Publications by authors named "Matthew P Miller"

27 Publications

  • Page 1 of 1

Kinetic analysis and optimisation of F-rhPSMA-7.3 PET imaging of prostate cancer.

Eur J Nucl Med Mol Imaging 2021 Apr 12. Epub 2021 Apr 12.

Clinical Research Services Turku - CRST Ltd, Turku, Finland.

Purpose: This phase 1 open-label study evaluated the uptake kinetics of a novel theranostic PET radiopharmaceutical, F-rhPSMA-7.3, to optimise its use for imaging of prostate cancer.

Methods: Nine men, three with high-risk localised prostate cancer, three with treatment-naïve hormone-sensitive metastatic disease and three with castration-resistant metastatic disease, underwent dynamic 45-min PET scanning of a target area immediately post-injection of 300 MBq F-rhPSMA-7.3, followed by two whole-body PET/CT scans acquired from 60 and 90 min post-injection. Volumes of interest (VoIs) corresponding to prostate cancer lesions and reference tissues were recorded. Standardised uptake values (SUV) and lesion-to-reference ratios were calculated for 3 time frames: 35-45, 60-88 and 90-118 min. Net influx rates (K) were calculated using Patlak plots.

Results: Altogether, 44 lesions from the target area were identified. Optimal visual lesion detection started 60 min post-injection. The F-rhPSMA-7.3 signal from prostate cancer lesions increased over time, while reference tissue signals remained stable or decreased. The mean (SD) SUV (g/mL) at the 3 time frames were 8.4 (5.6), 10.1 (7) and 10.6 (7.5), respectively, for prostate lesions, 11.2 (4.3), 13 (4.8) and 14 (5.2) for lymph node metastases, and 4.6 (2.6), 5.7 (3.1) and 6.4 (3.5) for bone metastases. The mean (SD) lesion-to-reference ratio increases from the earliest to the 2 later time frames were 40% (10) and 59% (9), respectively, for the prostate, 65% (27) and 125% (47) for metastatic lymph nodes and 25% (19) and 32% (30) for bone lesions. Patlak plots from lesion VoIs signified almost irreversible uptake kinetics. K, SUV and lesion-to-reference ratio estimates showed good agreement.

Conclusion: F-rhPSMA-7.3 uptake in prostate cancer lesions was high. Lesion-to-background ratios increased over time, with optimal visual detection starting from 60 min post-injection. Thus, F-rhPSMA-7.3 emerges as a very promising PET radiopharmaceutical for diagnostic imaging of prostate cancer.

Trial Registration: NCT03995888 (24 June 2019).
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http://dx.doi.org/10.1007/s00259-021-05346-8DOI Listing
April 2021

Structural basis of Stu2 recruitment to yeast kinetochores.

Elife 2021 Feb 16;10. Epub 2021 Feb 16.

Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States.

Chromosome segregation during cell division requires engagement of kinetochores of sister chromatids with microtubules emanating from opposite poles. As the corresponding microtubules shorten, these 'bioriented' sister kinetochores experience tension-dependent stabilization of microtubule attachments. The yeast XMAP215 family member and microtubule polymerase, Stu2, associates with kinetochores and contributes to tension-dependent stabilization in vitro. We show here that a C-terminal segment of Stu2 binds the four-way junction of the Ndc80 complex (Ndc80c) and that residues conserved both in yeast Stu2 orthologs and in their metazoan counterparts make specific contacts with Ndc80 and Spc24. Mutations that perturb this interaction prevent association of Stu2 with kinetochores, impair cell viability, produce biorientation defects, and delay cell cycle progression. Ectopic tethering of the mutant Stu2 species to the Ndc80c junction restores wild-type function in vivo. These findings show that the role of Stu2 in tension-sensing depends on its association with kinetochores by binding with Ndc80c.
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http://dx.doi.org/10.7554/eLife.65389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909949PMC
February 2021

Evaluation of information on the Internet regarding surgical mesh for hernia repair: analysis of websites found through three popular search engines.

Hernia 2021 Feb 7. Epub 2021 Feb 7.

Department of Surgery, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States.

Purpose: Hernia repair remains one of the most common surgical procedures. Surgical mesh usage has been highlighted in the media due to recent lawsuits and recalls. Patients can read potentially biased information on the Internet and this can influence a patient's healthcare decisions. The purpose of this study is to evaluate search engine listings and respective website content of surgical mesh for hernia repair.

Methods: Websites evaluated were derived from four keyword searches targeting surgical mesh with Google, Yahoo, and Bing. Websites from the first two pages of each search were evaluated for content comprehensiveness.

Results: The largest category of websites from search engine results was legal advertisements, accounting for 20% of all results. These websites also held the first position on every results page. Legal advertisements and blog/forum websites were the most skewed toward surgical mesh risks and complications vs. benefits. There was a reduction in advertisements in 2020 vs. 2018. The most comprehensive non-advertisement websites were found more frequently. Overall, only 44% of websites presented references and 50% cited supporting data. Finally, 46% of 'recommended search terms' displayed on the search engine results page had a risk, complication, or legal bias.

Conclusions: These results emphasize the challenges of using an Internet search engine to find comprehensive and appropriate information regarding surgical mesh. This manuscript underscores the importance for physicians to direct patients toward specific websites to mitigate their exposure to websites that are biased and not appropriate for patients searching for an accurate and comprehensive overview of surgical mesh.
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http://dx.doi.org/10.1007/s10029-021-02375-yDOI Listing
February 2021

chTOG is a conserved mitotic error correction factor.

Elife 2020 12 30;9. Epub 2020 Dec 30.

Howard Hughes Medical Institute, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States.

Accurate chromosome segregation requires kinetochores on duplicated chromatids to biorient by attaching to dynamic microtubules from opposite spindle poles, which exerts forces to bring kinetochores under tension. However, kinetochores initially bind to microtubules indiscriminately, resulting in errors that must be corrected. While the Aurora B protein kinase destabilizes low-tension attachments by phosphorylating kinetochores, low-tension attachments are intrinsically less stable than those under higher tension in vitro independent of Aurora activity. Intrinsic tension-sensitive behavior requires the microtubule regulator Stu2 (budding yeast Dis1/XMAP215 ortholog), which we demonstrate here is likely a conserved function for the TOG protein family. The human TOG protein, chTOG, localizes to kinetochores independent of microtubules by interacting with Hec1. We identify a chTOG mutant that regulates microtubule dynamics but accumulates erroneous kinetochore-microtubule attachments that are not destabilized by Aurora B. Thus, TOG proteins confer a unique, intrinsic error correction activity to kinetochores that ensures accurate chromosome segregation.
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http://dx.doi.org/10.7554/eLife.61773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773332PMC
December 2020

Safety, Biodistribution, and Radiation Dosimetry of F-rhPSMA-7.3 in Healthy Adult Volunteers.

J Nucl Med 2021 May 16;62(5):679-684. Epub 2020 Oct 16.

Clinical Research Services Turku-CRST Ltd., Turku, Finland.

This first-in-humans study investigated the safety, biodistribution, and radiation dosimetry of a novel F-labeled radiohybrid prostate-specific membrane antigen (rhPSMA) PET imaging agent, F-rhPSMA-7.3. Six healthy volunteers (3 men, 3 women) underwent multiple whole-body PET acquisitions at scheduled time points up to 248 min after the administration of F-rhPSMA-7.3 (mean activity, 220; range, 210-228 MBq). PET scans were conducted in 3 separate sessions, and subjects were encouraged to void between sessions. Blood and urine samples were collected for up to 4 h after injection to assess metabolite-corrected radioactivity in whole blood, plasma, and urine. Quantitative measurements of F radioactivity in volumes of interest over target organs were determined directly from the PET images at 8 time points, and normalized time-activity concentration curves were generated. These normalized cumulated activities were then inputted into the OLINDA/EXM package to calculate the internal radiation dosimetry and the subjects' effective dose. F-rhPSMA-7.3 was well tolerated. One adverse event (mild headache, not requiring medication) was considered possibly related to F-rhPSMA-7.3. The calculated effective dose was 0.0141 mSv/MBq when using a 3.5-h voiding interval. The organs with the highest mean absorbed dose per unit of administered radioactivity were the adrenals (0.1835 mSv/MBq), the kidneys (0.1722 mSv/MBq), the submandibular glands (0.1479 mSv), and the parotid glands (0.1137 mSv/MBq). At the end of the first scanning session (mean time, 111 min after injection), an average of 7.2% (range, 4.4%-9.0%) of the injected radioactivity of F-rhPSMA-7.3 was excreted into urine. The safety, biodistribution, and internal radiation dosimetry of F-rhPSMA-7.3 are considered favorable for PET imaging.
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http://dx.doi.org/10.2967/jnumed.120.252114DOI Listing
May 2021

Cdk1 Phosphorylation of the Dam1 Complex Strengthens Kinetochore-Microtubule Attachments.

Curr Biol 2020 11 17;30(22):4491-4499.e5. Epub 2020 Sep 17.

Howard Hughes Medical Institute, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA 98109, USA. Electronic address:

To ensure the faithful inheritance of DNA, a macromolecular protein complex called the kinetochore sustains the connection between chromosomes and force-generating dynamic microtubules during cell division. Defects in this process lead to aneuploidy, a common feature of cancer cells and the cause of many developmental diseases [1-4]. One of the major microtubule-binding activities in the kinetochore is mediated by the conserved Ndc80 complex (Ndc80c) [5-7]. In budding yeast, the retention of kinetochores on dynamic microtubule tips also depends on the essential heterodecameric Dam1 complex (Dam1c) [8-15], which binds to the Ndc80c and is proposed to be a functional ortholog of the metazoan Ska complex [16, 17]. The load-bearing activity of the Dam1c depends on its ability to oligomerize, and the purified complex spontaneously self-assembles into microtubule-encircling oligomeric rings, which are proposed to function as collars that allow kinetochores to processively track the plus-end tips of microtubules and harness the forces generated by disassembling microtubules [10-15, 18-22]. However, it is unknown whether there are specific regulatory events that promote Dam1c oligomerization to ensure accurate segregation. Here, we used a reconstitution system to discover that Cdk1, the major mitotic kinase that drives the cell cycle, phosphorylates the Ask1 component of the Dam1c to increase its residence time on microtubules and enhance kinetochore-microtubule attachment strength. We propose that Cdk1 activity promotes Dam1c oligomerization to ensure that kinetochore-microtubule attachments are stabilized as kinetochores come under tension in mitosis.
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http://dx.doi.org/10.1016/j.cub.2020.08.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497780PMC
November 2020

Effect of F-Fluciclovine Positron Emission Tomography on the Management of Patients With Recurrence of Prostate Cancer: Results From the FALCON Trial.

Int J Radiat Oncol Biol Phys 2020 06 14;107(2):316-324. Epub 2020 Feb 14.

Departments of Radiology and Nuclear Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

Purpose: Early and accurate localization of lesions in patients with biochemical recurrence (BCR) of prostate cancer may guide salvage therapy decisions. The present study, F-Fluciclovine PET/CT in biochemicAL reCurrence Of Prostate caNcer (FALCON; NCT02578940), aimed to evaluate the effect of F-fluciclovine on management of men with BCR of prostate cancer.

Methods And Materials: Men with a first episode of BCR after curative-intent primary therapy were enrolled at 6 UK sites. Patients underwent F-fluciclovine positron emission tomography/computed tomography (PET/CT) according to standardized procedures. Clinicians documented management plans before and after scanning, recording changes to treatment modality as major and changes within a modality as other. The primary outcome measure was record of a revised management plan postscan. Secondary endpoints were evaluation of optimal prostate specific antigen (PSA) threshold for detection, salvage treatment outcome assessment based on F-fluciclovine-involvement, and safety.

Results: F-Fluciclovine was well tolerated in the 104 scanned patients (median PSA = 0.79 ng/mL). Lesions were detected in 58 out of 104 (56%) patients. Detection was broadly proportional to PSA level; ≤1 ng/mL, 1 out of 3 of scans were positive, and 93% scans were positive at PSA >2.0 ng/mL. Sixty-six (64%) patients had a postscan management change (80% after a positive result). Major changes (43 out of 66; 65%) were salvage or systemic therapy to watchful waiting (16 out of 66; 24%); salvage therapy to systemic therapy (16 out of 66; 24%); and alternative changes to treatment modality (11 out of 66, 17%). The remaining 23 out of 66 (35%) management changes were modifications of the prescan plan: most (22 out of 66; 33%) were adjustments to planned brachytherapy/radiation therapy to include a F-fluciclovine-guided boost. Where F-fluciclovine guided salvage therapy, the PSA response rate was higher than when F-fluciclovine was not involved (15 out of 17 [88%] vs 28 out of 39 [72%]).

Conclusions: F-Fluciclovine PET/CT located recurrence in the majority of men with BCR, frequently resulting in major management plan changes. Incorporating F-fluciclovine PET/CT into treatment planning may optimize targeting of recurrence sites and avoid futile salvage therapy.
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http://dx.doi.org/10.1016/j.ijrobp.2020.01.050DOI Listing
June 2020

The impact of internet-based patient self-education of surgical mesh on patient attitudes and healthcare decisions prior to hernia surgery.

Surg Endosc 2020 11 12;34(11):5132-5141. Epub 2019 Dec 12.

Department of Surgery, Minimally Invasive Surgery, Washington University School of Medicine, Campus Box 8109, St. Louis, MO, 63110, USA.

Background: As internet access improves, patient self-education continues to increase. However, patient surgical background, e-literacy, and media exposure potentially influence what information patients search online. This impacts patient concern, healthcare decisions, and subsequent patient-physician interactions. The purpose of this pilot study is to characterize hernia patients' use and the impact of internet self-education regarding surgical mesh.

Methods: The target population included patients presenting for evaluation of hernia repair with mesh. A total of 30 patients were enrolled. Patients took surveys before and after the initial surgical consult. The surveys evaluated internet use, mesh research completed, the impact on patient opinions/decisions, and the impact of research on the patient-physician interaction.

Results: The average age of the patients was 58.7 years; sixteen had prior surgery with surgical mesh. 93% of patients were aware of surgical mesh through the media, and 60% were motivated by the media to conduct research. 90% of patients conducted research, and 67% used the internet. Patients with negative attitudes toward mesh had more media exposure in comparison to those with neutral or positive attitudes (p = 0.046), and they were more likely to have researched surgical mesh because of media influence (p = 0.033). This group had the highest rate of perceived knowledge on mesh risks and the lowest regarding benefits (p = 0.013). Patients who had prior surgery without complication had the most positive attitude toward surgical mesh (p = 0.010) and were less likely to plan to do future internet research (p = 0.041) in comparison to patients who had surgery with complications or no prior surgery.

Conclusions: Patients' attitudes and perceived knowledge regarding surgical mesh are associated with media exposure and internet research. These attributes along with prior surgical experience impact the patient-physician relationship and shared decision-making model regarding patient care.
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http://dx.doi.org/10.1007/s00464-019-07300-0DOI Listing
November 2020

Kinetochore-associated Stu2 promotes chromosome biorientation in vivo.

PLoS Genet 2019 10 4;15(10):e1008423. Epub 2019 Oct 4.

Howard Hughes Medical Institute, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

Accurate segregation of chromosomes to daughter cells is a critical aspect of cell division. It requires the kinetochores on duplicated chromosomes to biorient, attaching to microtubules from opposite poles of the cell. Bioriented attachments come under tension, while incorrect attachments lack tension and must be released to allow proper attachments to form. A well-studied error correction pathway is mediated by the Aurora B kinase, which destabilizes low tension-bearing attachments. We recently discovered that in vitro, kinetochores display an additional intrinsic tension-sensing pathway that utilizes Stu2. The contribution of kinetochore-associated Stu2 to error correction in cells, however, was unknown. Here, we identify a Stu2 mutant that abolishes its kinetochore function and show that it causes biorientation defects in vivo. We also show that this Stu2-mediated pathway functions together with the Aurora B-mediated pathway. Altogether, our work indicates that cells employ multiple pathways to ensure biorientation and the accuracy of chromosome segregation.
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http://dx.doi.org/10.1371/journal.pgen.1008423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795502PMC
October 2019

Design principles of a microtubule polymerase.

Elife 2018 06 13;7. Epub 2018 Jun 13.

Departments of Biophysics and Biochemistry, UT Southwestern Medical Center, Dallas, United States.

Stu2/XMAP215 microtubule polymerases use multiple tubulin-binding TOG domains and a lattice-binding basic region to processively promote faster elongation. How the domain composition and organization of these proteins dictate polymerase activity, end localization, and processivity is unknown. We show that polymerase activity does not require different kinds of TOGs, nor are there strict requirements for how the TOGs are linked. We identify an unexpected antagonism between the tubulin-binding TOGs and the lattice-binding basic region: lattice binding by the basic region is weak when at least two TOGs engage tubulins, strong when TOGs are empty. End-localization of Stu2 requires unpolymerized tubulin, at least two TOGs, and polymerase competence. We propose a 'ratcheting' model for processivity: transfer of tubulin from TOGs to the lattice activates the basic region, retaining the polymerase at the end for subsequent rounds of tubulin binding and incorporation. These results clarify design principles of the polymerase.
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http://dx.doi.org/10.7554/eLife.34574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999394PMC
June 2018

Reader Training for the Restaging of Biochemically Recurrent Prostate Cancer Using F-Fluciclovine PET/CT.

J Nucl Med 2017 10 6;58(10):1596-1602. Epub 2017 Apr 6.

Blue Earth Diagnostics (BED), Oxford, United Kingdom.

F-Fluciclovine is a novel PET/CT tracer. This blinded image evaluation (BIE) sought to demonstrate that, after limited training, readers naïve to F-fluciclovine could interpret F-fluciclovine images from subjects with biochemically recurrent prostate cancer with acceptable diagnostic performance and reproducibility. The primary objectives were to establish individual readers' diagnostic performance and the overall interpretation (2/3 reader concordance) compared with standard-of-truth data (histopathology or clinical follow-up) and to evaluate interreader reproducibility. Secondary objectives included comparison to the expert reader and assessment of intrareader reproducibility. F-Fluciclovine PET/CT images ( = 121) and corresponding standard-of-truth data were collected from 110 subjects at Emory University using a single-time-point static acquisition starting 5 min after injection of approximately 370 MBq of F-fluciclovine. Three readers were trained using standardized interpretation methodology and subsequently evaluated the images in a blinded manner. Analyses were conducted at the lesion, region (prostate, including bed and seminal vesicle, or extraprostatic, including all lymph nodes, bone, or soft-tissue metastasis), and subject level. Lesion-level overall positive predictive value was 70.5%. The readers' positive predictive value and negative predictive value were broadly consistent with each other and with the onsite read. Sensitivity was highest for readers 1 and 2 (68.5% and 63.9%, respectively) whereas specificity was highest for reader 3 (83.6%). Overall, prostate-level sensitivity was high (91.4%), but specificity was moderate (48.7%). Interreader agreement was 94.7%, 74.4%, and 70.3% for the lesion, prostate, and extraprostatic levels, respectively, with associated Fleiss' κ-values of 0.54, 0.50, and 0.57. Intrareader agreement was 97.8%, 96.9%, and 99.1% at the lesion level; 100%, 100%, and 91.7% in the prostate region; and 83.3%, 75.0%, and 83.3% in the extraprostatic region for readers 1, 2, and 3, respectively. Concordance between the BIE and the onsite reader exceeded 75% for each reader at the lesion, region, and subject levels. Specific training in the use of standardized interpretation methodology for assessment of F-fluciclovine PET/CT images enables naïve readers to achieve acceptable diagnostic performance and reproducibility when staging recurrent prostate cancer.
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http://dx.doi.org/10.2967/jnumed.116.188375DOI Listing
October 2017

Simplified Calvarial Reconstruction: Coverage of Bare Skull With GammaGraft Promotes Granulation and Facilitates Skin Grafting.

J Craniofac Surg 2016 Oct;27(7):1808-1809

*Department of Plastic Surgery, University of Pittsburgh †VA Pittsburgh Healthcare System ‡McGowan Institute for Regenerative Medicine, Pittsburgh, PA.

Repair of scalp defects with exposed calvaria remains a difficult clinical problem. Herein, we present a simple alternative method of scalp reconstruction. Coverage of bare skull with GammaGraft (Promethean LifeSciences, Inc, Pittsburgh, PA) promotes the evolution of granulation tissue and permits subsequent skin grafting without need for burring, drilling, or other manipulation of the outer table of the calvaria. A retrospective review of patients undergoing scalp reconstruction utilizing GammaGraft and subsequent skin grafting was performed at our institution. From our cohort, 5 patients treated with GammaGraft and subsequent skin grafting had both immediate and long-term follow-up available. Indications for scalp reconstruction included erosions of prior skin grafts and direct excision of full-thickness scalp and pericranium. Average time to definitive skin grafting was 3 weeks; repeat application of GammaGraft was required in some patients with reapplication to subsequent smaller wounds as healing occurred. Complications were minor and consisted of ongoing wound drainage. Alternative flap reconstruction was not required in any patient due to treatment failures. No major complications, wound infections, or early reoperations occurred in any of the patients; 1 patient to date has required repeat reconstruction due to recurrent disease. Coverage of bare skull with GammaGraft and subsequent skin grafting provides a simple and elegant solution to an often too difficult clinical problem. Confirmed by results in out limited series, the utilization of GammaGraft in calvarial reconstruction represents an alternative method in surgical care of complex scalp defects with exposed bone.
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http://dx.doi.org/10.1097/SCS.0000000000003037DOI Listing
October 2016

A TOG Protein Confers Tension Sensitivity to Kinetochore-Microtubule Attachments.

Cell 2016 Jun 5;165(6):1428-1439. Epub 2016 May 5.

Howard Hughes Medical Institute, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address:

The development and survival of all organisms depends on equal partitioning of their genomes during cell division. Accurate chromosome segregation requires selective stabilization of kinetochore-microtubule attachments that come under tension due to opposing pulling forces exerted on sister kinetochores by dynamic microtubule tips. Here, we show that the XMAP215 family member, Stu2, makes a major contribution to kinetochore-microtubule coupling. Stu2 and its human ortholog, ch-TOG, exhibit a conserved interaction with the Ndc80 kinetochore complex that strengthens its attachment to microtubule tips. Strikingly, Stu2 can either stabilize or destabilize kinetochore attachments, depending on the level of kinetochore tension and whether the microtubule tip is assembling or disassembling. These dichotomous effects of Stu2 are independent of its previously studied regulation of microtubule dynamics. Altogether, our results demonstrate how a kinetochore-associated factor can confer opposing, tension-dependent effects to selectively stabilize tension-bearing attachments, providing mechanistic insight into the basis for accuracy during chromosome segregation.
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http://dx.doi.org/10.1016/j.cell.2016.04.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892958PMC
June 2016

Multicenter Reproducibility of 18F-Fluciclatide PET Imaging in Subjects with Solid Tumors.

J Nucl Med 2015 Dec 17;56(12):1855-61. Epub 2015 Sep 17.

Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom

Unlabelled: Integrins are upregulated on both tumor cells and associated vasculature, where they play an important role in angiogenesis and metastasis. Fluciclatide is an arginine-glycine-aspartic acid peptide with high affinity for αvβ3/αvβ5 integrin, which can be radiolabeled for PET imaging of angiogenesis. Thus, (18)F-fluciclatide is a potential biomarker of therapeutic response to antiangiogenic inhibitors. The aim of this study was to evaluate the reproducibility of (18)F-fluciclatide in multiple solid-tumor types.

Methods: Thirty-nine patients underwent PET/CT scanning at 40, 65, and 90 min after injection of (18)F-fluciclatide (maximum, 370 MBq) on 2 separate days (2-9 d apart). Patients did not receive any therapy between PET/CT scans. (18)F-fluciclatide images were reported and quantitative measures of uptake were extracted using the PERCIST methodology. Intrasubject reproducibility of PET uptake in all measurable lesions was evaluated by calculating relative differences in SUV between PET scans for each lesion during the 2 imaging sessions.

Results: Thirty-nine measurable lesions were detected in 26 patients. Lesion uptake correlated strongly across imaging sessions (r = 0.92, P < 0.05, at 40 min; r = 0.94, P < 0.05, at 65 min; r = 0.94, P < 0.05, at 90 min) with a mean relative difference and SD of the relative difference of 0.006 ± 0.18 at 40 min, 0.003 ± 0.19 at 65 min, and 0.025 ± 0.20 at 90 min. This reflects 95% limits of repeatability of 35%-39% for the difference between the 2 SUV measurements or a variability of 18%-20% in agreement from that observed in well-calibrated multicenter (18)F-FDG studies.

Conclusion: The test-retest reproducibility of (18)F-fluciclatide across multiple tumor types has been measured and shown to be acceptable. This is an important step in the development of this in vivo biomarker to identify and quantify response to antiangiogenic therapy in cancer patients.
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http://dx.doi.org/10.2967/jnumed.115.158253DOI Listing
December 2015

Return to system within 30 days of discharge following pediatric non-shunt surgery.

J Neurosurg Pediatr 2014 Dec 17;14(6):654-61. Epub 2014 Oct 17.

Pediatric Neurosurgery Associates, Children's Healthcare of Atlanta;

Object: Hospital readmission after discharge is a commonly used quality measure. In a previous study, the authors had documented the rate of readmission and reoperation after pediatric CSF shunt surgery. This study documents the rate of readmission and reoperation after pediatric neurosurgical procedures excluding those related to CSF shunts.

Methods: Between May 1, 2009, and April 30, 2013, 3098 non-shunt surgeries during 2924 index admissions were performed at a single institution. Demographic, socioeconomic, and clinical characteristics were prospectively collected in the administrative, business, and clinical databases. Clinical events within the 30 days following discharge were reviewed and analyzed. The following events of interest were analyzed for risk factor associations using multivariate logistic regression: return to the emergency department (ED), all-cause readmission, readmission to the neurosurgical service, and reoperation.

Results: The number of all-cause readmissions within 30 days of discharge was 304 (10.4%, 304/2924). Admission sources consisted of the ED (n = 173), hospital transfers (n = 47), and others (n = 84). One hundred eighty of the 304 readmissions were associated with an operation, but only 153 were performed by the neurosurgical service (reoperation rate = 5.2%). These procedures included wound revisions (n = 30) and first-time shunt insertions (n = 35). The remaining 124 readmissions were nonsurgical, and only 54 were admitted to the neurosurgical service for issues related to the index non-shunt surgery. Thus, the rate of related readmission was 7.1% ([153 + 54]/2924). A longer length of stay and admission to the neonatal intensive care unit during the index admission were associated with an increased likelihood of return to the ED and readmission. Certain procedures, such as baclofen pump insertion and intracranial pressure monitor placement, were also found to be associated with adverse clinical events in the 30-day period. Lastly, patients were more likely to a undergo reoperation if the index procedure had started after 3 p.m.

Conclusions: The all-cause readmission rate within 30 days of discharge after a pediatric neurosurgical procedure was 10.4%, and the rate of related readmission was 7.1%. Whether these readmissions are preventable and to what extent they are preventable requires further study.
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http://dx.doi.org/10.3171/2014.8.PEDS14109DOI Listing
December 2014

Kinetochores require oligomerization of Dam1 complex to maintain microtubule attachments against tension and promote biorientation.

Nat Commun 2014 Sep 19;5:4951. Epub 2014 Sep 19.

Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.

Kinetochores assemble on centromeric DNA and present arrays of proteins that attach directly to the dynamic ends of microtubules. Kinetochore proteins coordinate at the microtubule interface through oligomerization, but how oligomerization contributes to kinetochore function has remained unclear. Here, using a combination of biophysical assays and live-cell imaging, we find that oligomerization of the Dam1 complex is required for its ability to form microtubule attachments that are robust against tension in vitro and in vivo. An oligomerization-deficient Dam1 complex that retains wild-type microtubule binding activity is primarily defective in coupling to disassembling microtubule ends under mechanical loads applied by a laser trap in vitro. In cells, the oligomerization-deficient Dam1 complex is unable to support stable bipolar alignment of sister chromatids, indicating failure of kinetochore-microtubule attachments under tension. We propose that oligomerization is an essential and conserved feature of kinetochore components that is required for accurate chromosome segregation during mitosis.
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http://dx.doi.org/10.1038/ncomms5951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197110PMC
September 2014

[¹⁸F]fluciclatide in the in vivo evaluation of human melanoma and renal tumors expressing αvβ 3 and α vβ 5 integrins.

Eur J Nucl Med Mol Imaging 2014 Oct 28;41(10):1879-88. Epub 2014 Jun 28.

Molecular Imaging Program, NCI, NIH, Bethesda, MD, USA.

Purpose: [(18)F]Fluciclatide is an integrin-targeted PET radiopharmaceutical. αvβ3 and αvβ5 are upregulated in tumor angiogenesis as well as on some tumor cell surfaces. Our aim was to use [(18)F]fluciclatide (formerly known as [(18)F]AH111585) for PET imaging of angiogenesis in melanoma and renal tumors and compare with tumor integrin expression.

Methods: Eighteen evaluable patients with solid tumors ≥2.0 cm underwent [(18)F]fluciclatide PET/CT. All patients underwent surgery and tumor tissue samples were obtained. Immunohistochemical (IHC) staining with mouse monoclonal antibodies and diaminobenzidine (DAB) was applied to snap-frozen tumor specimens, and additional IHC was done on formalin-fixed paraffin-embedded samples. DAB optical density (OD) data from digitized whole-tissue sections were compared with PET SUV80% max, and Patlak influx rate constant (K i) data, tumor by tumor.

Results: Tumors from all 18 patients demonstrated measurable [(18)F]fluciclatide uptake. At the final dynamic time-point (55 min after injection), renal malignancies (in 11 patients) demonstrated an average SUV80% max of 6.4 ± 2.0 (range 3.8 - 10.0), while the average SUV80% max for metastatic melanoma lesions (in 6 patients) was 3.0 ± 2.0 (range 0.7 - 6.5). There was a statistically significant difference in [(18)F]fluciclatide uptake between chromophobe and nonchromophobe renal cell carcinoma (RCCs, with SUV80% max of 8.2 ± 1.8 and 5.4 ± 1.4 (P = 0.020) and tumor-to-normal kidney (T/N) ratios of 1.5 ± 0.4 and 0.9 ± 0.2, respectively (P = 0.029). The highest Pearson's correlation coefficients were obtained when comparing Patlak K i and αvβ5 OD when segregating the patient population between melanoma and RCC (r = 0.83 for K i vs. melanoma and r = 0.91 for K i vs. RCC). SUV80% max showed a moderate correlation with αvβ5 and αvβ3 OD.

Conclusion: [(18)F]Fluciclatide PET imaging was well tolerated and demonstrated favorable characteristics for imaging αvβ3 and αvβ5 expression in melanoma and RCC. Higher uptake was observed in chromophobe than in nonchromophobe RCC. [(18)F]Fluciclatide may be a useful radiotracer to improve knowledge of integrin expression.
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http://dx.doi.org/10.1007/s00259-014-2791-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336392PMC
October 2014

Connecting heterogeneous single slip to diffraction peak evolution in high-energy monochromatic X-ray experiments.

J Appl Crystallogr 2014 Jun 10;47(Pt 3):887-898. Epub 2014 May 10.

Sibley School of Mechanical and Aerospace Engineering, Cornell University and Cornell High Energy Synchrotron Source, Ithaca, NY, USA.

A forward modeling diffraction framework is introduced and employed to identify slip system activity in high-energy diffraction microscopy (HEDM) experiments. In the framework, diffraction simulations are conducted on virtual mosaic crystals with orientation gradients consistent with Nye's model of heterogeneous single slip. Simulated diffraction peaks are then compared against experimental measurements to identify slip system activity. Simulation results compared against diffraction data measured from a silicon single-crystal specimen plastically deformed under single-slip conditions indicate that slip system activity can be identified during HEDM experiments.
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http://dx.doi.org/10.1107/S1600576714005779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038796PMC
June 2014

Polo kinase Cdc5 is a central regulator of meiosis I.

Proc Natl Acad Sci U S A 2013 Aug 5;110(35):14278-83. Epub 2013 Aug 5.

Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

During meiosis, two consecutive rounds of chromosome segregation yield four haploid gametes from one diploid cell. The Polo kinase Cdc5 is required for meiotic progression, but how Cdc5 coordinates multiple cell-cycle events during meiosis I is not understood. Here we show that CDC5-dependent phosphorylation of Rec8, a subunit of the cohesin complex that links sister chromatids, is required for efficient cohesin removal from chromosome arms, which is a prerequisite for meiosis I chromosome segregation. CDC5 also establishes conditions for centromeric cohesin removal during meiosis II by promoting the degradation of Spo13, a protein that protects centromeric cohesin during meiosis I. Despite CDC5's central role in meiosis I, the protein kinase is dispensable during meiosis II and does not even phosphorylate its meiosis I targets during the second meiotic division. We conclude that Cdc5 has evolved into a master regulator of the unique meiosis I chromosome segregation pattern.
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http://dx.doi.org/10.1073/pnas.1311845110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761645PMC
August 2013

Meiosis I: when chromosomes undergo extreme makeover.

Curr Opin Cell Biol 2013 Dec 2;25(6):687-96. Epub 2013 Aug 2.

Koch Institute for Integrative Cancer Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Howard Hughes Medical Institute, USA.

The ultimate success of cell division relies on the accurate partitioning of the genetic material. Errors in this process occur in nearly all tumors and are the leading cause of miscarriages and congenital birth defects in humans. Two cell divisions, mitosis and meiosis, use common as well as unique mechanisms to ensure faithful chromosome segregation. In mitosis, alternating rounds of DNA replication and chromosome segregation preserve the chromosome complement of the progenitor cell. In contrast, during meiosis two consecutive rounds of nuclear division, meiosis I and meiosis II, follow a single round of DNA replication to reduce the chromosome complement by half. Meiosis likely evolved through changes to the mitotic cell division program. This review will focus on the recent findings describing the modifications that transform mitosis into meiosis.
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http://dx.doi.org/10.1016/j.ceb.2013.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836829PMC
December 2013

An experimental system for high temperature X-ray diffraction studies with in situ mechanical loading.

Rev Sci Instrum 2013 Mar;84(3):033902

Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York 14853, USA.

An experimental system with in situ thermomechanical loading has been developed to enable high energy synchrotron x-ray diffraction studies of crystalline materials. The system applies and maintains loads of up to 2250 N in uniaxial tension or compression at a frequency of up to 100 Hz. The furnace heats the specimen uniformly up to a maximum temperature of 1200 °C in a variety of atmospheres (oxidizing, inert, reducing) that, combined with in situ mechanical loading, can be used to mimic processing and operating conditions of engineering components. The loaded specimen is reoriented with respect to the incident beam of x-rays using two rotational axes to increase the number of crystal orientations interrogated. The system was used at the Cornell High Energy Synchrotron Source to conduct experiments on single crystal silicon and polycrystalline Low Solvus High Refractory nickel-based superalloy. The data from these experiments provide new insights into how stresses evolve at the crystal scale during thermomechanical loading and complement the development of high-fidelity material models.
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http://dx.doi.org/10.1063/1.4793230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108638PMC
March 2013

Meiosis I chromosome segregation is established through regulation of microtubule-kinetochore interactions.

Elife 2012 Dec 18;1:e00117. Epub 2012 Dec 18.

Department of Biology , Massachusetts Institute of Technology , Cambridge , United States.

During meiosis, a single round of DNA replication is followed by two consecutive rounds of nuclear divisions called meiosis I and meiosis II. In meiosis I, homologous chromosomes segregate, while sister chromatids remain together. Determining how this unusual chromosome segregation behavior is established is central to understanding germ cell development. Here we show that preventing microtubule-kinetochore interactions during premeiotic S phase and prophase I is essential for establishing the meiosis I chromosome segregation pattern. Premature interactions of kinetochores with microtubules transform meiosis I into a mitosis-like division by disrupting two key meiosis I events: coorientation of sister kinetochores and protection of centromeric cohesin removal from chromosomes. Furthermore we find that restricting outer kinetochore assembly contributes to preventing premature engagement of microtubules with kinetochores. We propose that inhibition of microtubule-kinetochore interactions during premeiotic S phase and prophase I is central to establishing the unique meiosis I chromosome segregation pattern.DOI:http://dx.doi.org/10.7554/eLife.00117.001.
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http://dx.doi.org/10.7554/eLife.00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525924PMC
December 2012

Freshwater DOM quantity and quality from a two-component model of UV absorbance.

Water Res 2012 Sep 26;46(14):4532-42. Epub 2012 May 26.

Centre for Ecology and Hydrology, Lancaster Environment Centre, Bailrigg, Lancaster LA1 4AP, United Kingdom.

We present a model that considers UV-absorbing dissolved organic matter (DOM) to consist of two components (A and B), each with a distinct and constant spectrum. Component A absorbs UV light strongly, and is therefore presumed to possess aromatic chromophores and hydrophobic character, whereas B absorbs weakly and can be assumed hydrophilic. We parameterised the model with dissolved organic carbon concentrations [DOC] and corresponding UV spectra for c. 1700 filtered surface water samples from North America and the United Kingdom, by optimising extinction coefficients for A and B, together with a small constant concentration of non-absorbing DOM (0.80 mg DOCL⁻¹). Good unbiased predictions of [DOC] from absorbance data at 270 and 350 nm were obtained (r² = 0.98), the sum of squared residuals in [DOC] being reduced by 66% compared to a regression model fitted to absorbance at 270 nm alone. The parameterised model can use measured optical absorbance values at any pair of suitable wavelengths to calculate both [DOC] and the relative amounts of A and B in a water sample, i.e. measures of quantity and quality. Blind prediction of [DOC] was satisfactory for 9 of 11 independent data sets (181 of 213 individual samples).
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http://dx.doi.org/10.1016/j.watres.2012.05.021DOI Listing
September 2012

Dissolved organic matter sources and consequences for iron and arsenic mobilization in Bangladesh aquifers.

Environ Sci Technol 2010 Jan;44(1):123-8

INSTAAR, University of Colorado, 450 UCB, Boulder, Colorado 80309, USA.

Iron (Fe) and dissolved organic matter (DOM) cycling have been implicated in arsenic mobilization via microbially mediated Fe oxide reduction. To evaluate the sources and multiple roles of DOM in Bangladesh aquifers, we conducted spectroscopic analyses on various types of surface water and groundwater samples from a site representative of aquifer chemistry and hydrology. Surface water contained humic substances with oxidized quinone-like moieties and high concentrations of labile microbially derived DOM. In contrast, in shallow groundwater where dissolved iron and arsenic concentrations were high, the quinone-like moieties of humic substances were more reduced, with less abundant labile DOM than that of surface water. Instead, DOM at these depths was characterized by terrestrial (plant/soil) signatures. A sediment microcosm experiment demonstrated that Fe(II) and terrestrially derived DOM were released from sediment over time. The results provide new evidence to support a dual role of natural DOM in Bangladesh aquifers (1) as a labile substrate for Fe- and humic-reducing bacteria and (2) as an electron shuttle via humic substances to enhance microbial iron reduction. Fluorescence index, amino acid-like fluorescence, and redox index may serve as useful indicators of the type of DOM likely to be involved in Fe solubilization and potentially As mobilization reactions.
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http://dx.doi.org/10.1021/es901472gDOI Listing
January 2010

The biodistribution and radiation dosimetry of the Arg-Gly-Asp peptide 18F-AH111585 in healthy volunteers.

J Nucl Med 2008 Oct 15;49(10):1664-7. Epub 2008 Sep 15.

Medical Diagnostics, GE Healthcare Ltd., Amersham, Buckinghamshire, England.

Unlabelled: We report the safety, biodistribution, and internal radiation dosimetry of a new PET tracer, (18)F-AH111585, a peptide with a high affinity for the alpha(v)beta(3) integrin receptor involved in angiogenesis.

Methods: PET scans of 8 healthy volunteers were acquired at time points up to 4 h after a bolus injection of (18)F-AH111585. (18)F activity in whole blood and plasma and excreted urine were measured up to 4 h after injection. In vivo (18)F activities in up to 12 source regions were determined from quantitative analysis of the images. The cumulated activities subsequently calculated were then used to determine the internal radiation dosimetry, including the effective dose.

Results: Injection of (18)F-AH111585 was well tolerated in all subjects, with no serious or drug-related adverse events reported. The main route of (18)F excretion was renal (37%), and the 3 highest initial uptakes were by liver (15%); combined walls of the small, upper large, and lower large intestines (11%); and kidneys (9%). The 3 highest absorbed doses were received by the urinary bladder wall (124 microGy/MBq), kidneys (102 microGy/MBq), and cardiac wall (59 microGy/MBq). The effective dose was 26 microGy/MBq.

Conclusion: (18)F-AH111585 is a safe PET tracer with a dosimetry profile comparable to other common (18)F PET tracers.
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http://dx.doi.org/10.2967/jnumed.108.052126DOI Listing
October 2008

A methodology for measuring in situ lattice strain of bulk polycrystalline material under cyclic load.

Rev Sci Instrum 2007 Feb;78(2):023910

Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York 14853, USA.

The material response of polycrystalline materials under cyclic loading is not fully understood. Even during uniaxial loading, individual grains embedded within the polycrystalline material can experience complicated strain histories. By quantifying the deformation state at the crystal level, we can begin to understand the conditions that lead to fatigue failure. An in situ powder diffraction method was developed and employed at the Cornell High Energy Synchrotron Source to measure the aggregate crystal response at various points in a material's life using synchrotron x ray. A set of experiments was conducted using a load frame capable of exerting cyclic uniaxial loads on a specimen. A high speed x-ray shutter was developed to synchronize the x-ray beam and the loading cycle. Using the high speed shutter, the evolution of the lattice strains for the families of crystallographic planes was measured while the aggregate was under cyclic uniaxial loading, thus monitoring a live evolution of lattice strain in a cyclically loaded specimen. The methodology is demonstrated using uniaxial cyclic specimens machined from oxygen free conductivity (OFHC) copper sheet.
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http://dx.doi.org/10.1063/1.2670463DOI Listing
February 2007

Hyporheic exchange and fulvic acid redox reactions in an Alpine stream/wetland ecosystem, Colorado Front Range.

Environ Sci Technol 2006 Oct;40(19):5943-9

Department of Civil, Environmental, and Architectural Engineering, Institute of Arctic and Alpine Research, University of Colorado, Boulder 80309-0450, USA.

The influence of hyporheic zone interactions on the redox state of fulvic acids and other redox active species was investigated in an alpine stream and adjacent wetland, which is a more reducing environment. A tracer injection experiment using bromide (Br-) was conducted in the stream system. Simulations with a transport model showed that rates of exchange between the stream and hyporheic zone were rapid (alpha approximately 10(-3) s(-1)). Parallel factor analysis of fluorescence spectra was used to quantifythe redox state of dissolved fulvic acids. The rate coefficient for oxidation of reduced fulvic acids (lambda = 6.5 x 10(-3) s(-1)) in the stream indicates that electron-transfer reactions occur over short time scales. The rate coefficients for decay of ammonium (lambda = 1.2 x 10(-3) s(-1)) and production of nitrate (lambda = -1.0 x 10(-3) s(-1)) were opposite in sign but almost equal in magnitude. Our results suggest that fulvic acids are involved in rapid electron-transfer processes in and near the stream channel and may be important in determining ecological energy flow at the catchment scale.
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http://dx.doi.org/10.1021/es060635jDOI Listing
October 2006