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1.
JAMA Intern Med ; 183(10): 1168-1170, 2023 Oct 01.
Article in English | MEDLINE | ID: mdl-37639238

ABSTRACT

This cross-sectional study quantifies the portrayal of women as physicians in US movies over the past 3 decades.

2.
Cardiooncology ; 9(1): 4, 2023 Jan 18.
Article in English | MEDLINE | ID: mdl-36653885

ABSTRACT

BACKGROUND: Hypomethylating agents (HMAs) have shown efficacy in the treatment of hematological malignancies and are indicated for the treatment of chronic myelomonocytic leukemia (CMML). While the HMA decitabine, in its intravenous formulation, has been used since 2006 for the treatment of CMML, use of its oral formulation has been limited by poor bioavailability due to first-pass metabolism by the enzyme cytidine deaminase. The dose of intravenous decitabine is limited by toxicities such as cardiomyopathy and heart failure. Therefore, cedazuridine was developed as an inhibitor of cytidine deaminase. Cedazuridine decreases the first-pass metabolism of oral decitabine allowing therapeutic levels to be achieved at lower doses, and thus, the novel oral combination of cedazuridine with decitabine was developed. While cardiomyopathy and heart failure are well-established adverse effects associated with intravenous decitabine alone, there to our knowledge there have been no documented incidences of reversible cardiomyopathy in the literature or in patients who participated in the phase 2 and phase 3 clinical trials of oral decitabine-cedazuridine. CASE: This case study presents an 85 year-old Caucasian female with CMML who developed cardiomyopathy and heart failure with reduced ejection fraction after completing 5 cycles of therapy with decitabine/cedazuridine. Furthermore, her symptoms and cardiac function recovered upon discontinuation of the drug. CONCLUSIONS: We present an occurrence of reversible cardiomyopathy in a patient who completed 5 cycles of decitabine/cedazuridine, an oral combination therapy developed to enhance oral bioavailability of decitabine thereby limiting its adverse effects. As the decitabine/cedazuridine combination therapy rises in popularity due to its convenient oral formulation, more trials are needed to understand the prevalence of cardiomyopathy with this drug and to discover preventative strategies for cardiotoxic effects.

3.
J Nephrol ; 35(3): 1033-1040, 2022 04.
Article in English | MEDLINE | ID: mdl-34757576

ABSTRACT

BACKGROUND: Cystogenesis in polycystic kidney disease (PKD) is likely accelerated by various renal insults, including crystal deposition, that activate renal tubule obstruction and dilation. We developed a capsule-based device that can be applied to cystic kidneys to restrict tubular lumen dilatation and cyst expansion. METHODS: Kidney capsule devices were designed from computed tomography images of wild-type and Cy/+ rats. Capsule devices were surgically implanted on kidneys in six surgical sessions over a period of 14 months in 7 wild-type rats of 6.5-8 weeks (3 sham operations, 2 right, 2 left) and 6 Cy/+ rats of 6.5 weeks (2 sham, 3 left, 1 bilateral). After surgery, the rats were followed for 5.4-12.4 weeks' growth and sacrificed to retrieve the kidneys. During the follow-up, serum creatinine was measured and retrieved kidneys were weighed. Histological analysis including cystic area measurement and immunohistochemistry was performed. RESULTS: Morphometric capsule devices were configured and developed by an image processing technique and produced using a 3D printer. Encapsulated Cy/+ kidneys (n = 5; mean weight 3.64 g) were consistently smaller in size (by 21-36%; p < 0.001) than unencapsulated Cy/+ kidneys (n = 7; mean weight 5.52 g). Encapsulated Cy/+ kidneys (mean %cyst area: 29.4%) showed smaller histological cystic area (by 28-58%; p < 0.001) than unencapsulated Cy/+ kidneys (mean %cyst area 48.6%). Cell proliferation and macrophages were also markedly reduced in encapsulated Cy/+ kidneys, compared to unencapsulated Cy/+ kidneys. CONCLUSIONS: We report a pilot feasibility study for the application of a novel morphometric 3D capsule device to the Cy/+ rat model showing restricted kidney volume expansion on polycystic kidney disease progression.


Subject(s)
Cysts , Polycystic Kidney Diseases , Animals , Cell Proliferation , Cysts/pathology , Disease Models, Animal , Feasibility Studies , Humans , Kidney/pathology , Polycystic Kidney Diseases/pathology , Rats
4.
Chem Sci ; 12(42): 14309-14315, 2021 Nov 03.
Article in English | MEDLINE | ID: mdl-34760217

ABSTRACT

Azide moieties, unique linear species containing three nitrogen atoms, represent an attractive class of molecular tag for hyperpolarized magnetic resonance imaging (HP-MRI). Here we demonstrate (15N)3-azide-containing molecules exhibit long-lasting hyperpolarization lifetimes up to 9.8 min at 1 T with remarkably high polarization levels up to 11.6% in water, thus establishing (15N)3-azide as a powerful spin storage for hyperpolarization. A single (15N)-labeled azide has also been examined as an effective alternative tag with long-lived hyperpolarization. A variety of biologically important molecules are studied in this work, including choline, glucose, amino acid, and drug derivatives, demonstrating great potential of 15N-labeled azides as universal hyperpolarized tags for nuclear magnetic resonance imaging applications.

5.
NPJ Breast Cancer ; 7(1): 142, 2021 Nov 11.
Article in English | MEDLINE | ID: mdl-34764307

ABSTRACT

In the BrighTNess trial, carboplatin added to neoadjuvant chemotherapy (NAC) was associated with increased pathologic complete response (pCR) rates in patients with stage II/III triple-negative breast cancer (TNBC). In this matched cohort study, cases with a germline BRCA1/2 mutation (gBRCA; n = 75) were matched 1:2 with non-gBRCA controls (n = 150) by treatment arm, lymph node status, and age to evaluate pCR rates and association of benefit from platinum/PARP inhibitors with validated RNA expression-based immune, proliferation, and genomic instability scores among gBRCA with the addition of carboplatin ± veliparib to NAC. Among the well-matched cohorts, odds of pCR were not higher in gBRCA cancers who received standard NAC with carboplatin (OR 0.24, 95% CI [0.04-1.24], p = 0.09) or with carboplatin/veliparib (OR 0.44, 95% CI [0.10-1.84], p = 0.26) compared to non-gBRCA cancers. Higher PAM50 proliferation, GeparSixto immune, and CIN70 genomic instability scores were each associated with higher pCR rate in the overall cohort, but not specifically in gBRCA cases. In this study, gBRCA carriers did not have higher odds of pCR than non-gBRCA controls when carboplatin ± veliparib was added to NAC, and showed no significant differences in molecular, immune, chromosomal instability, or proliferation gene expression metrics.

7.
Adv Radiat Oncol ; 6(5): 100735, 2021.
Article in English | MEDLINE | ID: mdl-34278054

ABSTRACT

PURPOSE: We aimed to evaluate the growth of women within the general radiation oncology (RO) workforce in comparison to the growth among other medical specialties. We also sought to create a predictive model for gender diversity to guide future recruitment efforts. METHODS AND MATERIALS: We identified 16 medical specialties, including RO, for analyses. We used data from the Association of American Colleges and assessed female representation at 4 time points (2006, 2011, 2016, and 2020). Additionally, we determined characteristics of medical specialties that were predictive of increased gender diversity. We performed univariate statistical analysis with linear regression to evaluate factors predictive of greater gender diversity among the medical specialties in our cohort. RESULTS: The proportion of women within the represented specialties increased over time. Obstetrics/gynecology (14,750 [2006], 23,921 [2020]; 18.7% absolute growth) and dermatology (3568 [2006], 6329 [2020]; 15.1% absolute growth) experienced the highest absolute growth in female representation between 2006 and 2020. When assessing changes between various time points in RO, the absolute change in female physicians increased by 1.5% between 2006 and 2011, by 2.2% between 2011 and 2016, and by only 0.4% between 2016 and 2020, which was the lowest growth pattern relative to the other 15 specialties. Factors predictive of gender diversity among specialties were lower average step 1 scores (P = .0056), fewer years of training (P = .0078), fewer work hours (P = .046), the availability of a standard third year clerkship for a given specialty (P = .0061), and a high baseline number of female physicians within a specialty (P = .0078). Research activities (P = .099) and interest among matriculating medical students (P = .28) were not statistically significant. CONCLUSIONS: The percentage of women in RO lags behind other medical specialties and has been notably low in the last few years. Interventions that incorporate novel initiatives proposed within this study may accelerate current recruitment milestones.

9.
JAMA Oncol ; 7(4): 603-608, 2021 Apr 01.
Article in English | MEDLINE | ID: mdl-33599688

ABSTRACT

IMPORTANCE: Adding carboplatin to standard neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) likely benefits a subset of patients; however, determinants of benefit are poorly understood. OBJECTIVE: To define the association of molecular subtype, tumor proliferation, and immunophenotype with benefit of carboplatin added to NAC for patients with stages II to III TNBC. DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified secondary analysis of a phase 3, double-blind, randomized clinical trial (BrighTNess) that enrolled 634 women across 145 centers in 15 countries. Women with clinical stages II to III TNBC who had undergone pretreatment biopsy were eligible to participate. Whole transcriptome RNA sequencing was performed on the biopsy specimens. The prespecified end point was association of pathologic complete response (pCR) with gene expression-based molecular subtype, with secondary end points investigating established signatures (proliferation, immune) and exploratory analyses of immunophenotype. Data were collected from April 2014 to March 2016. The study analyses were performed from January 2018 to March 2019. INTERVENTIONS: Neoadjuvant chemotherapy with paclitaxel followed by doxorubicin and cyclophosphamide, or this same regimen with carboplatin or carboplatin plus veliparib. MAIN OUTCOMES AND MEASURES: Association of gene expression-based molecular subtype (PAM50 and TNBC subtypes) with pCR. RESULTS: Of the 634 women (median age, 51 [range, 22-78] years) enrolled in BrighTNess, 482 (76%) patients had evaluable RNA sequencing data, with similar baseline characteristics relative to the overall intention-to-treat population. Pathologic complete response was significantly more frequent in PAM50 basal-like vs nonbasal-like cancers overall (202 of 386 [52.3%] vs 34 of 96 [35.4%]; P = .003). Carboplatin benefit was not significantly different in basal-like vs nonbasal-like subgroups (P = .80 for interaction). In multivariable analysis, proliferation (hazard ratio, 0.36; 95% CI, 0.21-0.61; P < .001) and immune (hazard ratio, 0.62; 95% CI, 0.49-0.79; P < .001) signatures were independently associated with pCR. Tumors above the median for proliferation and immune signatures had the highest pCR rate (84 of 125; 67%), while those below the median for both signatures had the lowest pCR rate (42 of 125; 34%). Exploratory gene expression immune analyses suggested that tumors with higher inferred CD8+ T-cell infiltration may receive greater benefit with addition of carboplatin. CONCLUSIONS AND RELEVANCE: In this secondary analysis of a randomized clinical trial, triple-negative breast cancer subtyping revealed high pCR rates in basal-like and immunomodulatory subsets. Analysis of biological processes related to basal-like and immunomodulatory phenotypes identified tumor cell proliferation and immune scores as independent factors associated with achieving pCR; the benefit of carboplatin on pCR was seen across all molecular subtypes. Further validation of immunophenotype with existing biomarkers may help to escalate or de-escalate therapy for patients with TNBC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02032277.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Neoadjuvant Therapy , Triple Negative Breast Neoplasms , Carboplatin , Female , Humans , Immunophenotyping , Paclitaxel , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology
10.
Ann Surg Oncol ; 28(1): 59-66, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32424588

ABSTRACT

BACKGROUND: The objective of this study is to characterize the religion and spiritual (R&S) needs of patients who undergo cancer-directed surgery. In addition, we seek to examine how R&S needs vary based on R&S identity and clinical and surgical treatment characteristics. PATIENTS AND METHODS: A cross-sectional survey was administered to potential participants who were recruited through outpatient clinics and online. Respondent desires for R&S resources and engagement with the healthcare team  around R&S topics were assessed. RESULTS: Among 383 potential participants who were identified, 236 respondents were included in the analytic cohort. Mean age was 58.8 (SD 12.10) years, and most participants were female (75.8%) and White/Caucasian (94.1%). The majority (78.4%) identified as currently cancer free. Commonly treated malignancies included breast (43.2%), male reproductive (8.9%), skin (8.5%), and gastrointestinal (GI) (7.2%). Two-thirds of the respondents indicated a desire to have R&S incorporated into their cancer treatment (63.3%). Patients who identified as highly/moderately religious reported wanting R&S more often (highly religious: 95.2% versus moderately religious: 71.4% vs. nonreligious but spiritual: 4.5%). On multivariable analysis, patients who believed their health would improve in the future were more likely to report wanting R&S service (OR 2.2, 95% CI 1.0-4.7) as well as wanting to engage their healthcare providers on R&S topics (OR 2.4, 95% CI 1.2-4.7). In contrast, perception of current or future health status was not associated with patient desire for the actual surgeon/doctor him/herself to be involved in R&S activities (OR 1.83, 95% CI 0.97-3.45). CONCLUSIONS: Two-thirds of patients undergoing cancer-directed surgery expressed a desire to have R&S incorporated into their cancer treatment. Incorporating R&S into cancer treatment can help a subset of patients throughout their cancer experience.


Subject(s)
Neoplasms , Physicians , Religion , Spirituality , Cross-Sectional Studies , Female , Health Services Needs and Demand , Humans , Male , Middle Aged , Neoplasms/psychology , Neoplasms/therapy
11.
Palliat Support Care ; 19(2): 175-181, 2021 04.
Article in English | MEDLINE | ID: mdl-32854807

ABSTRACT

OBJECTIVE: We sought to characterize patients' preferences for the role of religious and spiritual (R&S) beliefs and practices during cancer treatment and describe the R&S resources desired by patients during the perioperative period. METHOD: A cross-sectional survey was administered to individuals who underwent cancer-directed surgery. Data on demographics and R&S beliefs/preferences were collected and analyzed. RESULTS: Among 236 participants, average age was 58.8 (SD = 12.10) years; the majority were female (76.2%), white (94.1%), had a significant other or spouse (60.2%), and were breast cancer survivors (43.6%). Overall, more than one-half (55.9%) of individuals identified themselves as being religious, while others identified as only spiritual (27.9%) or neither (16.2%). Patients who identified as religious wanted R&S integrated into their care more often than patients who were only spiritual or neither (p < 0.001). Nearly half of participants (49.6%) wanted R&S resources when admitted to the hospital including the opportunity to speak with an R&S leader (e.g., rabbi; 72.1%), R&S texts (64.0%), and journaling materials (54.1%). Irrespective of R&S identification, 68.0% of patients did not want their physician to engage with them about R&S topics. SIGNIFICANCE OF RESULTS: Access to R&S resources is important during cancer treatment, and incorporating R&S into cancer care may be especially important to patients that identify as religious. R&S needs should be addressed as part of the cancer care plan.


Subject(s)
Cancer Survivors , Neoplasms , Physician-Patient Relations , Religion and Medicine , Spirituality , Cancer Survivors/psychology , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Neoplasms/psychology , Neoplasms/surgery , Physicians/psychology , Religion , Surveys and Questionnaires
12.
Surgery ; 168(1): 56-61, 2020 07.
Article in English | MEDLINE | ID: mdl-32439206

ABSTRACT

BACKGROUND: Cholecystectomy is one of the most commonly performed operations in the United States, yet it still carries up to a 6% risk of major morbidity. Lawsuits are a major source of emotional, financial, and personal stress for surgeons. We sought to characterize malpractice claims associated with gallbladder surgery as well as define contributing factors and costs with these claims. METHODS: The Westlaw database (Thomson Reuters Corporation, Toronto, Canada) was queried for jury verdicts and settlements related to cholecystectomy and malpractice between 2000 and 2018. Data were abstracted from the case files and details of the settlements, jury verdicts, and factors related to the claims were assessed. RESULTS: Among 231 cases, a plaintiff verdict was reached in 45 (19.5%) and a defendant verdict was reached in 122 (53%); other cases were either settled (n = 29, 12%), dismissed (n = 31, 13%), or denied (n = 4, 2%). Plaintiff cases often involved young (median age, 44 years [interquartile range: 35-57]) female (n = 146, 63%) patients. The attending surgeon accounted for 59% of defendants. Procedural error (49%), wrongful death (18%), or failure to treat in a timely manner (13%) were the most commonly cited reasons for litigation. Among the 134 cases where a second surgical procedure was performed, the most common types of procedures were biliary tract repair (n = 82, 61%) and bowel repair (n = 16, 12%). The total cost of the claims over the study period was $22 million with a median payout of $500,000; the median time from operative event to final disposition was over 5 years (interquartile range: 4-7). CONCLUSION: A plaintiff verdict or settlement was reached in 1 in 3 cases, and large payouts were common. Minimizing procedural error and improving care of patients after cholecystectomy complications should be emphasized.


Subject(s)
Cholecystectomy/legislation & jurisprudence , Malpractice/legislation & jurisprudence , Malpractice/statistics & numerical data , Adult , Databases, Factual , Female , Humans , Male , Medical Errors/legislation & jurisprudence , Medical Errors/statistics & numerical data , Middle Aged
13.
Surgery ; 167(6): 985-990, 2020 06.
Article in English | MEDLINE | ID: mdl-32305231

ABSTRACT

BACKGROUND: Gastrointestinal cancers contribute substantially to the cost of health care. We sought to quantify and compare the financial burden associated with treatment of gastrointestinal cancers versus other common nongastrointestinal cancers. METHODS: The Medical Expenditure Panel Survey from 2006 to 2015 was used to identify individuals with gastrointestinal cancer, other nongastrointestinal cancer (breast/prostate or lung), or no history of malignancy. Total and out-of-pocket medical expenditures were compared. Among each cohort, risk of high and catastrophic financial burden was determined. RESULTS: A total of 90,344 individuals were identified, which was extrapolated to a national representative sample of 95,449,062 individuals. Overall, an estimated 365,367 (0.4%) individuals had a gastrointestinal cancer while 2,015,724 (2.1%) had lung, breast, or prostate cancer. Mean adjusted total health expenditures was greater among patients with gastrointestinal cancer ($13,716; 95% confidence interval, $9,805-$17,628) versus patients with nongastrointestinal cancer ($8,665; 95% confidence interval, $8,222-$9,108) or individuals without cancer ($5,807; 95% confidence interval $5,740-$5,874). An estimated 15.8% (n = 57,898) and 7.1% (n = 25,956) of patients with gastrointestinal cancer experienced a high and catastrophic financial burden, respectively. Patients with gastrointestinal cancer had a 64% increased odds of experiencing catastrophic financial burden compared with patients without a history of cancer (odds ratio 1.64, 95% confidence interval, 1.17-2.31). Furthermore, patients with a gastrointestinal cancer had nearly 40% increased odds of high financial burden associated with their care compared with patients without cancer (odds ratio 1.37; 95% confidence interval, 1.00-1.88). CONCLUSION: The risk of experiencing catastrophic financial burden among patients with gastrointestinal cancer was considerable, as roughly 1 in 7 patients experienced high financial burden, and 1 in 13 had a catastrophic financial burden.


Subject(s)
Gastrointestinal Neoplasms/economics , Health Expenditures/statistics & numerical data , Adult , Aged , Female , Gastrointestinal Neoplasms/epidemiology , Health Surveys , Humans , Insurance Coverage/statistics & numerical data , Insurance, Health/statistics & numerical data , Male , Medically Uninsured/statistics & numerical data , Middle Aged , United States/epidemiology
14.
Bioconjug Chem ; 31(3): 537-541, 2020 03 18.
Article in English | MEDLINE | ID: mdl-32023034

ABSTRACT

15N2-Diazirines represent an attractive class of imaging tags for hyperpolarized magnetic resonance imaging (HP-MRI), offering desirable biocompatibility, ease of incorporation into a variety of molecules, and ability to deliver long-lasting polarization. We have recently established hyperpolarization of 15N2-diazirines in organic solvents using SABRE-Shield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH). Yet, the current challenge of SABRE-SHEATH in water, specifically poor polarization efficiency, presents a barrier in examining the practical use of 15N2-diazirines for HP-MRI. Herein, we show that efficient polarization of diverse 15N2-diazirine-labeled molecules in water can be readily achieved by dissolution dynamic nuclear polarization (d-DNP), a hyperpolarization technique used in clinical practice. Hyperpolarization by d-DNP also demonstrates greater enhancement for long-lasting 15N signals, in comparison with SABRE-SHEATH. Various biologically important molecules are studied in this work, including amino acid, sugar, and drug compounds, demonstrating the great potential of 15N2-diazirines as molecular tags in broad biomedical and clinical applications.


Subject(s)
Diazomethane/chemistry , Magnetic Resonance Imaging/methods , Nitrogen Isotopes/chemistry
15.
Am J Surg ; 220(1): 120-126, 2020 07.
Article in English | MEDLINE | ID: mdl-31619377

ABSTRACT

INTRODUCTION: The Affordable Care Act introduced restrictions on the creation of new physician-owned hospitals (POH). We sought to define whether POH status was associated with differences in care. METHODS: Patients undergoing one of ten surgical procedures were identified using Medicare Standard Analytic Files. Patient and hospital-level characteristics and outcomes between POH and non-POH were compared. RESULTS: Among 1,255,442 patients identified, 14,560 (1.2%) were treated at POH. A majority of POHs were in urban areas (n = 30, 90.9%) and none were in low socioeconomic status areas. Patients at POH were slightly younger (POH:72, IQR:68-77 vs. non-POH:73, IQR:69-79) and healthier (CCI; POH:2; IQR: 1-3 vs. non-POH: 3; IQR: 1-4). Patients at non-POH had higher odds of postoperative complications (OR:1.67, 95%CI:1.55-1.80) and slightly higher medical expenditures (POH:$11,347, IQR:$11,139-$11,936 vs. non-POH:$13,389, IQR:$11,381-$19,592). CONCLUSIONS: POH were more likely to be located in socioeconomic advantaged areas, treat healthier patients and have lower associated expenditures.


Subject(s)
Health Expenditures/statistics & numerical data , Hospitals, Private/economics , Ownership , Physicians/economics , Postoperative Complications/epidemiology , Surgical Procedures, Operative/economics , Hospitalization/economics , Hospitalization/statistics & numerical data , Humans , Postoperative Complications/economics , Surgical Procedures, Operative/adverse effects , Surgical Procedures, Operative/statistics & numerical data , United States
16.
Nat Commun ; 10(1): 395, 2019 01 23.
Article in English | MEDLINE | ID: mdl-30674881

ABSTRACT

Signal amplification by reversible exchange (SABRE) is an efficient method to hyperpolarize spin-1/2 nuclei and affords signals that are orders of magnitude larger than those obtained by thermal spin polarization. Direct polarization transfer to heteronuclei such as 13C or 15N has been optimized at static microTesla fields or using coherence transfer at high field, and relies on steady state exchange with the polarization transfer catalyst dictated by chemical kinetics. Here we demonstrate that pulsing the excitation field induces complex coherent polarization transfer dynamics, but in fact pulsing with a roughly 1% duty cycle on resonance produces more magnetization than constantly being on resonance. We develop a Monte Carlo simulation approach to unravel the coherent polarization dynamics, show that existing SABRE approaches are quite inefficient in use of para-hydrogen order, and present improved sequences for efficient hyperpolarization.


Subject(s)
Hydrogen/chemistry , Magnetic Resonance Spectroscopy , Pyridines/chemistry , Catalysis , Kinetics , Magnetic Fields , Models, Molecular , Models, Theoretical , Nitrogen Isotopes/chemistry
17.
Sci Adv ; 4(3): eaar2978, 2018 03.
Article in English | MEDLINE | ID: mdl-29536045

ABSTRACT

Hyperpolarized magnetic resonance (HP-MR) is a powerful, sensitive, and noninvasive approach to visualize molecular structure, function, and dynamics in vitro and in vivo. Current applications of HP-MR mostly rely on hyperpolarization of target compounds in dedicated hyperpolarizers because biomolecules can typically not be hyperpolarized directly in vivo. The injected hyperpolarized probes often undergo multiple metabolic pathways in living systems, and it remains challenging to localize and identify specific targets with high chemical selectivity. To address these current limitations in HP-MR, we report a novel hyperpolarization tagging strategy that integrates bioorthogonal chemistry and hyperpolarization to achieve the specific hyperpolarization of targets. This strategy is demonstrated by studies of hyperpolarized 15N4-1,2,4,5-tetrazines, which undergo rapid and selective cycloaddition with cyclooctyne to provide hyperpolarized 15N2-containing cycloaddition products and hyperpolarized 15N2 gas. This work not only suggests great potential of 15N4-1,2,4,5-tetrazines as molecular tags in HP-MR imaging (HP-MRI) but also supports the production of hyperpolarized para-15N2 gas, a biologically and medically innocuous gas with great potential for HP-MRI. This bioorthogonal reaction-based hyperpolarization tagging strategy enables a new class of in vitro and in vivo applications.

18.
Angew Chem Int Ed Engl ; 56(40): 12112-12116, 2017 09 25.
Article in English | MEDLINE | ID: mdl-28664640

ABSTRACT

Diazirines are an attractive class of potential molecular tags for magnetic resonance imaging owing to their biocompatibility and ease of incorporation into a large variety of molecules. As recently reported, 15 N2 -diazirine can be hyperpolarized by the SABRE-SHEATH method, sustaining both singlet and magnetization states, thus offering a path to long-lived polarization storage. Herein, we show the generality of this approach by illustrating that the diazirine tag alone is sufficient for achieving excellent signal enhancements with long-lasting polarization. Our investigations reveal the critical role of Lewis basic additives, including water, on achieving SABRE-promoted hyperpolarization. The application of this strategy to a 15 N2 -diazirine-containing choline derivative demonstrates the potential of 15 N2 -diazirines as molecular imaging tags for biomedical applications.

19.
J Am Chem Soc ; 139(23): 7761-7767, 2017 06 14.
Article in English | MEDLINE | ID: mdl-28443329

ABSTRACT

Signal amplification by reversible exchange (SABRE) is an inexpensive, fast, and even continuous hyperpolarization technique that uses para-hydrogen as hyperpolarization source. However, current SABRE faces a number of stumbling blocks for translation to biochemical and clinical settings. Difficulties include inefficient polarization in water, relatively short-lived 1H-polarization, and relatively limited substrate scope. Here we use a water-soluble polarization transfer catalyst to hyperpolarize nitrogen-15 in a variety of molecules with SABRE-SHEATH (SABRE in shield enables alignment transfer to heteronuclei). This strategy works in pure H2O or D2O solutions, on substrates that could not be hyperpolarized in traditional 1H-SABRE experiments, and we record 15N T1 relaxation times of up to 2 min.


Subject(s)
Hydrogen/chemistry , Nitrogen Isotopes/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Water/chemistry
20.
Am J Nephrol ; 38(4): 333-41, 2013.
Article in English | MEDLINE | ID: mdl-24107679

ABSTRACT

OBJECTIVE: To evaluate whether kidney and cyst volumes can be accurately estimated based on limited area measurements from magnetic resonance (MR) images of patients with autosomal dominant polycystic kidney disease (ADPKD). MATERIALS AND METHODS: MR coronal images of 178 ADPKD participants from the Consortium for Radiologic Imaging Studies of ADPKD (CRISP) were analyzed. For each MR image slice, we measured kidney and renal cyst areas using stereology and region-based thresholding methods, respectively. The kidney and cyst 'observed' volumes were calculated by summing up the area measurements of all the slices covering the kidney. To estimate the volume, we selected a coronal mid-slice in each kidney and multiplied its area by the total number of slices ('PANK2' for kidney and 'PANC2' for cyst). We then compared the kidney and cyst volumes predicted from PANK2 and PANC2, respectively, to the corresponding observed volumes, using a linear regression analysis. RESULTS: The kidney volume predicted from PANK2 correlated extremely well with the observed kidney volume (R(2) = 0.994 for the right kidney and 0.991 for the left kidney). The linear regression coefficient multiplier to PANK2 that best fit the kidney volume was 0.637 (95% CI: 0.629-0.644) for the right kidney and 0.624 (95% CI: 0.616-0.633) for the left kidney. The correlation between the cyst volume predicted from PANC2 and the observed cyst volume was also very high (R(2) = 0.984 for the right kidney and 0.967 for the left kidney). The least squares linear regression coefficient for PANC2 was 0.637 (95% CI: 0.624-0.649) for the right kidney and 0.608 (95% CI: 0.591-0.625) for the left kidney. CONCLUSION: Kidney and cyst volumes can be closely approximated by multiplying the product of the mid-slice area measurement and the total number of slices in the coronal MR images of ADPKD kidneys by 0.61-0.64. This information will help save processing time needed to estimate total kidney and cyst volumes of ADPKD kidneys.


Subject(s)
Cysts/pathology , Magnetic Resonance Imaging/methods , Polycystic Kidney Diseases/pathology , Polycystic Kidney, Autosomal Dominant/pathology , Adolescent , Adult , Cysts/diagnosis , Female , Humans , Image Processing, Computer-Assisted , Kidney/pathology , Least-Squares Analysis , Longitudinal Studies , Male , Polycystic Kidney Diseases/diagnosis , Polycystic Kidney, Autosomal Dominant/diagnosis , Prospective Studies , Regression Analysis , Young Adult
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