Publications by authors named "James Hansen"

135 Publications

LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy.

Nat Cell Biol 2020 10 1;22(10):1276-1285. Epub 2020 Oct 1.

Department of Neurosurgery, Yale University, New Haven, CT, USA.

Breast cancer brain metastasis (BCBM) is a devastating disease. Radiation therapy remains the mainstay for treatment of this disease. Unfortunately, its efficacy is limited by the dose that can be safely applied. One promising approach to overcoming this limitation is to sensitize BCBMs to radiation by inhibiting their ability to repair DNA damage. Here, we report a DNA repair suppressor, leucine-rich repeat-containing protein 31 (LRRC31), that was identified through a genome-wide CRISPR screen. We found that overexpression of LRRC31 suppresses DNA repair and sensitizes BCBMs to radiation. Mechanistically, LRRC31 interacts with Ku70/Ku80 and the ataxia telangiectasia mutated and RAD3-related (ATR) at the protein level, resulting in inhibition of DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) recruitment and activation, and disruption of the MutS homologue 2 (MSH2)-ATR module. We demonstrate that targeted delivery of the LRRC31 gene via nanoparticles improves the survival of tumour-bearing mice after irradiation. Collectively, our study suggests LRRC31 as a major DNA repair suppressor that can be targeted for cancer radiosensitizing therapy.
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http://dx.doi.org/10.1038/s41556-020-00586-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962994PMC
October 2020

Multi-institutional retrospective review of stereotactic radiosurgery for brain metastasis in patients with small cell lung cancer without prior brain-directed radiotherapy.

J Radiosurg SBRT 2020 ;7(1):19-27

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06511, USA.

Patients with small cell lung cancer (SCLC) brain metastasis (BM) typically receive whole brain radiotherapy (WBRT) as data regarding upfront radiosurgery (SRS) in this setting are sparse. Patients receiving SRS for SCLC BM without prior brain radiation were identified at three U.S. institutions. Overall survival (OS), freedom from intracranial progression (FFIP), freedom from WBRT (FFWBRT), and freedom from neurologic death (FFND) were determined from time of SRS. Thirty-three patients were included with a median of 2 BM (IQR 1-6). Median OS and FFIP were 6.7 and 5.8 months, respectively. Median FFIP for patients with ≤2 versus >2 BM was 7.1 versus 3.6 months, p=0.0303. Eight patients received salvage WBRT and the 6-month FFWBRT and FFND were 87.8%. and 90.1%, respectively. Most SCLC patients with BM who received upfront SRS avoided WBRT and neurologic death, suggesting that SRS may be an option in select patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406345PMC
January 2020

Potential for large-scale CO removal via enhanced rock weathering with croplands.

Nature 2020 07 8;583(7815):242-248. Epub 2020 Jul 8.

Global Food and Environment Institute, University of Leeds, Leeds, UK.

Enhanced silicate rock weathering (ERW), deployable with croplands, has potential use for atmospheric carbon dioxide (CO) removal (CDR), which is now necessary to mitigate anthropogenic climate change. ERW also has possible co-benefits for improved food and soil security, and reduced ocean acidification. Here we use an integrated performance modelling approach to make an initial techno-economic assessment for 2050, quantifying how CDR potential and costs vary among nations in relation to business-as-usual energy policies and policies consistent with limiting future warming to 2 degrees Celsius. China, India, the USA and Brazil have great potential to help achieve average global CDR goals of 0.5 to 2 gigatonnes of carbon dioxide (CO) per year with extraction costs of approximately US$80-180 per tonne of CO. These goals and costs are robust, regardless of future energy policies. Deployment within existing croplands offers opportunities to align agriculture and climate policy. However, success will depend upon overcoming political and social inertia to develop regulatory and incentive frameworks. We discuss the challenges and opportunities of ERW deployment, including the potential for excess industrial silicate materials (basalt mine overburden, concrete, and iron and steel slag) to obviate the need for new mining, as well as uncertainties in soil weathering rates and land-ocean transfer of weathered products.
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http://dx.doi.org/10.1038/s41586-020-2448-9DOI Listing
July 2020

Cancer and Systemic Lupus Erythematosus.

Rheum Dis Clin North Am 2020 Aug 10;46(3):533-550. Epub 2020 Jun 10.

Department of Medicine, McGill University, 1001 Decarie Boulevard, Suite D05-2212, Montreal, Quebec H4A 3J1, Canada; Division of Clinical Epidemiology, Research Institute of McGill University Health Centre, 5252 de Maisonneuve West, 3rd Floor, Montreal, Quebec H4A 3S5, Canada. Electronic address:

Systemic lupus erythematosus is associated with a small overall increased cancer risk compared with the general population. This risk includes a 4-fold increased risk of non-Hodgkin lymphoma, but a decreased risk of other cancers (such as breast cancer). The pathophysiology underlying the increased risk of hematologic cancer is not fully understood, but many potential mechanisms have been proposed, including dysfunction of the tumor necrosis factor and other pathways. A decreased risk of breast, ovarian, and endometrial cancer might be driven by hormonal factors or lupus-related antibodies, but these links have not been proved.
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http://dx.doi.org/10.1016/j.rdc.2020.05.005DOI Listing
August 2020

A New Bronchodilator Response Grading Strategy Identifies Distinct Patient Populations.

Ann Am Thorac Soc 2019 12;16(12):1504-1517

Rehabilitation Clinical Trials Center and.

A positive bronchodilator response (BDR) according to American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines require both 200 ml and 12% increase in forced expiratory volume in 1 second (FEV) or forced vital capacity (FVC) after bronchodilator inhalation. This dual criterion is insensitive in those with high or low FEV. To establish BDR criteria with volume or percentage FEV change. The largest FEV and FVC were identified from three pre- and three post-bronchodilator maneuvers in COPDGene (Genetic Epidemiology of COPD) participants. A total of 7,741 individuals with coefficient of variation less than 15% for both FEV and FVC formed bronchodilator categories of FEV response: negative (≤0.00% or ≤0.00 L), minimal (>0.00% to ≤9.00% or >0.00 L to ≤0.09 L), mild (>9.00% to ≤16.00% or >0.09 L to ≤0.16 L), moderate (>16.00% to ≤26.00% or >0.16 L to ≤0.26 L), and marked (>26.00% or >0.26 L). These response size categories are based on empirical limits considering average FEV increase of approximately 160 ml and the clinically important difference for FEV. To compare flow and volume response characteristics, BDR-FEV category assignments were applied for the BDR-FVC response. Twenty percent met mild and 31% met moderate or marked BDR-FEV criteria, whereas 12% met mild and 33% met moderate or marked BDR-FVC criteria. In contrast, only 20.6% met ATS/ERS positive criteria. Compared with the negative BDR-FEV category, the minimal, mild, moderate, and marked BDR-FEV categories were associated with greater 6-minute-walk distance and lower St. George's Respiratory Questionnaire and modified Medical Research Council dyspnea scale scores. Compared with negative BDR, moderate and marked BDR-FEV categories were associated with fewer exacerbations, and minimal BDR was associated with lower computed tomography airway wall thickness. Compared with the negative category, all BDR-FVC categories were associated with increasing emphysema percentage and gas trapping percentage. Moderate and marked BDR-FVC categories were associated with higher St. George's Respiratory Questionnaire scores but fewer exacerbations and lower dyspnea scores. BDR grading by FEV volume or percentage response identified subjects otherwise missed by ATS/ERS criteria. BDR grades were associated with functional exercise performance, quality of life, exacerbation frequency, dyspnea, and radiological airway measures. BDR grades in FEV and FVC indicate different clinical and radiological characteristics.
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http://dx.doi.org/10.1513/AnnalsATS.201901-030OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956832PMC
December 2019

Publisher Correction: Farming with crops and rocks to address global climate, food and soil security.

Nat Plants 2018 Jun;4(6):392

Earth Institute, Columbia University, New York, NY, USA.

In the version of this Perspective originally published, 'acidification' was incorrectly spelt as 'adification' in Fig. 4. This has now been corrected.
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http://dx.doi.org/10.1038/s41477-018-0162-5DOI Listing
June 2018

Incidence of radiographically occult nodal metastases in HPV+ oropharyngeal carcinoma: Implications for reducing elective nodal coverage.

Pract Radiat Oncol 2018 Nov - Dec;8(6):397-403. Epub 2018 Mar 27.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut.

Purpose: Initial deescalation studies for human papilloma virus (HPV)-positive driven oropharyngeal squamous cell carcinomas (HPV+ OPSCC) altered radiation therapy dose or the systemic agent used. Newer trials examine the disease control achieved with a reduced elective nodal field. We examined patterns of nodal involvement in patients with HPV+ OPSCC with a focus on implications for radiation field design for treatment deescalation.

Methods And Materials: Records of patients with HPV+ OPSCC with preoperative imaging (computed tomography or fludeoxyglucose positron emission tomography/computed tomography) who underwent neck dissection without neoadjuvant therapy from 2010 to 2017 were retrospectively reviewed. The number and location of clinically positive lymph nodes on preoperative imaging were compared with those documented on pathology. These data were then used to establish the probability of missing nodal disease in 3 modified radiation field designs.

Results: One hundred patients were included. The median time between imaging and surgery was 22 days. The most common clinical N stage was cN2a (35%), whereas the most common pathologic N stage was pN2b (45%). The median number of radiographically and pathologically involved nodes was 1 (range, 0-6) and 2 (range, 0-11), respectively. Forty-three percent of patients had more pathologically involved nodes than predicted on imaging, whereas 21% had pathologic involvement at an additional nodal level not predicted on imaging. Of the 21 patients with additional pathologically involved nodal levels, 14 had involvement of a directly adjacent station, 4 were patients with a cN0 hemineck with pathologically positive level II disease, and 3 had pathologic involvement of level 2 echelons removed from that predicted on imaging.

Conclusion: Our study suggests that radiation fields encompassing only clinically involved nodes or levels has an unacceptably high likelihood of missing subclinical disease. Alternatively, treating the first uninvolved echelon nodes in addition would cover pathologic sites of disease in 97% of patients. This approach merits further study in prospective trials.
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http://dx.doi.org/10.1016/j.prro.2018.03.009DOI Listing
January 2019

Streamlining cardiopulmonary exercise testing for use as a screening and tracking tool in primary care.

Pulm Circ 2018 Apr-Jun;8(2):2045894018776489. Epub 2018 Apr 25.

1 Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.

Cardiopulmonary exercise testing (CPET) using a spectrum of different approaches demonstrates usefulness for objectively assessing patient disease severity in clinical and research settings. Still, an absence of trained specialists and/or improper data interpretation techniques can pose major limitations to the effective use of CPET for the clinical classification of patients. This study aimed to test an automated disease likelihood scoring algorithm system based on cardiopulmonary responses during a simplified step-test protocol. For patients with heart failure (HF), pulmonary hypertension (PAH), obstructive lung disease (OLD), or restrictive lung disease (RLD), we compared patient scores stratified into one of four "silos" generated from our novel algorithm system against patient evaluations provided by expert clinicians. Patients with HF (n = 12), PAH (n = 9), OLD (n = 16), or RLD (n = 10) performed baseline pulmonary function testing followed by submaximal step-testing. Breath-by-breath measures of ventilation and gas exchange, in addition to oxygen saturation and heart rate were collected continuously throughout testing. The algorithm demonstrated close alignment with patient assessments provided by clinical specialists: HF (r = 0.89, P < 0.01); PAH (r = 0.88, P < 0.01); OLD (r = 0.70, P < 0.01); and RLD (r = 0.88, P < 0.01). Furthermore, the algorithm was capable of differentiating major disease from other disease pathologies. Thus, in a clinically relevant manner, these data suggest this simplified automated disease algorithm scoring system used during step-testing to identify the likelihood that patients have HF, PAH, OLD, or RLD closely correlates with patient assessments conducted by trained clinicians.
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http://dx.doi.org/10.1177/2045894018776489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987906PMC
April 2018

Reliability and Physiological Interpretation of Pulmonary Gas Exchange by "Circulatory Equivalents" in Chronic Heart Failure.

J Am Heart Assoc 2018 03 27;7(7). Epub 2018 Mar 27.

Division of Respiratory and Critical Care Physiology and Medicine, Rehabilitation Clinical Trials Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.

Background: Peak ratios of pulmonary gas-exchange to ventilation during exercise (V˙O2/V˙E and V˙CO2/V˙E, termed "circulatory equivalents") are sensitive to heart failure (HF) severity, likely reflecting low and/or poorly distributed pulmonary perfusion. We tested whether peak V˙O2/V˙E and V˙CO2/V˙E would: (1) distinguish HF patients from controls; (2) be independent of incremental exercise protocol; and (3) correlate with lactate threshold (LT) and ventilatory compensation point (VCP), respectively.

Methods And Results: Twenty-four HF patients (61±11 years) with reduced ejection fraction (31±8%) and 11 controls (63±7 years) performed ramp-incremental cycle ergometry. Eighteen HF patients also performed slow (5±1 W/min), medium (9±4 W/min), and fast (19±6 W/min) ramps. Peak V˙O2/V˙E and V˙CO2/V˙E from X-Y plot, and LT and VCP from 9-panel plot, were determined by 2 independent, blinded, assessors. Peak V˙O2/V˙E (31.2±4.4 versus 41.8±4.8 mL/L; <0.0001) and V˙CO2/V˙E (29.3±3.0 versus 36.9±4.0 mL/L; <0.0001) were lower in HF than controls. Within individuals, there was no difference across 3 ramp rates in peak V˙O2/V˙E (=0.62) or V˙CO2/V˙E (=0.97). Coefficient of variation (CV) in peak V˙O2/V˙E was lower than for LT (5.1±2.1% versus 8.2±3.7%; =0.014), and coefficient of variation in peak V˙CO2/V˙E was lower than for VCP (3.3±1.8% versus 8.7±4.2%; <0.001). In all participants, peak V˙O2/V˙E was correlated with, but occurred earlier than, LT (=0.94; mean bias, -0.11 L/min), and peak V˙CO2/V˙E was correlated with, but occurred earlier than, VCP (=0.98; mean bias -0.08 L/min).

Conclusions: Peak circulatory equivalents during exercise are strongly associated with (but not identical to) LT and VCP. Peak circulatory equivalents are reliable, objective, effort-independent indices of gas-exchange abnormality in HF.
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http://dx.doi.org/10.1161/JAHA.117.008072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907590PMC
March 2018

Farming with crops and rocks to address global climate, food and soil security.

Nat Plants 2018 03 19;4(3):138-147. Epub 2018 Feb 19.

Earth Institute, Columbia University, New York, NY, USA.

The magnitude of future climate change could be moderated by immediately reducing the amount of CO entering the atmosphere as a result of energy generation and by adopting strategies that actively remove CO from it. Biogeochemical improvement of soils by adding crushed, fast-reacting silicate rocks to croplands is one such CO-removal strategy. This approach has the potential to improve crop production, increase protection from pests and diseases, and restore soil fertility and structure. Managed croplands worldwide are already equipped for frequent rock dust additions to soils, making rapid adoption at scale feasible, and the potential benefits could generate financial incentives for widespread adoption in the agricultural sector. However, there are still obstacles to be surmounted. Audited field-scale assessments of the efficacy of CO capture are urgently required together with detailed environmental monitoring. A cost-effective way to meet the rock requirements for CO removal must be found, possibly involving the recycling of silicate waste materials. Finally, issues of public perception, trust and acceptance must also be addressed.
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http://dx.doi.org/10.1038/s41477-018-0108-yDOI Listing
March 2018

Re-engineering and evaluation of anti-DNA autoantibody 3E10 for therapeutic applications.

Biochem Biophys Res Commun 2018 02 31;496(3):858-864. Epub 2018 Jan 31.

Department of Therapeutic Radiology, Yale School of Medicine, Yale University, New Haven, CT, USA; Yale Cancer Center, New Haven, CT, USA. Electronic address:

A key challenge in the development of novel chemotherapeutics is the design of molecules capable of selective toxicity to cancer cells. Antibodies have greater target specificity compared to small molecule drugs, but most are unable to penetrate cells, and predominantly target extracellular antigens. A nuclear-penetrating anti-DNA autoantibody isolated from the MRL/lpr lupus mouse model, 3E10, preferentially localizes to tumors, inhibits DNA repair, and selectively kills cancer cells with defects in DNA repair. A murine divalent single chain variable fragment of 3E10 with mutations for improved DNA binding affinity, 3E10 (D31N) di-scFv, has previously been produced in P. pastoris and yielded promising pre-clinical findings, but is unsuitable for clinical testing. The present study reports the design, expression and testing of a panel of humanized 3E10 (D31N) di-scFvs, some of which contain CDR substitution. These variants were expressed in a modified CHO system and evaluated for their physicochemical attributes and ability to penetrate nuclei to selectively cause DNA damage accumulation in and kill cancer cells with DNA repair defects. Secondary structure was conserved and most variants retained the key characteristics of the murine 3E10 (D31N) di-scFv produced in P. pastoris. Moreover, several variants with CDR substitutions outperformed the murine prototype. In conclusion, we have designed several humanized variants of 3E10 (D31N) di-scFv that have potential for application as monotherapy or conjugates for targeted nuclear drug delivery.
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http://dx.doi.org/10.1016/j.bbrc.2018.01.139DOI Listing
February 2018

Smoking Is the Most Significant Modifiable Lung Cancer Risk Factor in Systemic Lupus Erythematosus.

J Rheumatol 2018 03 15;45(3):393-396. Epub 2018 Jan 15.

From The Research Institute of the McGill University Health Centre, Montreal; Université de Laval, Service de rheumatologie, Quebec City, Quebec; Toronto Western Hospital, Toronto, Ontario; Dalhousie University and Capital Health, Halifax, Nova Scotia; University of Manitoba, Winnipeg, Manitoba; Division of Rheumatology, University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada; Northwestern University Feinberg School of Medicine, Chicago, Illinois; Johns Hopkins University School of Medicine, Baltimore, Maryland; University of California at San Francisco, Department of Medicine, San Francisco, California; State University of New York-Downstate Medical Center, Brooklyn; The Feinstein Institute for Medical Research, Manhasset, New York; Therapeutic Radiology, Yale University, New Haven, Connecticut, USA; University of Birmingham, College of Medical and Dental Sciences, Birmingham; University College London, Faculty of Medicine, Department of Rheumatology, London, UK; Lund University Hospital, Lund, Sweden; The Hospital for Rheumatic Diseases, Hanyang University, Seoul, Korea.

Objective: To assess lung cancer risk in systemic lupus erythematosus (SLE), relative to demographics, drug exposures, smoking, and disease activity.

Methods: We analyzed data from 14 SLE cohorts. We calculated adjusted HR estimates for lung cancer in SLE, relative to demographics, smoking, time-dependent medication exposures, and cumulative disease activity [mean adjusted SLE Disease Activity Index (SLEDAI) scores]. This project was approved by the ethics boards of all participating institutions, including the Institutional Review Board of the McGill University Health Centre. The ethics approval number for the Cancer Risk study is GEN-06-031.

Results: Within these 14 SLE cohorts, 49 incident lung cancers occurred. Among lung cancer cases, 59.0% were in the highest SLEDAI quartile at baseline versus 40.8% of lung cancer-free SLE controls. The vast majority (84.2%) of SLE lung cancer cases were ever-smokers at baseline, versus 40.1% of those without lung cancer. In adjusted models, the principal factors associated with lung cancer were ever smoking (at cohort entry) and current age. Estimated adjusted effects of all drugs were relatively imprecise, but did not point toward any drug exposures as strong lung cancer risk factors.

Conclusion: We saw no clear evidence for drugs as a trigger for lung cancer risk in SLE, although drug risk estimates were relatively imprecise. Smoking may be the most significant modifiable lung cancer risk factor in SLE.
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http://dx.doi.org/10.3899/jrheum.170652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834350PMC
March 2018

Metabolomics guided pathway analysis reveals link between cancer metastasis, cholesterol sulfate, and phospholipids.

Cancer Metab 2017 31;5. Epub 2017 Oct 31.

Scripps Center for Metabolomics, The Scripps Research Institute, La Jolla, CA USA.

Background: Cancer cells that enter the metastatic cascade require traits that allow them to survive within the circulation and colonize distant organ sites. As disseminating cancer cells adapt to their changing microenvironments, they also modify their metabolism and metabolite production.

Methods: A mouse xenograft model of spontaneous tumor metastasis was used to determine the metabolic rewiring that occurs between primary cancers and their metastases. An "autonomous" mass spectrometry-based untargeted metabolomic workflow with integrative metabolic pathway analysis revealed a number of differentially regulated metabolites in primary mammary fat pad (MFP) tumors compared to microdissected paired lung metastases. The study was further extended to analyze metabolites in paired normal tissues which determined the potential influence of metabolites from the microenvironment.

Results: Metabolomic analysis revealed that multiple metabolites were increased in metastases, including cholesterol sulfate and phospholipids (phosphatidylglycerols and phosphatidylethanolamine). Metabolite analysis of normal lung tissue in the mouse model also revealed increased levels of these metabolites compared to tissues from normal MFP and primary MFP tumors, indicating potential extracellular uptake by cancer cells in lung metastases. These results indicate a potential functional importance of cholesterol sulfate and phospholipids in propagating metastasis. In addition, metabolites involved in DNA/RNA synthesis and the TCA cycle were decreased in lung metastases compared to primary MFP tumors.

Conclusions: Using an integrated metabolomic workflow, this study identified a link between cholesterol sulfate and phospholipids, metabolic characteristics of the metastatic niche, and the capacity of tumor cells to colonize distant sites.
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http://dx.doi.org/10.1186/s40170-017-0171-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663111PMC
October 2017

Death and Dialysis After Transcatheter Aortic Valve Replacement: An Analysis of the STS/ACC TVT Registry.

JACC Cardiovasc Interv 2017 10;10(20):2064-2075

Henry Ford Health System, Detroit, Michigan.

Objectives: The authors sought to elucidate the true incidence of renal replacement therapy (RRT) after transcatheter aortic valve replacement (TAVR).

Background: There is a wide discrepancy in the reported rate of RRT after TAVR (1.4% to 40%). The true incidence of RRT after TAVR is unknown.

Methods: The STS/ACC TVT (Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy) registry was linked to the Centers for Medicare & Medicaid database to identify all patients that underwent TAVR from November 2011 through September 2015 and their outcomes. The authors compared rates of death, new RRT, and a composite of both as a function of pre-procedure glomerular filtration rate (GFR), both in stages of chronic kidney disease (CKD), as well as on a continuous scale.

Results: Pre-procedure GFR is associated with the risk of death and new RRT after TAVR when GFR is <60 ml/min/m, and increases significantly when GFR falls below 30 ml/min/m. Incremental increases in GFR of 5 ml/min/m were statistically significant (unadjusted hazard ratio: 0.71; p < 0.001) at 30 days, and continued to be significant at 1 year when pre-procedure GFR was <60 ml/min/m. One in 3 CKD stage 4 patients will be dead within 1 year, with 14.6% (roughly 1 in 6) requiring dialysis. In CKD stage 5, more than one-third of patients will require RRT within 30 days; nearly two-thirds will require RRT at 1 year.

Conclusions: In both unadjusted and adjusted analysis, pre-procedural GFR was associated with the outcomes of death and new RRT. Increasing CKD stage leads to an increased risk of death and/or RRT. Continuous analysis showed significant differences in outcomes in all levels of CKD when GFR was <60 ml/min/m. Pre-procedure GFR should be considered when selecting CKD patients for TAVR.
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http://dx.doi.org/10.1016/j.jcin.2017.09.001DOI Listing
October 2017

Prosthetic mitral valve paravalvular leak: A problem that requires dexterity.

Cardiovasc Revasc Med 2018 Jan - Feb;19(1 Pt B):126-132. Epub 2017 Jul 24.

Lahey Hospital and Medical Center, Burlington, MA, United States; Cardiosolutions Inc., West Bridgewater, MA, United States.

Prosthetic valve paravalvular leak (PVL) is a known and relatively common complication of surgical valve replacement, which may lead to significant morbidity. Patients with significant mitral valve replacement (MVR) PVL typically present with symptoms of heart failure and elevated filling pressures or with hemolytic anemia. Percutaneous closure of these leaks has become the preferred therapy. Percutaneous closure of MVR PVL can be technically challenging, given the anatomy of the approach (trans-septal, trans-apical), the level of associated comorbidities and the geographic location of the paravalvular defect. Steerable catheters offer a unique ability to position themselves coaxial to the PVL. The Dexterity catheter (Spirus Medical LLC, Bridgewater, MA, USA) is a semi-rigid steerable catheter used in our lab with the ability to articulate at two separate points on the distal tip and flex greater than 360 degrees. We present cases of surgical valves that developed PVL which underwent successful repair with a Dexterity catheter.
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http://dx.doi.org/10.1016/j.carrev.2017.07.014DOI Listing
March 2019

Algorithm for Predicting Disease Likelihood From a Submaximal Exercise Test.

Clin Med Insights Circ Respir Pulm Med 2017 13;11:1179548417719248. Epub 2017 Jul 13.

Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.

We developed a simplified automated algorithm to interpret noninvasive gas exchange in healthy subjects and patients with heart failure (HF, n = 12), pulmonary arterial hypertension (PAH, n = 11), chronic obstructive lung disease (OLD, n = 16), and restrictive lung disease (RLD, n = 12). They underwent spirometry and thereafter an incremental 3-minute step test where heart rate and SpO respiratory gas exchange were obtained. A custom-developed algorithm for each disease pathology was used to interpret outcomes. Each algorithm for HF, PAH, OLD, and RLD was capable of differentiating disease groups ( < .05) as well as healthy cohorts (n = 19,  < .05). In addition, this algorithm identified referral pathology and coexisting disease. Our primary finding was that the ranking algorithm worked well to identify the primary referral pathology; however, coexisting disease in many of these pathologies in some cases equally contributed to the cardiorespiratory abnormalities. Automated algorithms will help guide decision making and simplify a traditionally complex and often time-consuming process.
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http://dx.doi.org/10.1177/1179548417719248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513526PMC
July 2017

Environmental influences in the etiology of colorectal cancer: the premise of metabolomics.

Curr Pharmacol Rep 2017 Jun 7;3(3):114-125. Epub 2017 Apr 7.

Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA, 06520.

Purpose Of Review: In this review we discuss how environmental exposures predominate the etiology of colorectal cancer (CRC). With CRC being a personalized disease influenced by genes and environment, our goal was to explore the role metabolomics can play in identifying exposures, assessing the interplay between co-exposures, and the development of personalized therapeutic interventions.

Recent Findings: Approximately 10 % of CRC cases can be explained by germ-line mutations, whereas the prevailing majority are caused by an initiating exposure event occurring decades prior to diagnosis. Recent research has shown that dietary metabolites are linked to a procarcinogenic or protective environment in the colon which is modulated by the microbiome. In addition, excessive alcohol has been shown to increase the risk of CRC and is dependent on diet (folate), the response of microbiome, and genetic polymorphisms within the folate and alcohol metabolic pathways. Metabolomics can not only be used to identify this modulation of host metabolism, which could affect the progression of the tumors but also response to targeted therapeutics.

Summary: This review highlights the current understanding of the multifaceted etiology and mechanisms of CRC development but also highlights where the field of metabolomics can contribute to a greater understanding of environmental exposure in CRC.
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http://dx.doi.org/10.1007/s40495-017-0088-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5475285PMC
June 2017

A Dual-Snare Percutaneous Retrieval of Venous Stent Embolization to the Right Heart.

JACC Cardiovasc Interv 2017 06 31;10(12):e111-e113. Epub 2017 May 31.

Department of Cardiovascular Medicine, Lahey Hospital and Medical Center, Burlington, Massachusetts.

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http://dx.doi.org/10.1016/j.jcin.2017.03.043DOI Listing
June 2017

Life Cycle Assessment of Solar Photovoltaic Microgrid Systems in Off-Grid Communities.

Environ Sci Technol 2017 01 23;51(2):1043-1052. Epub 2016 Dec 23.

First Solar , 350 W. Washington St., Suite 600, Tempe, Arizona 85281, United States.

Access to a reliable source of electricity creates significant benefits for developing communities. Smaller versions of electricity grids, known as microgrids, have been developed as a solution to energy access problems. Using attributional life cycle assessment, this project evaluates the environmental and energy impacts of three photovoltiac (PV) microgrids compared to other energy options for a model village in Kenya. When normalized per kilowatt hour of electricity consumed, PV microgrids, particularly PV-battery systems, have lower impacts than other energy access solutions in climate change, particulate matter, photochemical oxidants, and terrestrial acidification. When compared to small-scale diesel generators, PV-battery systems save 94-99% in the above categories. When compared to the marginal electricity grid in Kenya, PV-battery systems save 80-88%. Contribution analysis suggests that electricity and primary metal use during component, particularly battery, manufacturing are the largest contributors to overall PV-battery microgrid impacts. Accordingly, additional savings could be seen from changing battery manufacturing location and ensuring end of life recycling. Overall, this project highlights the potential for PV microgrids to be feasible, adaptable, long-term energy access solutions, with health and environmental advantages compared to traditional electrification options.
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http://dx.doi.org/10.1021/acs.est.6b05455DOI Listing
January 2017

Nuclear power: Deployment speed-Response.

Science 2016 Dec;354(6316):1112-1113

Shanghai Institute of Applied Physics, Shanghai, 21203, China.

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http://dx.doi.org/10.1126/science.aal2561DOI Listing
December 2016

Congenital single coronary artery: A rare anatomic variant.

Cardiovasc Revasc Med 2017 Apr - May;18(3):212. Epub 2016 Sep 29.

Lahey Hospital & Medical Center, 41 Mall Rd., Burlington, MA. Electronic address:

Isolated congenital single coronary artery (SCA) is rare (incidence 0.024-0.066%). We present a case of a Lipton -1 subtype single coronary artery, incidentally discovered on coronary angiography prior to mitral valve surgery.
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http://dx.doi.org/10.1016/j.carrev.2016.09.001DOI Listing
December 2017

A lupus anti-DNA autoantibody mediates autocatalytic, targeted delivery of nanoparticles to tumors.

Oncotarget 2016 Sep;7(37):59965-59975

Department of Neurosurgery, Yale University, New Haven, CT 06510, USA.

Strategies to target nanoparticles to tumors that rely on surface modification with ligands that bind molecules overexpressed on cancer cells or the tumor neovasculature suffer from a major limitation: with delivery of toxic agents the amount of molecules available for targeting decreases with time; consequently, the efficiency of nanoparticle delivery is reduced. To overcome this limitation, here we propose an autocatalytic tumor-targeting mechanism based on targeting extracellular DNA (exDNA). exDNA is enriched in the tumor microenviroment and increases with treatment with cytotoxic agents, such as doxorubicin (DOX), due to release of DNA by dying tumor cells. We tested this approach using poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface-conjugated with fragments of 3E10 (3E10EN), a lupus anti-DNA autoantibody. We demonstrated that 3E10EN-conjugated nanoparticles bound to DNA and preferentially localized to tumors in vivo. The efficiency of tumor localization of 3E10EN-conjugated, DOX-loaded nanoparticles increased with time and subsequent treatments, demonstrating an autocatalytic effect. 3E10EN-conjugated DOX-loaded nanoparticles exhibited a significant anti-tumor effect that was superior to all controls. This work demonstrates the promise of autocatalytic drug delivery mechanisms and establishes proof of concept for a new anti-DNA autoantibody-based approach for enhancing delivery of nanoparticles to tumors.
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http://dx.doi.org/10.18632/oncotarget.11015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312362PMC
September 2016

NUCLEAR ENERGY. China-U.S. cooperation to advance nuclear power.

Science 2016 Aug;353(6299):547-8

Shanghai Institute of Applied Physics, Shanghai 21203, China.

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http://dx.doi.org/10.1126/science.aaf7131DOI Listing
August 2016

A Novel Spirometric Measure Identifies Mild COPD Unidentified by Standard Criteria.

Chest 2016 Nov 22;150(5):1080-1090. Epub 2016 Jul 22.

Rehabilitation Clinical Trials Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.

Background: In chronic obstructive pulmonary disease, both smaller and larger airways are affected. FEV mainly reflects large airways obstruction, while the later fraction of forced exhalation reflects reduction in terminal expiratory flow. In this study, the objective was to evaluate the relationship between spirometric ratios, including the ratio of forced expiratory volume in 3 and 6 seconds (FEV/FEV), and small airways measures and gas trapping at quantitative chest CT scanning, and clinical outcomes in the Genetic Epidemiology of COPD (COPDGene) cohort.

Methods: Seven thousand eight hundred fifty-three current and ex-smokers were evaluated for airflow obstruction by using recently defined linear iteratively derived equations of Hansen et al to determine lower limit of normal (LLN) equations for prebronchodilator FEV/FVC, FEV/FEV, FEV/FEV, and FEV/FVC. General linear and ordinal regression models were applied to the relationship between prebronchodilator spirometric and radiologic and clinical data.

Results: Of the 10,311 participants included in the COPDGene phase I study, participants with incomplete quantitative CT scanning or relevant spirometric data were excluded, resulting in 7,853 participants in the present study. Of 4,386 participants with FEV/FVC greater than or equal to the LLN, 15.4% had abnormal FEV/FEV. Compared with normal FEV/FEV and FEV/FVC, abnormal FEV/FEV was associated with significantly greater gas trapping; St. George's Respiratory Questionnaire score; modified Medical Research Council dyspnea score; and BMI, airflow obstruction, dyspnea, and exercise index and with shorter 6-min walking distance (all P < .0001) but not with CT scanning evidence of emphysema.

Conclusions: Current and ex-smokers with prebronchodilator FEV/FEV less than the LLN as the sole abnormality identifies a distinct population with evidence of small airways disease in quantitative CT scanning, impaired indexes of physical function and quality of life otherwise deemed normal by using the current spirometric definition.
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http://dx.doi.org/10.1016/j.chest.2016.06.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5103018PMC
November 2016

Between a rock and a hard place: TAVR and ESRD.

Catheter Cardiovasc Interv 2016 06;87(7):1322-3

College of Medicine, Heart & Vascular Institute, MS Hershey Medical Center, Penn State University, Hershey, Pennsylvania.

Aortic stenosis in combination with end-stage renal disease (ESRD) is a high-risk combination for surgical valve replacement and little data exists on the role of transcatheter aortic valve replacement (TAVR) Pooled retrospective data from eight experienced TAVR sites suggests that TAVR can be accomplished in ESRD patients with first generation percutaneous valve at a risk similar to surgical approaches. Even with TAVR, valve replacement in the ESRD patient remain high risk and future improvements in technology and approaches to this poorly studied group are needed.
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http://dx.doi.org/10.1002/ccd.26614DOI Listing
June 2016

Better parameters of ventilation-CO₂output relationship predict death in CHF patients.

Zhongguo Ying Yong Sheng Li Xue Za Zhi 2015 Nov;31(6):508-16

Objective: Measures of ventilation-CO₂output relationship have been shown to be more prognostic than peak O₂uptake in assessing life expectancy in patients with chronic heart failure (CHF). Because both the ratios (VE/Vco₂) and slopes (VE-vs-Vco₂) of ventilation-co₂ output of differing durations can be used, we aim to ascertain which measurements best predicted CHF life expectancy.

Methods: Two hundred and seventy-one CHF patients with NYHA class II-IV underwent incremental cardiopulmonary exercise testing (CPET) and were followed-up for a median duration of 479 days. Four different linear regression VE-vs- Vco₂ slopes were calculated from warm-up exercise onset to: 180 s, anaerobic threshold (AT), ventilatory compensation point (VCP); and peak exercise. Five VE/Vco₂ ratios were calculated for the following durations: rest (120 s), warm-up (30 s), AT (60 s), lowest value (90 s), and peak exercise (30 s). Death or heart transplant were considered end-points. Multiple statistical analyses were performed.

Results: CHF patients had high lowest VE/Vco₂ (41.0 ± 9.2, 141 ± 30%pred), high VE/Vco₂ at AT (42.5 ± 10.4, 145 ± 35%pred), and high VE-vs-Vco₂ slope to VCP (37.6 ± 12.1, 126 ± 41%pred). The best predictor of death was a higher lowest VE/Vco₂ (≥ 42, ≥ 141%pred), whereas the VE-vs-Vco₂slope to VCP was less variable than other slopes. For death prognosis in 6 months, %pred values were superior: for longer times, absolute values were superior.

Conclusion: The increased lowest VE/Vco₂ ratio easily identifiable and simply measured during exercise, is the best measurement to assess the ventilation-co₂output relationship in prognosticating death in CHF patients.
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November 2015

Fluoroscopy pulse rate reduction during diagnostic and therapeutic imaging in the cardiac catheterization laboratory: An evaluation of radiation dose, procedure complications and outcomes.

Catheter Cardiovasc Interv 2017 Mar 28;89(4):665-670. Epub 2016 Apr 28.

Penn State Milton S. Hershey Medical Center, Hershey, PA, 17033.

Objectives: To evaluate radiation reduction by reducing fluoroscopy pulse rate in diagnostic cardiac catheterizations and percutaneous coronary interventions (PCI) as well as outcomes at 30 days and six months.

Background: Radiation exposure to the public at large has increased dramatically over the past three decades, and the cardiac catheterization laboratory is a large contributor. Fluoroscopy pulse rate is one way to decrease radiation exposure.

Methods: Fluoroscopy pulse rate was reduced from 10 pulses/sec (p/s) to 7.5 p/s as part of an internal quality improvement project. A retrospective analysis of all cardiac catheterizations was performed, evaluating Air KERMA at the interventional reference point (K ), Air KERMA area product (P ), procedural complications and major adverse cardiac events at 30 days and 6 months.

Results: In diagnostic catheterization median P (µGy·m ) and K (mGy) were significantly reduced (P - 5,613.3 vs. 4,400, P < 0.001; K - 703.0 vs. 621.0, P = 0.041). In PCI, median P and K were further reduced (P - 13,481.6 vs. 10,648.0, P < 0.001; K - 1787.0 vs. 1,459.0, P = 0.002). There was no difference in complications, fluoroscopy time or number of stents placed. There was no difference in MACE after adjustment for number of STEMIs.

Conclusions: Reducing fluoroscopy pulse rates to 7.5 from 10 is an effective way to reduce patient radiation exposure across meaningful dose indices. A pulse rate of 7.5 p/s is safe, with no difference in complications or outcomes. A fluoroscopy pulse rate of 7.5 p/s should be given strong consideration for a new standard. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ccd.26555DOI Listing
March 2017

DNA-damaging autoantibodies and cancer: the lupus butterfly theory.

Nat Rev Rheumatol 2016 07 24;12(7):429-34. Epub 2016 Mar 24.

Department of Therapeutic Radiology, Yale School of Medicine, 15 York Street, New Haven, Connecticut 06520, USA.

Autoantibodies reactive against host DNA are detectable in the circulation of most people with systemic lupus erythematosus (SLE). The long-held view that antibodies cannot penetrate live cells has been disproved. A subset of lupus autoantibodies penetrate cells, translocate to nuclei, and inhibit DNA repair or directly damages DNA. The result of these effects depends on the microenvironment and genetic traits of the cell. Some DNA-damaging antibodies alone have little impact on normal cells, but in the presence of other conditions, such as pre-existing DNA-repair defects, can become highly toxic. These findings raise new questions about autoimmunity and DNA damage, and reveal opportunities for new targeted therapies against malignancies particularly vulnerable to DNA damage. In this Perspectives article, we review the known associations between SLE, DNA damage and cancer, and propose a theory for the effects of DNA-damaging autoantibodies on SLE pathophysiology and cancer risk.
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http://dx.doi.org/10.1038/nrrheum.2016.23DOI Listing
July 2016

DNA-dependent targeting of cell nuclei by a lupus autoantibody.

Sci Rep 2015 Jul 9;5:12022. Epub 2015 Jul 9.

1] Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520 [2] Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520.

A nuclear-penetrating lupus anti-DNA autoantibody, 3E10, has been found to inhibit DNA repair and selectively kill certain cancer cells that are highly vulnerable to DNA damage. In addition, a 3E10 single chain variable fragment (scFv) has been developed for use as a delivery vehicle to carry therapeutic cargo proteins into cell nuclei. A greater understanding of the mechanism by which 3E10 penetrates cell nuclei is needed to help determine the scope of its potential therapeutic applications. Here we show that the presence of extracellular DNA significantly enhances the nuclear uptake of 3E10 scFv. In addition, we find that 3E10 scFv preferentially localizes into tumor cell nuclei in vivo, likely due to increased DNA in the local environment released from ischemic and necrotic regions of tumor. These data provide insight into the mechanism of nuclear penetration by 3E10 and demonstrate the potential for use of 3E10 in therapeutic approaches to diseases ranging from malignancy to ischemic conditions such as stroke.
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http://dx.doi.org/10.1038/srep12022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496662PMC
July 2015

Optimizing a lupus autoantibody for targeted cancer therapy.

Cancer Res 2015 Jun 1;75(11):2285-91. Epub 2015 Apr 1.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut. Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.

The specificity of binding by antibodies to target antigens is a compelling advantage to antibody-based cancer therapy, but most antibodies cannot penetrate cells to affect intracellular processes. Select lupus autoantibodies penetrate into cell nuclei, and the potential for application of these antibodies in cancer therapy is an emerging concept. Here, we show that a divalent lupus anti-DNA autoantibody fragment with enhancing mutations that increase its ability to penetrate cell nuclei and bind DNA causes accumulation of DNA double-strand breaks in and is highly and selectively toxic to cancer cells and tumors with defective homology-directed repair of DNA double-strand breaks. These findings provide proof of principle for the use of optimized lupus autoantibodies in targeted cancer therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-2278DOI Listing
June 2015