Publications by authors named "Ananth Srinivasan"

37 Publications

Single-port laparoscopic appendicectomy versus conventional three-port approach for acute appendicitis: A systematic review, meta-analysis and trial sequential analysis of randomised controlled trials.

Surgeon 2021 Mar 19. Epub 2021 Mar 19.

Department of General Surgery, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.

Aims: The aim of this systematic review and meta-analysis is to compare outcomes of single-port laparoscopic appendicectomy (SPLA) and conventional three-port laparoscopic appendicectomy (CLA) in the management of acute appendicitis.

Methods: A comprehensive systematic review of randomised controlled trials (RCTs) with subsequent meta-analysis and trial sequential analysis of outcomes were conducted. Post-operative pain at 12-h, cosmesis, need for an additional port(s), operative time, port-site hernia, ileus, surgical site infection (SSI), intra-abdominal collection, length of hospital stay (LOS), readmission, and reoperation were the evaluated outcome parameters.

Results: Sixteen RCTs with total number of 2017 patients who underwent SPLA (n = 1009) or CLA (n = 1008) were included. SPLA was associated with a significantly higher cosmetic score (MD 1.11, P= 0.03) but significantly longer operative time (MD 7.08, P = 0.00001) compared to CLA. However, the difference was not significant between SPLA and CLA in the post-operative pain score at 12-h (MD -0.13, P = 0.69), need for additional port(s) (RR0.03, P = 0.07), port-site hernia (RD: 0.00, P = 0.68), ileus (RR 0.74, P = 0.51), SSI (RR 1.38, P = 0.28), post-operative intra-abdominal collection (RR 0.00, P = 0.62), LOS (MD -2.41, P = 0.16), readmission to the hospital (RR 0.45, P = 0.22), and return to theatre (RR 0.00, P = 0.49). Trial sequential analysis demonstrated that the meta-analysis is conclusive for most of the outcomes, except LOS and intra-abdominal collection.

Conclusion: Although SPLA is associated with a slightly longer operative time, its efficacy and safety are comparable to CLA in management of uncomplicated appendicitis. Moreover, it offers improved post-operative cosmesis. The available evidence is conclusive, and further trials may not be required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.surge.2021.01.018DOI Listing
March 2021

Do we need to routinely perform cavity shaving with breast-conserving surgery for breast cancer? A systematic review and meta-analysis.

Surg Oncol 2021 Mar 25;36:7-14. Epub 2020 Nov 25.

Department of General Surgery, Peterborough City Hospital, Peterborough, UK.

Aims: To evaluate comparative outcomes of breast-conserving surgery (BCS) of breast cancer with and without cavity shaving.

Methods: A systematic search of multiple electronic data sources was conducted, and all randomised controlled trials (RCTs) comparing BCS with or without cavity shaving for breast cancer were included. Positive margin rate, second operation rate, operative time, post-operative haematoma, cosmetic appearance and budget cost were the evaluated outcome parameters for the meta-analysis.

Results: Six RCTs reporting a total number of 971 patients; 495 of these underwent BCS plus shaving (BCS + S), and 473 underwent BCS alone were included. BCS + S showed significantly lower positive margin rate (Risk Ratio [RR] 0.40, P = 0.00001) and second operation rate (RR 0.38, P = 0.00001). BCS + S demonstrated longer operative time than BCS (79 ± 4 min vs 67 ± 3 min, Mean Difference 12.14, P = 0.002), and there was no significant difference in the risk of post-operative haematoma (RR 0.33, P = 0.20).

Conclusion: BCS + S is superior to BCS in terms of positive margins rate and second operation rate. Operative time is longer when cavity shaving is performed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.suronc.2020.11.003DOI Listing
March 2021

Single-port laparoscopic appendicectomy versus conventional three-port approach for acute appendicitis in children: a systematic review and meta-analysis.

Pediatr Surg Int 2021 Jan 17;37(1):119-127. Epub 2020 Nov 17.

Department of General Surgery, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.

Aim: To evaluate comparative outcomes of single-port laparoscopic appendicectomy (SPLA) and conventional three-port laparoscopic appendicectomy (CLA) in the management of acute appendicitis in children.

Methods: A comprehensive systematic review of randomised controlled trials (RCTs) with subsequent meta-analysis of outcomes were conducted in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement standards. Operative time, surgical site infection, intra-abdominal collection, incisional hernia, length of hospital stay (LOS), additional port/s and conversion to open were the evaluated outcome parameters.

Results: Four RCTs reporting a total number of 520 patients who underwent SPLA (n = 260) or CLA (n = 260) were included. There was no difference between SPLA and CLA group in post-operative collection (risk difference (RD) - 0.00, P = 0.94), surgical site infection (RD 0.02, P = 0.25), incisional hernia (RD 0.00 P = 1), LOS (mean difference (MD) 0.73 P = 0.93), need for additional port/s (RD 0.04, P = 0.24) and conversion to open (RD 0.00, P = 1). However, there was a significantly longer operative time in the SPLA group (MD 9.80, P = 0.00001). The certainty of the evidence was judged to be moderate for all outcomes.

Conclusions: SPLA and CLA seem to have comparable efficacy and safety in children with acute appendicitis although the former may be associated with longer procedure time. Future high-quality RCTs with adequate sample sizes are required to provide stronger evidence in favour of an intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00383-020-04776-zDOI Listing
January 2021

Author Correction: An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer's disease.

Nat Genet 2020 Nov;52(11):1266

Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-00733-7DOI Listing
November 2020

An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer's disease.

Nat Genet 2020 10 28;52(10):1024-1035. Epub 2020 Sep 28.

Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer's disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as the main enrichments specific to AD. In turn, epigenomic profiling revealed gains in the histone H3 modifications H3K27ac and H3K9ac linked to transcription, chromatin and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-β42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin-gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-0696-0DOI Listing
October 2020

New synthesis of 6″-[ F]fluoromaltotriose for positron emission tomography imaging of bacterial infection.

J Labelled Comp Radiopharm 2020 09 21;63(11):466-475. Epub 2020 Jul 21.

Bio-X Program and Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California, USA.

6″-[ F]fluoromaltotriose is a positron emission tomography tracer that can differentiate between bacterial infection and inflammation in vivo. Bacteria-specific uptake of 6″-[ F]fluoromaltotriose is attributed to the targeting of maltodextrin transporter in bacteria that is absent in mammalian cells. Herein, we report a new synthesis of 6″-[ F]fluoromaltotriose as a key step for its clinical translation. In comparison with the previously reported synthesis, the new synthesis features unambiguous assignment of the fluorine-18 position on the maltotriose unit. The new method utilizes direct fluorination of 2″,3″,4″-tri-O-acetyl-6″-O-trifyl-α-D-glucopyranosyl-(1-4)-O-2',3',6'-tri-O-acetyl-α-D-glucopyranosyl-(1-4)-1,2,3,6-tetra-O-acetyl-D-glucopyranose followed by basic hydrolysis. Radiolabeling of the new maltotriose triflate precursor proceeds using a single HPLC purification step, which results in shorter reaction time in comparison with the previously reported synthesis. Successful synthesis of 6″-[ F]fluoromaltotriose has been achieved in 3.5 ± 0.3% radiochemical yield (decay corrected, n = 7) and radiochemical purity above 95%. The efficient radiosynthesis of 6″-[ F]fluoromaltotriose would be critical in advancing this positron emission tomography tracer into clinical trials for imaging bacterial infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jlcr.3868DOI Listing
September 2020

Outcomes and Health Care Utilization After Early Hospital Dismissal in Kidney Transplantation: An Analysis of 1001 Consecutive Cases.

Ann Surg 2020 Jun 9. Epub 2020 Jun 9.

Department of Surgery, Mayo Clinic, Phoenix, Arizona.

Objective: To understand whether reduced lengths of stay after kidney transplantation were associated with excess health care utilization in the first 90 days or long-term graft and patient survival outcomes.

Background: Reducing length of stay after kidney transplant has an unknown effect on post-transplant health care utilization. We studied this association in a cohort of 1001 consecutive kidney transplants.

Methods: We retrospectively reviewed 2011-2015 data from a prospectively-maintained kidney transplant database from a single center.

Results: A total of 1001 patients underwent kidney transplant, and were dismissed from the hospital in 3 groups: Early [≤2 days] (19.8%), Normal [3-7 days] (79.4%) and Late [>7 days] (3.8%). 34.8% of patients had living donor transplants (Early 51%, Normal 31.4%, Late 18.4%, P < 0.001). Early patients had lower delayed graft function rates (Early 19.2%, Normal 32%, Late73.7%, P = 0.001). By the hospital dismissal group, there were no differences in readmissions or emergency room visits at 30 or 90 days. Glomerular filtration rate at 12 months and rates of biopsy-proven acute rejection were also similar between groups. The timing of hospital dismissal was not associated with the risk-adjusted likelihood of readmission. Early and Normal patients had similar graft and patient survival. Late dismissal patients, who had higher rates of cardiovascular complications, had significantly higher late mortality versus Normal dismissal patients in unadjusted and risk-adjusted models.

Conclusion: Dismissing patients from the hospital 2 days after kidney transplant is safe, feasible, and improves value. It is not associated with excess health care utilization or worse short or long-term transplant outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SLA.0000000000003948DOI Listing
June 2020

Does sites of recurrence impact survival in secondary cytoreduction surgery for recurrent epithelial ovarian cancer?

J Obstet Gynaecol 2020 Aug 14;40(6):849-855. Epub 2020 Jan 14.

Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.

Outcomes of secondary cytoreduction surgery (SCS) were evaluated for morbidity, progression free survival (PFS) and overall survival (OS) and factors influencing results were explored. Retrospective analysis of all cases of SCS for epithelial ovarian cancer (EOC) was performed from October 2010 to December 2017. 62 patients were prospectively identified as candidates for SCS and 57 underwent SCS. 20(35%) patients required bowel resection/s, 24(42%) had nodal resections and 11(19%) had extensive upper abdominal surgery. 51(89%) achieved complete cytoreduction. After a median follow-up of 30 months (range 9-95 months), median PFS was 32 months (CI 17-76 months) and median OS has not reached. Seventeen patients have died and 32 have progressed. Three patients had Clavien-Dindo grade-3 and two had grade-4 morbidity. Patients who had multi-site recurrence had shorter median PFS ( = 0.04) and patients who required bowel resections had lower median OS ( = 0.009) compared to rest of the cohort.IMPACT STATEMENT Retrospective studies have confirmed survival advantage for recurrence in epithelial ovarian cancer and recommend SCS for carefully selected patients. This finding is being evaluated in randomised control trials currently. This study presents excellent results for survival outcomes after SCS and highlights importance of careful selection of patients with a goal to achieve complete cytoreduction. In addition, for the first time in literature, this study also explores various factors that may influence results and finds that there are no differences in survival outcomes whether these patients had early stage or advanced stage disease earlier. Patients who have multisite recurrence tend to have shorter PFS but no difference were noted for overall survival. Patients who have recurrence in bowels necessitating resection/s have a shorter median OS compared to rest of cohorts, however, still achieving a good survival time. These findings will raise awareness for the clinicians and patients while discussing surgical outcomes and would set an achievable standard to improve cancer services. The pattern of recurrence and associated outcomes also point towards difference in biological nature of recurrent disease and could provide an opportunity for scientists to study the biological makeup of these recurrent tumours.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01443615.2019.1674264DOI Listing
August 2020

Clinical Outcomes of Portosystemic Shunts on the Outcome of Liver Transplantation.

Liver Transpl 2020 05 12;26(5):693-701. Epub 2020 Mar 12.

Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Phoenix, AZ.

Spontaneous portosystemic shunts (SPSSs) have been associated with worse clinical outcomes in the pre-liver transplantation (LT) setting, but little is known about their post-LT impacts. Our aim was to compare LT candidates with and without SPSSs and assess the impact of SPSSs on patient mortality and graft survival in the post-LT setting. Patients 18 years or older with abdominal imaging done prior to LT were included. Exclusion criteria were the presence of pre-LT surgical shunts, LT indications other than cirrhosis, and combined solid organ transplantations. SPSSs were classified as absent, small, or large according to their maximum diameter (8 mm). Multiple variables that could influence the post-LT course were extracted for analysis. Patient and graft survival were estimated using the Kaplan-Meier method and were compared between groups using a log-rank test. The project received institutional review board approval. We extracted data from 326 patients. After comparing patients without SPSS or with small or large SPSSs, no statistical difference was found for overall patient survival: no SPSS (n = 8/63), reference; small SPSS (n = 18/150), hazard ratio (HR), 1.05 (95% confidence interval [CI], 0.45-2.46); and large SPSS (n = 6/113), HR, 0.60 (95% CI, 0.20-1.78); P = 0.20. Also, no difference was found for graft survival: no SPSS (n = 11/63), reference; small SPSS (n = 21/150), HR, 0.80 (95% CI, 0.38-1.70); large SPSS (n = 11/113), HR, 0.59 (95% CI, 0.25-1.40); P = 0.48. Similarly, no statistical significance was found for these variables when comparing if the graft used was procured from a donation after circulatory death donor versus a donation after brain death donor. In conclusion, the previously described association between SPSSs and worse clinical outcomes in pre-LT patients seems not to persist once patients undergo LT. This study suggests that no steps to correct SPSS intraoperatively are necessary.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lt.25710DOI Listing
May 2020

Evaluation of integrin αvβ cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis.

Nat Commun 2019 10 14;10(1):4673. Epub 2019 Oct 14.

Department of Radiology, Stanford University, Stanford, CA, 94305, USA.

Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin αvβ with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer's safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin αβ.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-11863-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791878PMC
October 2019

Long-term Outcomes Following Kidney Transplantation From Donors With Acute Kidney Injury.

Transplantation 2019 09;103(9):e263-e272

Department of Surgery, Mayo Clinic, Phoenix, AZ.

Background: Kidneys from deceased donors with acute kidney injury (AKI) are more likely to be discarded because of concerns for poor outcomes after transplantation. The aim of this study was to determine the long-term outcomes of a large cohort of patients transplanted utilizing kidneys from deceased donors with AKI.

Methods: All patients receiving a deceased donor kidney transplant during a recent 10-year period were included. Acute Kidney Injury Network (AKIN) criteria were used to classify the donors. Donor kidneys with >10% cortical necrosis or more than mild chronic changes were discarded. The primary outcome is the combined endpoint of death or graft loss.

Results: The cohort included 1313 kidneys from 974 donors, AKIN stage 0 (no AKI) in 319 (24.3%), stage 1 in 370 (28.2%), stage 2 in 177 (13.5), and stage 3 in 447 (34.0%). Estimated 5-year graft survival (95% confidence interval) was 78.5% (72.5-84.5), 77.8% (72.8-82.1), 83.8% (76.8-88.9), and 84.6% (79.5-88.7) for AKIN donor stage 0 to 3, respectively (log-rank P = 0.10). After adjusting for baseline differences, the hazard ratio (95% confidence interval) for the combined endpoint for the AKIN stage 3 group (relative to AKIN 0 group) was 0.70 (0.45-1.10). Delayed graft function occurred in 44.6% and 75.4% of AKIN 2 and 3 groups, as compared to 33.9% and 33.5% in AKIN 0 and 1 (P < 0.001).

Conclusion: We conclude that transplanting selected kidneys from deceased donors with AKI with preimplantation biopsy showing <10% cortical necrosis and no more than mild chronic changes have excellent long-term graft survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000002792DOI Listing
September 2019

The Characterization of F-hGTS13 for Molecular Imaging of x Transporter Activity with PET.

J Nucl Med 2019 12 6;60(12):1812-1817. Epub 2019 Jun 6.

Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, Stanford, California

The aim of this study was development of an improved PET radiotracer for measuring x activity with increased tumor uptake and reduced uptake in inflammatory cells compared with ()-4-(3-F-fluoropropyl)-l-glutamate (F-FSPG). A racemic glutamate derivative, F-hGTS13, was evaluated in cell culture and animal tumor models. F-hGTS13 was separated into C5 epimers, and the corresponding F-hGTS13-isomer1 and F-hGTS13-isomer2 were evaluated in H460 tumor-bearing rats. Preliminary studies investigated the cellular uptake of F-hGTS13-isomer2 in multiple immune cell populations and states. F-hGTS13 demonstrated excellent H460 tumor visualization with high tumor-to-background ratios, confirmed by ex vivo biodistribution studies. Tumor-associated radioactivity was significantly higher for F-hGTS13 (7.5 ± 0.9 percentage injected dose [%ID]/g, = 3) than for F-FSPG (4.6 ± 0.7 %ID/g, = 3, = 0.01). F-hGTS13-isomer2 exhibited excellent H460 tumor visualization (6.3 ± 1.1 %ID/g, = 3) and significantly reduced uptake in multiple immune cell populations relative to F-FSPG. F-hGTS13-isomer2 exhibited increased liver uptake relative to F-FSPG (4.6 ± 0.8 vs. 0.7 ± 0.01 %ID/g), limiting its application in hepatocellular carcinoma. F-hGTS13-isomer2 is a new PET radiotracer for molecular imaging of x activity that may provide information on tumor oxidation states. F-hGTS13-isomer2 has potential for clinical translation for imaging cancers of the thorax because of the low background signal in healthy tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.119.225870DOI Listing
December 2019

Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD.

Nat Neurosci 2019 06 20;22(6):863-874. Epub 2019 May 20.

Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

An expanded GGGGCC hexanucleotide of more than 30 repeats (termed (G4C2)) within C9orf72 is the most prominent mutation in familial frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) (termed C9). Through an unbiased large-scale screen of (G4C2)-expressing Drosophila we identify the CDC73/PAF1 complex (PAF1C), a transcriptional regulator of RNA polymerase II, as a suppressor of G4C2-associated toxicity when knocked-down. Depletion of PAF1C reduces RNA and GR dipeptide production from (G4C2) transgenes. Notably, in Drosophila, the PAF1C components Paf1 and Leo1 appear to be selective for the transcription of long, toxic repeat expansions, but not shorter, nontoxic expansions. In yeast, PAF1C components regulate the expression of both sense and antisense repeats. PAF1C is upregulated following (G4C2) expression in flies and mice. In humans, PAF1 is also upregulated in C9-derived cells, and its heterodimer partner, LEO1, binds C9 repeat chromatin. In C9 FTD, PAF1 and LEO1 are upregulated and their expression positively correlates with the expression of repeat-containing C9orf72 transcripts. These data indicate that PAF1C activity is an important factor for transcription of the long, toxic repeat in C9 FTD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41593-019-0396-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535128PMC
June 2019

eIF4B and eIF4H mediate GR production from expanded G4C2 in a Drosophila model for C9orf72-associated ALS.

Acta Neuropathol Commun 2019 04 25;7(1):62. Epub 2019 Apr 25.

Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

The discovery of an expanded (GGGGCC)n repeat (termed G4C2) within the first intron of C9orf72 in familial ALS/FTD has led to a number of studies showing that the aberrant expression of G4C2 RNA can produce toxic dipeptides through repeat-associated non-AUG (RAN-) translation. To reveal canonical translation factors that impact this process, an unbiased loss-of-function screen was performed in a G4C2 fly model that maintained the upstream intronic sequence of the human gene and contained a GFP tag in the GR reading frame. 11 of 48 translation factors were identified that impact production of the GR-GFP protein. Further investigations into two of these, eIF4B and eIF4H, revealed that downregulation of these factors reduced toxicity caused by the expression of expanded G4C2 and reduced production of toxic GR dipeptides from G4C2 transcripts. In patient-derived cells and in post-mortem tissue from ALS/FTD patients, eIF4H was found to be downregulated in cases harboring the G4C2 mutation compared to patients lacking the mutation and healthy individuals. Overall, these data define eIF4B and eIF4H as disease modifiers whose activity is important for RAN-translation of the GR peptide from G4C2-transcripts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-019-0711-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485101PMC
April 2019

A novel synthesis of 6''-[ F]-fluoromaltotriose as a PET tracer for imaging bacterial infection.

J Labelled Comp Radiopharm 2018 05 30;61(5):408-414. Epub 2018 Mar 30.

Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bioengineering Bio-X Program, Stanford University, Stanford, California, USA.

The aim of this study was to develop a positron emission tomography (PET) tracer to visualize and monitor therapeutic response to bacterial infections. In our continued efforts to find maltose based PET tracers that can image bacterial infections, we have designed and prepared 6''-[ F]fluoromaltotriose as a second generation PET imaging tracer targeting the maltodextrin transporter of bacteria. We have developed methods to synthesize 6''-deoxy-6''-[ F]fluoro-α-D-glucopyranosyl-(1-4)-O-α-D-glucopyranosyl-(1-4)-O-D-glucopyranose (6''-[ F]-fluoromaltotriose) as a bacterial infection PET imaging agent. 6''-[ F]fluoromaltotriose was prepared from precursor, 2'',3'',4''-tri-O-acetyl-6''-O-nosyl-α-D-glucopyranosyl-(1-4)-O-2',3',6'-tri-O-acetyl-α-D-glucopyranosyl-(1-4)-1,2,3,6-tetra-O-acetyl-D-glucopyranose (per-O-acetyl-6''-O-nosyl-maltotriose 4). This method utilizes the reaction between precursor 4 and anhydrous [ F]KF/Kryptofix 2.2.2 in dimethylformamide (DMF) at 85°C for 10 minutes to yield per-O-acetyl-6''-deoxy-6-'' [ F]-fluoromaltotriose (7). Successive acidic and basic hydrolysis of the acetyl protecting groups in 7 produced 6''-[ F]fluoromaltotriose (8). Also, cold 6''- [ F]fluoromaltotriose was prepared from per-O-acetyl-6''-hydroxymaltotriose via a diethylaminosulfur trifluoride reaction followed by a basic hydrolysis. A successful synthesis of 6''-[ F]-fluoromaltotriose has been accomplished in 8 ± 1.2% radiochemical yield (decay corrected). Total synthesis time was 120 minutes. Serum stability of 6''-[ F]fluoromaltotriose at 37°C indicated that 6''-[ F]-fluoromaltotriose remained intact up to 2 hours. In conclusion, we have successfully synthesized 6''-[ F]-fluoromaltotriose via direct fluorination of an appropriate precursor of a protected maltotriose.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jlcr.3601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326343PMC
May 2018

Specific Imaging of Bacterial Infection Using 6″-F-Fluoromaltotriose: A Second-Generation PET Tracer Targeting the Maltodextrin Transporter in Bacteria.

J Nucl Med 2017 10 10;58(10):1679-1684. Epub 2017 May 10.

Department of Radiology, Stanford University School of Medicine, Stanford, California

6″-F-fluoromaltotriose is a PET tracer that can potentially be used to image and localize most bacterial infections, much like F-FDG has been used to image and localize most cancers. However, unlike F-FDG, 6″-F-fluoromaltotriose is not taken up by inflammatory lesions and appears to be specific to bacterial infections by targeting the maltodextrin transporter that is expressed in gram-positive and gram-negative strains of bacteria. 6″-F-fluoromaltotriose was synthesized with high radiochemical purity and evaluated in several clinically relevant bacterial strains in cultures and in living mice. 6″-F-fluoromaltotriose was taken up in both gram-positive and gram-negative bacterial strains. 6″-F-fluoromaltotriose was also able to detect in a clinically relevant mouse model of wound infection. The utility of 6″-F-fluoromaltotriose to help monitor antibiotic therapies was also evaluated in rats. 6″-F-fluoromaltotriose is a promising new tracer that has significant diagnostic utility, with the potential to change the clinical management of patients with infectious diseases of bacterial origin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.117.191452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632736PMC
October 2017

Development of [F]DASA-23 for Imaging Tumor Glycolysis Through Noninvasive Measurement of Pyruvate Kinase M2.

Mol Imaging Biol 2017 10;19(5):665-672

Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, 943065, USA.

Purpose: A hallmark of cancer is metabolic reprogramming, which is exploited by cancer cells to ensure rapid growth and survival. Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key step in tumor metabolism and growth. Recently, we reported the radiosynthesis of the first positron emission tomography tracer for visualizing PKM2 in vivo-i.e., [C]DASA-23. Due to the highly promising imaging results obtained with [C]DASA-23 in rodent model glioblastoma, we set out to generate an F-18-labeled version of this tracer, with the end goal of clinical translation in mind. Herein, we report the radiosynthesis of 1-((2-fluoro-6-[F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([F]DASA-23) and our initial investigation of its binding properties in cancer cells.

Procedure: We synthesized [F]DASA-23 via fluorination of 1-((2-fluoro-6-nitrophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine (10) with K[F]F/K2.2.2 in N,N-dimethylformamide at 110 °C for 20 min. Subsequently, we evaluated uptake of [F]DASA-23 in HeLa cervical adenocarcinoma cells and in vitro stability in human and mouse serum.

Results: We successfully prepared [F]DASA-23 in 2.61 ± 1.54 % radiochemical yield (n = 10, non-decay corrected at end of synthesis) with a specific activity of 2.59 ± 0.44 Ci/μmol. Preliminary cell uptake experiments revealed high uptake in HeLa cells, which was effectively blocked by pretreating cells with the structurally distinct PKM2 activator, TEPP-46. [F]DASA-23 remained intact in human and mouse serum up to 120 min.

Conclusion: Herein, we have identified a F-18-labeled PKM2 specific radiotracer which shows potential for in vivo imaging. The promising cell uptake results reported herein warrant the further evaluation of [F]DASA-23 for its ability to detect and monitor cancer noninvasively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11307-017-1068-8DOI Listing
October 2017

TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite .

mSphere 2017 Jan-Feb;2(1). Epub 2017 Feb 1.

Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

New drugs to control infection with the protozoan parasite are needed as current treatments exert toxic side effects on patients. Approaches to develop novel compounds for drug development include screening of compound libraries and targeted inhibition of essential cellular pathways. We identified two distinct compounds that display inhibitory activity against the parasite's replicative stage: F3215-0002, which we previously identified during a compound library screen, and I-BET151, an inhibitor of bromodomains, the "reader" module of acetylated lysines. In independent studies, we sought to determine the targets of these two compounds using forward genetics, generating resistant mutants and identifying the determinants of resistance with comparative genome sequencing. Despite the dissimilarity of the two compounds, we recovered resistant mutants with nonsynonymous mutations in the same domain of the same gene, , which we found encodes a protein that localizes to the parasite mitochondrion (designated TgPRELID after the name of said domain). We found that mutants selected with one compound were cross resistant to the other compound, suggesting a common mechanism of resistance. To further support our hypothesis that mutations facilitate resistance to both I-BET151 and F3215-0002, CRISPR (clustered regularly interspaced short palindromic repeat)/CAS9-mediated mutation of directly led to increased F3215-0002 resistance. Finally, all resistance mutations clustered in the same subdomain of TgPRELID. These findings suggest that may encode a multidrug resistance factor or that I-BET151 and F3215-0002 have the same target(s) despite their distinct chemical structures. We report the discovery of TgPRELID, a previously uncharacterized mitochondrial protein linked to multidrug resistance in the parasite . Drug resistance remains a major problem in the battle against parasitic infection, and understanding how TgPRELID mutations augment resistance to multiple, distinct compounds will reveal needed insights into the development of new therapies for toxoplasmosis and other related parasitic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSphere.00229-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288566PMC
February 2017

Development and Validation of an Immuno-PET Tracer as a Companion Diagnostic Agent for Antibody-Drug Conjugate Therapy to Target the CA6 Epitope.

Radiology 2015 Jul 27;276(1):191-8. Epub 2015 Feb 27.

From the Department of Radiology (O.I., A.N., S.H., A. Sathirachinda, R.K., A. Srinivasan, S.S.G.) and Departments of Bioengineering and Materials Science & Engineering (S.S.G.), Stanford University, 318 Campus Dr, Room E153, Stanford, CA 94305; Sanofi R&D, BioInnovation Novel Protein Therapeutics, Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany (M.G., J.K., I.F., C.L.); Sanofi Oncology, Vitry, France (C.C., I.S., V.B.); and Sanofi Oncology, Cambridge, Mass (S.K.S.).

Purpose: To develop and compare three copper 64 ((64)Cu)-labeled antibody fragments derived from a CA6-targeting antibody (huDS6) as immuno-positron emission tomography (immuno-PET)-based companion diagnostic agents for an antibody-drug conjugate by using huDS6.

Materials And Methods: Three antibody fragments derived from huDS6 were produced, purified, conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and evaluated in the following ways: (a) the affinity of the fragments and the DOTA conjugates was measured via flow cytometry, (b) the stability of the labeled fragments was determined ex vivo in human serum over 24 hours, and (c) comparison of the in vivo imaging potential of the fragments was evaluated in mice bearing subcutaneous CA6-positive and CA6-negative xenografts by using serial PET imaging and biodistribution. Isotype controls with antilysozyme and anti-DM4 B-Fabs and blocking experiments with an excess of either B-Fab or huDS6 were used to determine the extent of the antibody fragment (64)Cu-DOTA-B-Fab binding specificity. Immunoreactivity and tracer kinetics were evaluated by using cellular uptake and 48-hour imaging experiments, respectively. Statistical analyses were performed by using t tests, one-way analysis of variance, and Wilcoxon and Mann-Whitney tests.

Results: The antibody fragment (64)Cu-DOTA-B-Fab was more than 95% stable after 24 hours in human serum, had an immunoreactivity of more than 70%, and allowed differentiation between CA6-positive and CA6-negative tumors in vivo as early as 6 hours after injection, with a 1.7-fold uptake ratio between tumors. Isotype and blocking studies experiments showed tracer-specific uptake in antigen-positive tumors, despite some nonspecific uptake in both tumor models.

Conclusion: Three antibody fragments were produced and examined as potential companion diagnostic agents. (64)Cu-DOTA-B-Fab is a stable and effective immuno-PET tracer for CA6 imaging in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1148/radiol.15140058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570559PMC
July 2015

Dosimetry and first clinical evaluation of the new 18F-radiolabeled bombesin analogue BAY 864367 in patients with prostate cancer.

J Nucl Med 2015 Mar 12;56(3):372-8. Epub 2015 Feb 12.

Division of Nuclear Medicine, Department of Medical Radiology, University Hospital of Zurich, Zurich, Switzerland Division of Medical Oncology, Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland

Unlabelled: The aim of this first-in-man study was to demonstrate the feasibility, safety, and tolerability, as well as provide dosimetric data and evaluate the imaging properties, of the bombesin analogue BAY 864367 for PET/CT in a small group of patients with primary and recurrent prostate cancer (PCa).

Methods: Ten patients with biopsy-proven PCa (5 with primary PCa and 5 with prostate-specific antigen recurrence after radical prostatectomy) were prospectively selected for this exploratory clinical trial with BAY 864367, a new (18)F-labeled bombesin analogue. PET scans were assessed at 6 time points, up to 110 min after intravenous administration of 302 ± 11 MBq of BAY 864367. Imaging results were compared with (18)F-fluorocholine PET/CT scans. Dosimetry was calculated using the OLINDA/EXM software.

Results: Three of 5 patients with primary disease showed positive tumor delineation in the prostate, and 2 of 5 patients with biochemical relapse showed a lesion suggestive of recurrence on the BAY 864367 scan. Tumor-to-background ratio averaged 12.9 ± 7.0. The ratio of malignant prostate tissue to normal prostate tissue was 4.4 ± 0.6 in 3 patients with tracer uptake in the primary PCa. Mean effective dose was 4.3 ± 0.3 mSv/patient (range, 3.7-4.9 mSv).

Conclusion: BAY 864367, a novel (18)F-labeled bombesin tracer, was successfully investigated in a first-in-man clinical trial of PCa and showed favorable dosimetric values. Additionally, the application was safe and well tolerated. The tracer delineated tumors in a subset of patients, demonstrating the potential of gastrin-releasing-peptide receptor imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.114.147116DOI Listing
March 2015

Readmission and risk factors for readmission following esophagectomy for esophageal cancer.

J Gastrointest Surg 2015 Apr 12;19(4):581-5; discussion 586. Epub 2015 Feb 12.

Creighton University, Omaha, NE, USA.

Introduction: Readmission after esophagectomy for esophageal cancer has not been systematically evaluated.

Study Objective: The objectives of this study were to determine national 30-day readmission rates after esophagectomy for esophageal cancer and evaluate risk factors associated with readmission.

Methods: Retrospective review of the 2011-2012 National Surgical Quality Improvement Program dataset was performed to identify patients who underwent elective esophagectomy for esophageal cancer.

Results: One thousand sixty-eight patients satisfied study criteria. One hundred and thirty-five patients were admitted within 30 days resulting in a readmission rate of 12.6%. Patients with a history of pulmonary disease were 3.9 times more likely to be readmitted. Patients who developed postoperative wound-related complications were 9 times more likely to be readmitted than patients who did not develop wound-related complications. Increasing length of hospital stay was associated with a marginal but significant decrease in risk of readmission.

Conclusions: National 30-day readmission rate after esophagectomy for esophageal cancer is around 12.6%. Risk factors associated with 30-day readmission include history of pulmonary disease, postoperative wound-related complications, and length of hospital stay.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11605-015-2756-9DOI Listing
April 2015

Hammondia hammondi harbors functional orthologs of the host-modulating effectors GRA15 and ROP16 but is distinguished from Toxoplasma gondii by a unique transcriptional profile.

Eukaryot Cell 2014 Dec 3;13(12):1507-18. Epub 2014 Oct 3.

Dietrich School of Arts and Sciences, Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

Toxoplasma gondii and its nearest extant relative, Hammondia hammondi, are phenotypically distinct despite their remarkable similarity in gene content, synteny, and functionality. To begin to identify genetic differences that might drive distinct infection phenotypes of T. gondii and H. hammondi, in the present study we (i) determined whether two known host-interacting proteins, dense granule protein 15 (GRA15) and rhoptry protein 16 (ROP16), were functionally conserved in H. hammondi and (ii) performed the first comparative transcriptional analysis of H. hammondi and T. gondii sporulated oocysts. We found that GRA15 and ROP16 from H. hammondi (HhGRA15 and HhROP16) modulate the host NF-κB and STAT6 pathways, respectively, when expressed heterologously in T. gondii. We also found the transcriptomes of H. hammondi and T. gondii to be highly distinct. Consistent with the spontaneous conversion of H. hammondi tachyzoites into bradyzoites both in vitro and in vivo, H. hammondi high-abundance transcripts are enriched for genes that are of greater abundance in T. gondii bradyzoites. We also identified genes that are of high transcript abundance in H. hammondi but are poorly expressed in multiple T. gondii life stages, suggesting that these genes are uniquely expressed in H. hammondi. Taken together, these data confirm the functional conservation of known T. gondii virulence effectors in H. hammondi and point to transcriptional differences as a potential source of the phenotypic differences between these species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/EC.00215-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248688PMC
December 2014

Orbital varix thrombosis: a rare cause of unilateral proptosis.

BMJ Case Rep 2013 Jan 25;2013. Epub 2013 Jan 25.

Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, Norfolk, UK.

Orbital varices are thin walled, low flow, distensible veins which may rarely present with periorbital pain, proptosis or visual loss. Most orbital varices may be managed conservatively and only warrant surgery in the presence of recurrent thrombosis, disfiguring proptosis or acute visual loss. This report concerns an 84-year-old Caucasian woman who was admitted following a fall and noted to have isolated proptosis of the right eye, with vertical diplopia. All biochemical and haematological investigations were normal. A CT scan of the orbits demonstrated a serpiginous soft tissue mass within the superior portion of the right orbit, consistent with a thrombosed orbital varix. Conservative management was agreed with prism glasses and ophthalmological follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bcr-2012-007935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3604262PMC
January 2013

A focused small-molecule screen identifies 14 compounds with distinct effects on Toxoplasma gondii.

Antimicrob Agents Chemother 2012 Nov 20;56(11):5581-90. Epub 2012 Aug 20.

University of Pittsburgh, Department of Biological Sciences, Pittsburgh, Pennsylvania, USA.

Toxoplasma gondii is a globally ubiquitous pathogen that can cause severe disease in immunocompromised humans and the developing fetus. Given the proven role of Toxoplasma-secreted kinases in the interaction of Toxoplasma with its host cell, identification of novel kinase inhibitors could precipitate the development of new anti-Toxoplasma drugs and define new pathways important for parasite survival. We selected a small (n = 527) but diverse set of putative kinase inhibitors and screened them for effects on the growth of Toxoplasma in vitro. We identified and validated 14 noncytotoxic compounds, all of which had 50% effective concentrations in the nanomolar to micromolar range. We further characterized eight of these compounds, four inhibitors and four enhancers, by determining their effects on parasite motility, invasion, and the likely cellular target (parasite or host cell). Only two compounds had an effect on parasite motility and invasion. All the inhibitors appeared to target the parasite, and interestingly, two of the enhancers appeared to rather target the host cell, suggesting modulation of host cell pathways beneficial for parasite growth. For the four inhibitors, we also tested their efficacy in a mouse model, where one compound proved potent. Overall, these 14 compounds represent a new and diverse set of small molecules that are likely targeting distinct parasite and host cell pathways. Future work will aim to characterize their molecular targets in both the host and parasite.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.00868-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486605PMC
November 2012

Insights gained from symptom evaluation of esophageal motility disorders: a review of 4,215 patients.

Digestion 2012 29;85(3):236-42. Epub 2012 Mar 29.

Department of Surgery, Creighton University Medical Center, Omaha, NE, USA.

Background/aims: Achalasia (Ach), diffuse esophageal spasm (DES), nutcracker esophagus (NE), and nonspecific motility disorder (NSMD) are described primary esophageal body motility disorders; however, their clinical symptom correlation is poorly understood. The aim of this study is to examine the association between a patient's presenting symptoms and their manometric diagnosis.

Methods: Manometric findings and reported symptoms of all patients undergoing esophageal manometry at the Creighton University Medical Center were prospectively entered in a database. Twenty-four-year data from 1984 through 2008 were accessed and analyzed.

Results: Of the 4,215 patients, 130 (3.1%) had Ach, 192 (4.6%) had DES, 290 (6.9%) had NE, 508 (12.1%) had NSMD, and 3,095 (73.4%) had normal esophageal body motility. There was significant symptom overlap between the groups. Ach and DES had a similar symptom distribution, with dysphagia being the predominant symptom. Patients with NE, normal body motility, and NSMD presented predominantly with reflux symptoms. There was an increasing prevalence of esophageal dysmotility (DES and NSMD) with age, and women were found to be more likely to have NE than men.

Conclusion: In an individual, reported symptoms do not correlate with their manometric diagnosis in a predictable fashion, and a thorough physiological assessment should be obtained to understand and diagnose the disease process. Esophageal motility deteriorates with age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000336072DOI Listing
September 2012

High-resolution manometry patterns of lower esophageal sphincter complex in symptomatic post-fundoplication patients.

J Gastrointest Surg 2012 Apr 10;16(4):705-14. Epub 2012 Jan 10.

Department of Surgery, Creighton University Medical Center, 601, North 30th Street, Suite 3700, Omaha, NE 68131, USA.

Introduction: There has been an increase in the number of patients seeking treatment after an anti-reflux surgical procedure. The objective of this study is to describe high-resolution manometry (HRM) topography as it relates to the post-fundoplication anatomy.

Methods: Retrospective review of a prospectively maintained database was conducted to identify patients who underwent esophagogastroduodenoscopy and HRM at Creighton University Medical Center (CUMC) between November 2008 and October 2010, for symptoms after a previous fundoplication. Patients were categorized as having intact, intrathoracic, disruptured, twisted, or slipped fundoplication based on endoscopic findings.

Results: Sixty-one patients {intact, 17(28%), disrupted, 2(3%), twisted, 3(5%), intra-thoracic, 18(30%), slipped, 21(34%)} are included in this study. A double high-pressure zone (HPZ) configuration was identified in both intra-thoracic and slipped fundoplication. This was not noted in appropriately positioned fundoplications. In intra-thoracic fundoplications, the HPZ below the fundoplication was lower pressure and showed respiratory variations. In slipped fundoplication, the higher HPZ had lower pressure and no respiratory variations. In appropriately positioned fundoplication, the lower esophageal sphincter (LES) pressure and extent of relaxation in the single HPZ correlated with intact (normal pressure and good relaxation), disrupted (low pressure and good relaxation), and twisted (high pressure with incomplete relaxation) fundoplication. Patients with only a recurrent para-esophageal hernia had characteristics of an appropriately positioned fundoplication.

Conclusion: LES complex HRM findings correlate well with anatomical status of the fundoplication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11605-011-1803-4DOI Listing
April 2012

The relationship between dysphagia, pump function, and lower esophageal sphincter pressures on high-resolution manometry.

J Gastrointest Surg 2012 Mar 20;16(3):495-502. Epub 2011 Dec 20.

Department of Surgery, Creighton University Medical Center, 601 North 30th Street, Suite 3700, Omaha, NE 68131, USA.

Introduction: Study objective was to compare high-resolution impedance manometry (HRIM) findings between patients with and without dysphagia.

Methods: After Institutional Review Board approval, a prospectively maintained database was reviewed to identify patients who underwent HRIM. Patients without upper endoscopy within 7 days of manometry, patients with achalasia, history of previous foregut surgery, esophageal strictures, or a large hiatus hernia were excluded. A new parameter called lower esophageal sphincter pressure integral (LESPI) was compared between patients with and without dysphagia. For subanalysis, subjects were categorized: (a) group A: no dysphagia and <60% hypocontractile or absent waves, (b) group B: dysphagia and <60% hypocontractile or absent waves, and (c) group C: ≥ 60% hypocontractile or absent waves.

Results: One hundred thirteen patients satisfied study criteria. Patients with dysphagia had a significantly higher LESPI and distal contractile integral (DCI). On multivariate regression analysis, the following were associated with dysphagia: (a) ≥ 60% hypocontractile or absent waves, (b) LESPI >400 mmHg s cm, and (c) DCI >3,000 mmHg s cm. However, 32% of patients with <60% hypocontractile or absent waves (group B) had dysphagia. These patients had a significantly higher DCI and LESPI than group A. Group C had a significantly lower DCI than all other patients.

Conclusions: Dysphagia in patients with ≥ 60% hypocontractile or absent waves is indicative of an intrinsic pump failure as they have low DCI, while dysphagia in patients with <60% hypocontractile or absent waves is more indicative of significant outflow obstruction as they have high LESPI and integrated relaxation pressure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11605-011-1799-9DOI Listing
March 2012

GLUT 5 is not over-expressed in breast cancer cells and patient breast cancer tissues.

PLoS One 2011 2;6(11):e26902. Epub 2011 Nov 2.

Molecular Imaging Program, Department of Radiology, Division of Nuclear Medicine, Stanford, California, United States of America.

F18 2-Fluoro 2-deoxyglucose (FDG) has been the gold standard in positron emission tomography (PET) oncologic imaging since its introduction into the clinics several years ago. Seeking to complement FDG in the diagnosis of breast cancer using radio labeled fructose based analogs, we investigated the expression of the chief fructose transporter-GLUT 5 in breast cancer cells and human tissues. Our results indicate that GLUT 5 is not over-expressed in breast cancer tissues as assessed by an extensive immunohistochemistry study. RT-PCR studies showed that the GLUT 5 mRNA was present at minimal amounts in breast cancer cell lines. Further knocking down the expression of GLUT 5 in breast cancer cells using RNA interference did not affect the fructose uptake in these cell lines. Taken together these results are consistent with GLUT 5 not being essential for fructose uptake in breast cancer cells and tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026902PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206880PMC
March 2012

18F-labeled bombesin analog for specific and effective targeting of prostate tumors expressing gastrin-releasing peptide receptors.

J Nucl Med 2011 Feb 13;52(2):270-8. Epub 2011 Jan 13.

Department of Chemistry and Applied Biosciences, Center for Radiopharmaceutical Sciences of ETH, PSI, and USZ, Zurich, Switzerland.

Unlabelled: Bombesin is a peptide exhibiting high affinity for the gastrin-releasing peptide receptor (GRPr), which is highly overexpressed on prostate cancer cells. In the present study, we developed an (18)F-labeled bombesin analog, (18)F-BAY 86-4367, which is currently being clinically tested for use in PET of prostate cancer.

Methods: In vitro pharmacologic studies were performed to characterize the nonradioactive ((19)F) standard of the bombesin analog for binding affinity and selectivity for GRPr. The stability of (18)F-BAY 86-4367 was determined in murine and human plasma. In vivo, the tumor-targeting potential and pharmacokinetic profile of the (18)F tracer were analyzed with biodistribution experiments and PET studies of prostate tumor-bearing mice.

Results: The nonradioactive ((19)F) standard of the bombesin analog showed subnanomolar and GRPr-selective binding affinity. The stability of the tracer in murine and human plasma was found to be high. In 2 prostate cancer xenograft models (PC-3 and LNCaP), (18)F-BAY 86-4367 showed more specific and effective GRPr-based targeting in vivo than the benchmark radiotracers (18)F-fluoroethylcholine and (18)F-FDG. In addition, rapid tumor targeting and fast renal excretion (∼70%) and hepatobiliary excretion (∼10%) were identified in both xenograft models. Furthermore, PET studies provided clear and specific visualization of PC-3 tumors in mice.

Conclusion: Favorable preclinical data showing specific and effective tumor targeting by (18)F-BAY 86-4367 suggest that a clinical trial be undertaken to test its diagnostic utility in PET for prostate carcinoma patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.110.081620DOI Listing
February 2011

In vitro and in vivo characterization of novel 18F-labeled bombesin analogues for targeting GRPR-positive tumors.

Bioconjug Chem 2010 Oct;21(10):1864-71

Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Zurich, Switzerland.

The gastrin-releasing peptide receptor (GRPR) is overexpressed on a number of human tumors and has been targeted with radiolabeled bombesin analogues for the diagnosis and therapy of these cancers. Seven bombesin analogues containing various linkers and peptide sequences were designed, synthesized, radiolabeled with (18)F, and characterized in vitro and in vivo as potential PET imaging agents. Binding studies displayed nanomolar binding affinities toward human GRPR for all synthesized bombesin analogues. Two high-affinity peptide candidates 6b (K(i) = 0.7 nM) and 7b (K(i) = 0.1 nM) were chosen for further in vivo evaluation. Both tracers revealed specific uptake in GRPR-expressing PC-3 tumors and the pancreas. Compared to [(18)F]6b, compound [(18)F]7b was characterized by superior tumor uptake, higher specificity of tracer uptake, and more favorable tumor-to-nontarget ratios. In vivo PET imaging allowed for the visualization of PC-3 tumor in nude mice suggesting that [(18)F]7b is a promising PET tracer candidate for the diagnosis of GRPR-positive tumors in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/bc100222uDOI Listing
October 2010