Search

Abstract Background Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. Methods Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. Results Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2–3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. Conclusions Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2–3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.

The alpha emitter astatine-211 ( 211 At) is a promising candidate for cancer treatment based on Targeted Alpha (α) Therapy (TAT). A small number of facilities, distributed across the United States, are capable of accelerating α-particle beams to produce 211 At. However, challenges remain regarding strategic methods for shipping 211 At in a form adaptable to advanced radiochemistry reactions and other uses of the radioisotope., Purpose: Our method allows shipment of 211 At in various quantities in a form convenient for further radiochemistry., Procedures: For this study, a 3-octanone impregnated Amberchrom CG300M resin bed in a column cartridge was used to separate 211 At from the bismuth matrix on site at the production accelerator (Texas A&M) in preparation for shipping. Aliquots of 6 M HNO 3 containing up to ≈2.22 GBq of 211 At from the dissolved target were successfully loaded and retained on columns. Exempt packages (<370 MBq) were shipped to a destination radiochemistry facility, University of Texas MD Anderson Cancer Center, in the form of a convenient air-dried column. Type A packages have been shipped overnight to University of Alabama at Birmingham., Main Findings: Air-dried column hold times of various lengths did not inhibit simple and efficient recovery of 211 At. Solution eluted from the column was sufficiently high in specific activity to successfully radiolabel a model compound, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1), with 211 At. The method to prepare and ship 211 At described in this manuscript has also been used to ship larger quantities of 211 At a greater distance to University of Alabama at Birmingham., Principal Conclusions: The successful proof of this method paves the way for the distribution of 211 At from Texas A&M University to research institutions and clinical oncology centers in Texas and elsewhere. Use of this simple method at other facilities has the potential increase the overall availability of 211 At for preclinical and clinical studies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare the following competing financial interest(s): J.D.B., E.E.T., L.A. McIntosh, G.C.T., S.J.Y. have patent #PCT/US21/25156 Rapid At-211 purification method and E.E.T., J.D.B., L.A. McIntosh, G.C.T., S.J.Y. have patent #PCT/US21/63241 Systems and Methods for Automated Separation and Recovery of Astatine pending to Texas A&M University., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Ketones have been proven effective in extracting astatine(III) from aqueous solvents. Previous theoretical studies suggested a mechanism where the "sp 2 " lone pair on the carbonyl oxygen donates electron density into the π system of the AtO + molecular cation to form a dative-type bond. In this study, co-extraction of NO 3 - as AtO(NO 3 )·(O═CR 1 R 2 ) species into the organic phase appears to be a key factor. Adjusting the electronic properties of the ketone, by having an aryl group instead of an alkyl group in the alpha position of the ketone, increased the electron density on C═O, increased the bond strength between the ketone and AtO + , and in turn increased the extraction of 211 At into the organic phase. Extraction with diketones shows dependence on the bridging distance between the two carbonyl moieties, where a C 3 or longer bridge results in a 10-fold increase in extraction into the organic phase. DFT calculations show the longer bridge allows for the chelation of AtO(NO 3 ) by either the second carbonyl or the phenyl ring.

The radionuclide 149 Tb (t 1/2  = 4.1 h) is a potential theranostic isotope which can simultaneously be used for targeted-alpha-particle therapy and positron-emission tomography. Feasibility experiments were performed to test a near-symmetric heavy-ion reaction of 63 Cu bombardment on monoisotopic 89 Y. The indirect reaction was studied to avoid isomer production. Offline gamma spectroscopy was used to quantify thick-target physical yields and experimental results show modest agreement to the fusion-evaporation code PACE4. A near-symmetric fission yield was also observed., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Astatine-211 has been produced at Texas A&M University on the K150 cyclotron, with a yield of 890 ± 80 MBq through the 209 Bi(α,2n) 211 At reaction via an 8 h bombardment with a beam current of 4-8 μA and an α-particle beam energy of 28.8 MeV. The target was then dissolved in HNO 3 and the extraction of 211 At was investigated into a variety of organic solvents in 1-3 M HNO 3 . Extraction of 211 At with distribution ratios as high as 11.3 ± 0.6, 12.3 ± 0.8, 42.2 ± 2.2, 69 ± 4, and 95 ± 6 were observed for diisopropyl ether, 1-decanol, 1-octanol, 3-octanone, and methyl isobutyl ketone, respectively, while the distribution ratios for 207 Bi were ≤0.05 in all cases. The extraction of 211 At into both methyl isobutyl ketone and 3-octanone showed a strong, linear dependence on the HNO 3 initial aqueous concentration and better extraction than other solvents. DFT calculations show stronger binding between the carbonyl oxygen of the ketone and the At metal center.

Objective: Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and has a strong genomic component. To date, JIA genetic association studies have had limited sample sizes, used heterogeneous patient populations, or included only candidate regions. The aim of this study was to identify new associations between JIA patients with oligoarticular disease and those with IgM rheumatoid factor (RF)-negative polyarticular disease, which are clinically similar and the most prevalent JIA disease subtypes., Methods: Three cohorts comprising 2,751 patients with oligoarticular or RF-negative polyarticular JIA were genotyped using the Affymetrix Genome-Wide SNP Array 6.0 or the Illumina HumanCoreExome-12+ Array. Overall, 15,886 local and out-of-study controls, typed on these platforms or the Illumina HumanOmni2.5, were used for association analyses. High-quality single-nucleotide polymorphisms (SNPs) were used for imputation to 1000 Genomes prior to SNP association analysis., Results: Meta-analysis showed evidence of association (P < 1 × 10 -6 ) at 9 regions: PRR9&#95;LOR (P = 5.12 × 10 -8 ), ILDR1&#95;CD86 (P = 6.73 × 10 -8 ), WDFY4 (P = 1.79 × 10 -7 ), PTH1R (P = 1.87 × 10 -7 ), RNF215 (P = 3.09 × 10 -7 ), AHI1&#95;LINC00271 (P = 3.48 × 10 -7 ), JAK1 (P = 4.18 × 10 -7 ), LINC00951 (P = 5.80 × 10 -7 ), and HBP1 (P = 7.29 × 10 -7 ). Of these, PRR9&#95;LOR, ILDR1&#95;CD86, RNF215, LINC00951, and HBP1 were shown, for the first time, to be autoimmune disease susceptibility loci. Furthermore, associated SNPs included cis expression quantitative trait loci for WDFY4, CCDC12, MTP18, SF3A1, AHI1, COG5, HBP1, and GPR22., Conclusion: This study provides evidence of both unique JIA risk loci and risk loci overlapping between JIA and other autoimmune diseases. These newly associated SNPs are shown to influence gene expression, and their bounding regions tie into molecular pathways of immunologic relevance. Thus, they likely represent regions that contribute to the pathology of oligoarticular JIA and RF-negative polyarticular JIA., (© 2017, American College of Rheumatology.)

Backgrounds and Aims: Portacaths are regularly used in children with cystic fibrosis (CF). We aimed to assess patient satisfaction with lateral chest wall portacaths in children with CF., Methods: All children in a geographical region with CF and portacath in situ were identified. Site of chest wall placement was identified on X-ray; only children with lateral chest wall portacaths were sent questionnaires. Data collected included preoperative information, cosmesis and interference with activities., Results: Of the 46 patients identified, 42 had lateral chest wall ports. 25 of this 42(60%) submitted their questionnaires. 22(88%) were happy with preoperative information although only 8(32%) recall being offered choice of position. 23(92%) were satisfied with cosmesis. 2 patients reported problems with physiotherapy only with indwelling needles. 6(24%) patients had problems with clothing, 7(32%) with sports and 3(12%) with seatbelts., Conclusions: Lateral chest wall portacaths are cosmetically acceptable. Impact on daily activities is less common than that reported with anterior chest wall placement., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To review the primary orchidopexy failure rate and outcome of repeat orchidopexy in a tertiary paediatric surgical centre and identify risk factors., Methods: A prospectively collected and validated audits system was used to identify all boys having a repeat orchidopexy from August 1990 to December 2008 (18 years)., Results: In total, 1538 boys underwent orchidopexy with 1886 testicles operated on. Of these 348 (22.6%) patients had bilateral cryptorchidism. A need for repeat orchidopexy was identified in 31 boys resulting in a primary failure rate of 1.6% over the 18 years. Unilateral orchidopexy as the primary operation had a 1.5% failure rate. The failure rate for bilateral cryptorchidism was 1.87% per testicle rising to 1.93% per testicle when the primary operation was synchronous bilateral orchidopexy. Orchidopexy failure occurred in 9 patients (1.97%) who were under 24 months, 15 (2.67%) who were between 24 and 72 months and 7 (0.8%) over 72 months at time of first operation., Conclusion: Possible risk factors for primary orchidopexy failure are bilateral operation and older age at time of operation. Failure in achieving a satisfactory scrotal position (and testicular loss) following orchidopexy has been postulated as a potential surgical standard for revalidation of paediatric surgeons. This study adds important contemporary data to inform that process., (Copyright © 2012 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)