutations of each gene, which may reflect the presence of region-specific founder effects. Taken together BRCA1/2 recurrent point mutations account for 65.2% (15/23) of the BRCA1/2 (+) families. No large deletions or duplications involving BRCA1/2 were identified in a subgroup of 56 index cases negative for BRCA1/2 point mutations. Our study, which is the largest conducted to date in a South American population, provides a comprehensive analysis on the type and distribution of BRCA1/2 mutations and allelic variants.

Variants in DNA double-strand break repair genes and risk of familial breast cancer in a South American population.

The double-strand break (DSB) DNA repair pathway has been implicated in breast cancer (BC). RAD51 and its paralogs XRCC3 and RAD51D play an important role in the repair of DSB through homologous recombination (HR). Some polymorphisms including XRCC3-Thr241Met, RAD51-135G>C, and RAD51D-E233G have been found to confer increased BC susceptibility. In order to detect novel mutations that may contribute to BC susceptibility, 150 patients belonging to 150 Chilean BRCA1/2-negative families were screened for mutations in XRCC3. No mutations were detected in the XRCC3 gene. In addition, using a case-control design we studied the XRCC3-Thr241Met, and RAD51D-E233G polymorphisms in 267 BC cases and 500 controls to evaluate their possible association with BC susceptibility. The XRCC3 Met/Met genotype was associated with an increased BC risk (P = 0.003, OR = 2.44 [95%CI 1.34-4.43]). We did not find an association between E233G polymorphism and BC risk. We also analyzed the effect of combined genotypes among RAD51-135G>C, Thr241Met, and E233G polymorphisms on BC risk. No interaction was observed between Thr241Met and 135G>C. The combined genotype Thr/Met-E/G was associated with an increased BC risk among women who (a) have a family history of BC, (b) are BRCA1/2-negative, and (c) were <50 years at onset (n = 195) (P = 0.037, OR = 10.5 [95%CI 1.16-94.5]). Our results suggested that the variability of the DNA HR repair genes XRCC3 and RAD51D may play a role in BC risk, but this role may be underlined by a mutual interaction between these genes. These findings should be confirmed in other populations.

Association of common ATM variants with familial breast cancer in a South American population.

BACKGROUND: The ATM gene has been frequently involved in hereditary breast cancer as a low-penetrance susceptibility gene but evidence regarding the role of ATM as a breast cancer susceptibility gene has been contradictory. METHODS: In this study, a full mutation analysis of the ATM gene was carried out in patients from 137 Chilean breast cancer families, of which 126 were BRCA1/2 negatives and 11 BRCA1/2 positives. We further perform a case-control study between the subgroup of 126 cases BRCA1/2 negatives and 200 controls for the 5557G>A missense variant and the IVS38-8T>C and the IVS24-9delT polymorphisms. RESULTS: In the full mutation analysis we detected two missense variants and eight intronic polymorphisms. Carriers of the variant IVS24-9delT, or IVS38-8T>C, or 5557G>A showed an increase in breast cancer risk. The higher significance was observed in the carriers of IVS38-8T>C (OR = 3.09 [95%CI 1.11-8.59], p = 0.024). The IVS24-9 T/(-T), IVS38-8 T/C, 5557 G/A composite genotype confered a 3.19 fold increase in breast cancer risk (OR = 3.19 [95%CI 1.16-8.89], p = 0.021). The haplotype estimation suggested a strong linkage disequilibrium between the three markers (D' = 1). We detected only three haplotypes in the cases and control samples, some of these may be founder haplotypes in the Chilean population. CONCLUSION: The IVS24-9 T/(-T), IVS38-8 T/C, 5557 G/A composite genotype alone or in combination with certain genetic background and/or environmental factors, could modify the cancer risk by increasing genetic instability or by altering the effect of the normal DNA damage response.

A peptide derived from alpha-fetoprotein inhibits the proliferation induced by estradiol in mammary tumor cells in culture.

This study was aimed to obtain additional information on the activity of a cyclized 9-amino acid peptide (cP) containing the active site of alpha fetoprotein, which inhibits the estrogen-stimulated proliferation of tumor cells in culture and of xenografts in immunodeficient mice. Breast cancer cells cultured in the presence of 2 nM estradiol were exposed to cP for different periods and their proliferation, estradiol binding parameters, clustering tendency and expression of E-cadherin and p21Cip1 were analyzed by biochemical and cell biology methods. The proliferation of MCF7 cells was significantly decreased by the addition of 2 microg/ml cP to the medium. cP did not increase cell death rate nor alter the number of binding sites for estradiol nor the endogenous aromatase activity of MCF7 cells. cP also decreased the proliferation of estrogen-dependent ZR75-1 cells but had no effect on estrogen-independent MDA-MB-231 cells. An increased nuclear p21Cip1 expression detected after cP treatment suggests that cP slows MCF7 cell proliferation via this regulator. We propose that cP could represent a novel breast cancer therapeutic agent whose mechanism of action is different from that of tamoxifen or of inhibitors of aromatase.

A synthetic peptide derived from alpha-fetoprotein inhibits the estradiol-induced proliferation of mammary tumor cells in culture through the modulation of p21.

A stable cyclized 9-mer peptide (cP) containing the active site of alpha-alpha fetoprotein (alphaFP) has been shown to be effective for prevention of estrogen-stimulated tumor cell proliferation in culture or of xenographt growth in immunodeficient mice. cP does not block 17beta-estradiol (E2) binding to its receptors, but rather appears to interfere with intracellular processing of the signal that supports growth. To obtain insight on that mechanism we studied the effect of cP on the proliferation of MCF-7 cells in culture. Proliferation in the presence of 2 microM E2 is decreased up to 40% upon addition of 2 microg ml(-1) cP to the medium; the presence of cP did not increase cell death, cP reduced also the proliferation of estrogen-dependent ZR75-1 cells but had no effect on autonomous MDA-MB-231 cells, cP did not modify the number of binding sites for labeled E2 or affected cell death. We detected increased nuclear p21Cip1 immunoreactivity after cP treatment. Our results suggest that cP acts via p21Cip1 to slow the process of MCF-7 cells through the cycle.

RAD51 135G>C polymorphism and risk of familial breast cancer in a South American population.

Several studies have reported that mutations in genes involved in maintenance of genome integrity may be responsible for increased cancer risk. Human RAD51, known to function in DNA repair, interacts with a number of proteins implicated in breast cancer (BC), including BRCA1 and BRCA2. Few studies have investigated the role of RAD51 gene variations in familial BC. To detect potential novel gene defects that may contribute to hereditary BC susceptibility, 143 patients belonging to 143 Chilean families tested for BRCA1 and BRCA2 mutations were screened for mutations in RAD51, using conformational sensitive gel electrophoresis (CSGE) and DNA sequencing. No mutations were detected in the exon or splice-boundary regions of the RAD51 gene in these families. The RAD51 135G>C polymorphism (c.-98G>C, rs1801320) was studied in a case-control design, to evaluate its possible association with BC susceptibility. The frequency of the RAD51 135C allele was established in 143 cases and 247 controls, using restriction fragment length polymorphism-polymerase chain reaction. RAD51 135C genotypes (G/C and C/C) were associated with an increased BC risk only among women with (a) a family history of BC, (b) BRCA1/2 negative (n = 131), and (c) age at onset <50 years (P = 0.020; OR = 2.17, 95% CI = 1.11-4.24). Thus, we propose that RAD51 135G>C polymorphism presents an increased risk of familial BC in women with age < 50 years at diagnosis, and this polymorphism may be a BC risk variant. This finding should be confirmed in other populations.

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