Publications by authors named "Catherine Park"

73 Publications

Digital Biomarker Representing Frailty Phenotypes: The Use of Machine Learning and Sensor-Based Sit-to-Stand Test.

Sensors (Basel) 2021 May 8;21(9). Epub 2021 May 8.

Interdisciplinary Consortium on Advanced Motion Performance (iCAMP), Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.

Since conventional screening tools for assessing frailty phenotypes are resource intensive and unsuitable for routine application, efforts are underway to simplify and shorten the frailty screening protocol by using sensor-based technologies. This study explores whether machine learning combined with frailty modeling could determine the least sensor-derived features required to identify physical frailty and three key frailty phenotypes (slowness, weakness, and exhaustion). Older participants (n = 102, age = 76.54 ± 7.72 years) were fitted with five wearable sensors and completed a five times sit-to-stand test. Seventeen sensor-derived features were extracted and used for optimal feature selection based on a machine learning technique combined with frailty modeling. Mean of hip angular velocity range (indicator of slowness), mean of vertical power range (indicator of weakness), and coefficient of variation of vertical power range (indicator of exhaustion) were selected as the optimal features. A frailty model with the three optimal features had an area under the curve of 85.20%, a sensitivity of 82.70%, and a specificity of 71.09%. This study suggests that the three sensor-derived features could be used as digital biomarkers of physical frailty and phenotypes of slowness, weakness, and exhaustion. Our findings could facilitate future design of low-cost sensor-based technologies for remote physical frailty assessments via telemedicine.
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http://dx.doi.org/10.3390/s21093258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125840PMC
May 2021

The Fractalkine Receptor CXCR1 Links Lymphocyte Kinetics in CMV-Seropositive Patients and Acute Myocardial Infarction With Adverse Left Ventricular Remodeling.

Front Immunol 2021 5;12:605857. Epub 2021 May 5.

Cardiology Department, Freeman Hospital, Newcastle upon Tyne, United Kingdom.

Aims: Latent cytomegalovirus (CMV) infection is associated with adverse cardiovascular outcomes. Virus-specific CXCR1 effector memory T-cells may be instrumental in this process due to their pro-inflammatory properties. We investigated the role of CXCR1 (fractalkine receptor) in CMV-related lymphocyte kinetics and cardiac remodeling in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI).

Methods And Results: We retrospectively analysed lymphocyte count, troponin, and survival in 4874 STEMI/pPCI patients, evaluated lymphocyte kinetics during reperfusion in a prospective cohort, and obtained sequential cardiac MRI (cMRI) to assess remodeling. Pre-reperfusion lymphopenia independently predicted mortality at 7.5 years. Prior to reperfusion, CCR7 T-lymphocytes appeared to be depleted. After reperfusion, T-lymphocytes expressing CXCR1 were depleted predominantly in CMV-seropositive patients. During ischaemia/reperfusion, a drop in CXCR1 T-lymphocytes was significantly linked with microvascular obstruction in CMV+ patients, suggesting increased fractalkine-receptor interaction. At 12 weeks, CMV+ patients displayed adverse LV remodeling.

Conclusion: We show that lymphopenia occurs before and after reperfusion in STEMI by different mechanisms and predicts long-term outcome. In CMV+ patients, increased fractalkine induction and sequestration of CXCR1 T-cells may contribute to adverse remodeling, suggesting a pro-inflammatory pathomechanism which presents a novel therapeutic target.
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http://dx.doi.org/10.3389/fimmu.2021.605857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147691PMC
May 2021

Digital Biomarkers of Cognitive Frailty: The Value of Detailed Gait Assessment Beyond Gait Speed.

Gerontology 2021 May 10:1-10. Epub 2021 May 10.

Interdisciplinary Consortium on Advanced Motion Performance (iCAMP), Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA.

Background: Cognitive frailty (CF), defined as the simultaneous presence of cognitive impairment and physical frailty, is a clinical symptom in early-stage dementia with promise in assessing the risk of dementia. The purpose of this study was to use wearables to determine the most sensitive digital gait biomarkers to identify CF.

Methods: Of 121 older adults (age = 78.9 ± 8.2 years, body mass index = 26.6 ± 5.5 kg/m2) who were evaluated with a comprehensive neurological exam and the Fried frailty criteria, 41 participants (34%) were identified with CF and 80 participants (66%) were identified without CF. Gait performance of participants was assessed under single task (walking without cognitive distraction) and dual task (walking while counting backward from a random number) using a validated wearable platform. Participants walked at habitual speed over a distance of 10 m. A validated algorithm was used to determine steady-state walking. Gait parameters of interest include steady-state gait speed, stride length, gait cycle time, double support, and gait unsteadiness. In addition, speed and stride length were normalized by height.

Results: Our results suggest that compared to the group without CF, the CF group had deteriorated gait performances in both single-task and dual-task walking (Cohen's effect size d = 0.42-0.97, p < 0.050). The largest effect size was observed in normalized dual-task gait speed (d = 0.97, p < 0.001). The use of dual-task gait speed improved the area under the curve (AUC) to distinguish CF cases to 0.76 from 0.73 observed for the single-task gait speed. Adding both single-task and dual-task gait speeds did not noticeably change AUC. However, when additional gait parameters such as gait unsteadiness, stride length, and double support were included in the model, AUC was improved to 0.87.

Conclusions: This study suggests that gait performances measured by wearable sensors are potential digital biomarkers of CF among older adults. Dual-task gait and other detailed gait metrics provide value for identifying CF above gait speed alone. Future studies need to examine the potential benefits of gait performances for early diagnosis of CF and/or tracking its severity over time.
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http://dx.doi.org/10.1159/000515939DOI Listing
May 2021

Decrease in Mobility during the COVID-19 Pandemic and Its Association with Increase in Depression among Older Adults: A Longitudinal Remote Mobility Monitoring Using a Wearable Sensor.

Sensors (Basel) 2021 Apr 29;21(9). Epub 2021 Apr 29.

Interdisciplinary Consortium on Advanced Motion Performance (iCAMP), Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.

Background: Social isolation during COVID-19 may negatively impact older adults' wellbeing. To assess its impact, we measured changes in physical activity and sleep among community-dwelling older adults, from pre-to post-pandemic declaration.

Method: Physical activity and sleep in older adults (n = 10, age = 77.3 ± 1.9 years, female = 40%) were remotely assessed within 3-month pre-to 6-month post-pandemic declaration using a pendant-wearable system. Depression was assessed pre-and post-pandemic declaration using the Center for Epidemiologic Studies Depression scale and was compared with 48 h continuous physical activity monitoring data before and during pandemic.

Results: Compared to pre-pandemic, post-pandemic time spent in standing declined by 32.7% (Cohen's d = 0.78, < 0.01), walking by 52.2% (d = 1.1, < 0.01), step-counts by 55.1% (d = 1.0, = 0.016), and postural transitions by 44.6% (d = 0.82, = 0.017) with increase in sitting duration by 20.5% (d = 0.5, = 0.049). Depression symptoms increased by 150% (d = 0.8, = 0.046). Interestingly, increase in depression was significantly correlated with unbroken-prolong sitting bout (ρ = 0.677, = 0.032), cadence (ρ = -0.70, = 0.024), and sleep duration (ρ = -0.72, = 0.019).

Conclusion: This is one of the early longitudinal studies highlighting adverse effect of the pandemic on objectively assessed physical activity and sleep in older adults. Our observations showed need for timely intervention to mitigate hard to reverse consequences of decreased physical activity such as depression.
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http://dx.doi.org/10.3390/s21093090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125705PMC
April 2021

Evaluation of Motor and Cognitive Performance in People with Parkinson's Disease Using Instrumented Trail-Making Test.

Gerontology 2021 May 3:1-7. Epub 2021 May 3.

Department of Health and Human Performance, Center for Neuromotor and Biomechanics Research, University of Houston, Houston, Texas, USA.

Introduction: Parkinson's disease (PD) progressively impairs motor and cognitive performance. The current tools to detect decline in motor and cognitive functioning are often impractical for busy clinics and home settings. To address the gap, we designed an instrumented trail-making task (iTMT) based on a wearable sensor (worn on the shin) with interactive game-based software installed on a tablet. The iTMT test includes reaching to 5 indexed circles, a combination of numbers (1-3) and letters (A&B) randomly positioned inside target circles, in a sequential order, which virtually appears on a screen kept in front of the participants, by rotating one's ankle joint while standing and holding a chair for safety. By measuring time to complete iTMT task (iTMT time), iTMT enables quantifying cognitive-motor performance.

Purpose: This study's objective is to examine the feasibility of iTMT to detect early cognitive-motor decline in PDs.

Method: Three groups of volunteers, including 14 cognitively normal (CN) older adults, 14 PDs, and 11 mild cognitive impaireds (MCI), were recruited. Participants completed MoCA, 20 m walking test, and 3 trials of iTMT.

Results: All participants enabled to complete iTMT with <3 min, indicating high feasibility. The average iTMT time for CN-Older, PD, and MCI participants were 20.9 ± 0.9 s, 32.3 ± 2.4 s, and 40.9 ± 4.5 s, respectively. After adjusting for age and education level, pairwise comparison suggested large effect sizes for iTMT between CN-older versus PD (Cohen's d = 1.7, p = 0.024) and CN-older versus MCI (d = 1.57, p < 0.01). Significant correlations were observed when comparing iTMT time with the gait speed (r = -0.4, p = 0.011) and MoCA score (r = -0.56, p < 0.01).

Conclusion: This study demonstrated the feasibility and early results supporting the potential application of iTMT to determine cognitive-motor and distinguishing individuals with MCI and PD from CN-older adults. Future studies are warranted to test the ability of iTMT to track its subtle changes over time.
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http://dx.doi.org/10.1159/000515940DOI Listing
May 2021

Rapid fall in circulating non-classical monocytes in ST elevation myocardial infarction patients correlates with cardiac injury.

FASEB J 2021 May;35(5):e21604

Biosciences Institute, Centre for Life, Newcastle University, Newcastle, UK.

Myocardial infarction leads to a rapid innate immune response that is ultimately required for repair of damaged heart tissue. We therefore examined circulating monocyte dynamics immediately after reperfusion of the culprit coronary vessel in STEMI patients to determine whether this correlated with level of cardiac injury. A mouse model of cardiac ischemia/reperfusion injury was subsequently used to establish the degree of monocyte margination to the coronary vasculature that could potentially contribute to the drop in circulating monocytes. We retrospectively analyzed blood samples from 51 STEMI patients to assess the number of non-classical (NC), classical, and intermediate monocytes immediately following primary percutaneous coronary intervention. Classical and intermediate monocytes showed minimal change. On the other hand, circulating numbers of NC monocytes fell by approximately 50% at 90 minutes post-reperfusion. This rapid decrease in NC monocytes was greatest in patients with the largest infarct size (P < .05) and correlated inversely with left ventricular function (r = 0.41, P = .04). The early fall in NC monocytes post-reperfusion was confirmed in a second prospective study of 13 STEMI patients. Furthermore, in a mouse cardiac ischemia model, there was significant monocyte adhesion to coronary vessel endothelium at 2 hours post-reperfusion pointing to a specific and rapid vessel margination response to cardiac injury. In conclusion, rapid depletion of NC monocytes from the circulation in STEMI patients following coronary artery reperfusion correlates with the level of acute cardiac injury and involves rapid margination to the coronary vasculature.
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http://dx.doi.org/10.1096/fj.202100240RDOI Listing
May 2021

Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer.

J Exp Med 2021 May;218(5)

Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA.

Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment resistance. TNBCs are fibrotic, yet little is known regarding how the extracellular matrix (ECM) evolves following therapy and whether it impacts treatment response. Analysis revealed that while primary untreated TNBCs are surrounded by a rigid stromal microenvironment, chemotherapy-resistant residual tumors inhabit a softer niche. TNBC organoid cultures and xenograft studies showed that organoids interacting with soft ECM exhibit striking resistance to chemotherapy, ionizing radiation, and death receptor ligand TRAIL. A stiff ECM enhanced proapoptotic JNK activity to sensitize cells to treatment, whereas a soft ECM promoted treatment resistance by elevating NF-κB activity and compromising JNK activity. Treatment-resistant residual TNBCs residing within soft stroma had elevated activated NF-κB levels, and disengaging NF-κB activity sensitized tumors in a soft matrix to therapy. Thus, the biophysical properties of the ECM modify treatment response, and agents that modulate stiffness-dependent NF-κB or JNK activity could enhance therapeutic efficacy in patients with TNBC.
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http://dx.doi.org/10.1084/jem.20191360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025243PMC
May 2021

Effectiveness of Lower-Extremity Electrical Stimulation to Improve Skin Perfusion.

J Am Podiatr Med Assoc 2021 Mar 3. Epub 2021 Mar 3.

Background: While numerous studies suggest the benefit of electrical stimulation (E-Stim) therapy to accelerate wound healing, the underlying mechanism of action is still debated. In this pilot study, we examined the potential effectiveness of lower extremity E-Stim therapy to improve tissue perfusion in patients with diabetic foot ulcers (DFUs).

Methods: Thirty-eight patients with DFUs were recruited. Participants underwent 60-minutes of active E-Stim therapy provided on acupuncture points above the level of the ankle joint using a bio-electric stimulation technology® (BEST) platform (Tennant Biomodulator® PRO). As primary outcome, changes in perfusion in response to E-Stim were assessed by measuring skin perfusion pressure (SPP) at baseline, 30-, and 60-min during therapy. In addition, retention was assessed 10-min post-therapy. As secondary outcome, tissue oxygen saturation (SatO2) was measured using a non-invasive near-infrared camera (Snapshot NIR, KENT Imaging Inc).

Results: SPP increased in response to E-Stim therapy (p = 0.02) with maximum improvement observed at 60-min (11%, p = 0.007) compared to baseline. SPP reduced at 10-min post therapy, but remained higher than baseline (9%, p = 0.1). Magnitude of improvement at 60-min was negatively correlated with baseline SPP values (r = -0.45, p = 0.01) suggesting those with lower perfusion could benefit more from E-Stim therapy. Similar trends were observed for SatO2 with statistically significant improvement for a sub-sample (n=16) with moderate-severe peripheral arterial disease (Ankle brachial index < 0.8 or > 1.4).

Conclusions: This study provides early results on the feasibility and effectiveness of E-Stim therapy to improve skin perfusion and SatO2. The magnitude of benefit is higher among those with poorer skin perfusion. Results also suggest the effects of E-Stim could be washed out after stopping therapy and thus regular daily application may be required for the effective benefit for wound healing.
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http://dx.doi.org/10.7547/20-172DOI Listing
March 2021

Toward Remote Assessment of Physical Frailty Using Sensor-based Sit-to-stand Test.

J Surg Res 2021 Jul 27;263:130-139. Epub 2021 Feb 27.

Interdisciplinary Consortium on Advanced Motion Performance (iCAMP), Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas. Electronic address:

Background: Traditional physical frailty (PF) screening tools are resource intensive and unsuitable for remote assessment. In this study, we used five times sit-to-stand test (5×STS) with wearable sensors to determine PF and three key frailty phenotypes (slowness, weakness, and exhaustion) objectively.

Materials And Methods: Older adults (n = 102, age: 76.54 ± 7.72 y, 72% women) performed 5×STS while wearing sensors attached to the trunk and bilateral thigh and shank. Duration of 5×STS was recorded using a stopwatch. Seventeen sensor-derived variables were analyzed to determine the ability of 5×STS to distinguish PF, slowness, weakness, and exhaustion. Binary logistic regression was used, and its area under curve was calculated.

Results: A strong correlation was observed between sensor-based and manually-recorded 5xSTS durations (r = 0.93, P < 0.0001). Sensor-derived variables indicators of slowness (5×STS duration, hip angular velocity range, and knee angular velocity range), weakness (hip power range and knee power range), and exhaustion (coefficient of variation (CV) of hip angular velocity range, CV of vertical velocity range, and CV of vertical power range) were different between the robust group and prefrail/frail group (P < 0.05) with medium to large effect sizes (Cohen's d = 0.50-1.09). The results suggested that sensor-derived variables enable identifying PF, slowness, weakness, and exhaustion with an area under curve of 0.861, 0.865, 0.720, and 0.723, respectively.

Conclusions: Our study suggests that sensor-based 5×STS can provide digital biomarkers of PF, slowness, weakness, and exhaustion. The simplicity, ease of administration in front of a camera, and safety of 5xSTS may facilitate a remote assessment of PF, slowness, weakness, and exhaustion via telemedicine.
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http://dx.doi.org/10.1016/j.jss.2021.01.023DOI Listing
July 2021

Association Between Wearable Device-Based Measures of Physical Frailty and Major Adverse Events Following Lower Extremity Revascularization.

JAMA Netw Open 2020 11 2;3(11):e2020161. Epub 2020 Nov 2.

Keck School of Medicine, University of Southern California, Los Angeles.

Importance: Physical frailty is a key risk factor associated with higher rates of major adverse events (MAEs) after surgery. Assessing physical frailty is often challenging among patients with chronic limb-threatening ischemia (CLTI) who are often unable to perform gait-based assessments because of the presence of plantar wounds.

Objective: To test a frailty meter (FM) that does not rely on gait to determine the risk of occurrence of MAEs after revascularization for patients with CLTI.

Design, Setting, And Participants: This cohort study included 184 consecutively recruited patients with CLTI at 2 tertiary care centers. After 32 individuals were excluded, 152 participants were included in the study. Data collection was conducted between May 2018 and June 2019.

Exposures: Physical frailty measurement within 1 week before limb revascularization and incidence of MAEs for as long as 1 month after surgery.

Main Outcomes And Measures: The FM works by quantifying weakness, slowness, rigidity, and exhaustion during a 20-second repetitive elbow flexion-extension exercise using a wrist-worn sensor. The FM generates a frailty index (FI) ranging from 0 to 1; higher values indicate progressively greater severity of physical frailty.

Results: Of 152 eligible participants (mean [SD] age, 67.0 [11.8] years; 59 [38.8%] women), 119 (78.2%) were unable to perform the gait test, while all could perform the FM test. Overall, 53 (34.9%), 58 (38.1%), and 41 (27.0%) were classified as robust (FI <0.20), prefrail (FI ≥0.20 to <0.35), or frail (FI ≥0.35), respectively. Within 30 days after surgery, 24 (15.7%) developed MAEs, either major adverse cardiovascular events (MACE; 8 [5.2%]) or major adverse limb events (MALE; 16 [10.5%]). Baseline demographic characteristics were not significantly different between frailty groups. In contrast, the FI was approximately 30% higher in the group that developed MAEs (mean [SD] score, 0.36 [0.14]) than those who were MAE free (mean [SD] score, 0.26 [0.13]; P = .001), with observed MAE rates of 4 patients (7.5%), 7 patients (12.1%), and 13 patients (31.7%) in the robust, prefrail and frail groups, respectively (P = .004). The FI distinguished individuals who developed MACE and MALE from those who were MAE free (MACE: mean [SD] FI score, 0.38 [0.16]; P = .03; MALE: mean [SD] FI score, 0.35 [0.13]; P = .004) after adjusting by body mass index.

Conclusions And Relevance: In this cohort study, measuring physical frailty using a wrist-worn sensor during a short upper extremity test was a practical method for stratifying the risk of MAEs following revascularization for CLTI when the administration of gait-based tests is often challenging.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.20161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677765PMC
November 2020

Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies.

Clin Sci (Lond) 2020 09;134(17):2243-2262

Freeman Hospital, Newcastle upon Tyne, U.K.

In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term 'inflammageing', which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be 'druggable' by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the 'druggability' of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.
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http://dx.doi.org/10.1042/CS20191213DOI Listing
September 2020

Evaluating the impact of axillary dissection on recurrence-free survival by extent of nodal disease in invasive lobular carcinoma of the breast.

Breast Cancer Res Treat 2020 Oct 21;183(3):661-667. Epub 2020 Jul 21.

Department of Surgery, University of California, San Francisco, 1825 4th Street, 3rd Floor, Box 1710, San Francisco, CA, 94158, USA.

Purpose: Clinical trials have shown that axillary lymph node dissection (ALND) can be avoided for many breast cancer patients with limited nodal involvement. However, whether its omission is safe for those with invasive lobular carcinoma (ILC) is still questioned. We sought to evaluate the impact of ALND on recurrence-free survival (RFS) by extent of nodal disease in patients with ILC.

Methods: We performed a retrospective, cross-sectional analysis of ILC patients treated between 1990 and 2019 at our institution. Patients underwent either breast conservation surgery (BCS) or mastectomy. We used univariate and multivariate statistics in Stata 14.2 to evaluate associations between extent of axillary surgery and time to recurrence stratified by nodal burden.

Results: Of 520 cases, 387 (78.4%) were node negative, 74 (14.9%) had 1-2 positive nodes, and 59 (11.4%) had three or more positive nodes. Most patients (93.3%) had hormone receptor-positive disease, and 94.8% had low or intermediate-grade tumors. The rate of ALND significantly decreased over time (p < 0.002). Using a multivariate model, there was no significant difference in RFS estimates based on receipt of ALND (HR = 0.53, 95% CI 0.17-1.64, p = 0.27), which also held true for patients with 1-2 positive nodes using a test of interaction (HR = 0.91, 95% CI 0.12-6.76, p = 0.92).

Conclusions: These findings support the safety of omitting ALND in selected patients with ILC. Further studies of axillary management in ILC and imaging tools to predict nodal involvement and therapeutic response are warranted.
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http://dx.doi.org/10.1007/s10549-020-05794-0DOI Listing
October 2020

Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document.

Radiother Oncol 2020 07 22;148:157-166. Epub 2020 Apr 22.

Department of Radiation Oncology, UT MD Anderson Cancer Center, Houston, USA.

Background: Recognizing the rapidly increasing interest and evidence in using metastasis-directed radiotherapy (MDRT) for oligometastatic disease (OMD), ESTRO and ASTRO convened a committee to establish consensus regarding definitions of OMD and define gaps in current evidence.

Methods: A systematic literature review focused on curative intent MDRT was performed in Medline, Embase and Cochrane. Subsequent consensus opinion, using a Delphi process, highlighted the current state of evidence and the limitations in the available literature.

Results: Available evidence regarding the use of MDRT for OMD mostly derives from retrospective, single-centre series, with significant heterogeneity in patient inclusion criteria, definition of OMD, and outcomes reported. Consensus was reached that OMD is largely independent of primary tumour, metastatic location and the presence or length of a disease-free interval, supporting both synchronous and metachronous OMD. In the absence of clinical data supporting a maximum number of metastases and organs to define OMD, and of validated molecular biomarkers, consensus supported the ability to deliver safe and clinically meaningful radiotherapy with curative intent to all metastatic sites as a minimum requirement for defining OMD in the context of radiotherapy. Systemic therapy induced OMD was identified as a distinct state of OMD. High-resolution imaging to assess and confirm OMD is crucial, including brain imaging when indicated. Minimum common endpoints such as progression-free and overall survival, local control, toxicity and quality-of-life should be reported; uncommon endpoints as deferral of systemic therapy and cost were endorsed.

Conclusion: While significant heterogeneity exists in the current OMD definitions in the literature, consensus was reached on multiple key questions. Based on available data, OMD can to date be defined as 1-5 metastatic lesions, a controlled primary tumor being optional, but where all metastatic sites must be safely treatable. Consistent definitions and reporting are warranted and encouraged in ongoing trials and reports generating further evidence to optimize patient benefits.
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http://dx.doi.org/10.1016/j.radonc.2020.04.003DOI Listing
July 2020

Signal to Noise Ratio as a Cross-Platform Metric for Intraoperative Fluorescence Imaging.

Mol Imaging 2020 Jan-Dec;19:1536012120913693

Department of Radiation Oncology, University of California-San Francisco, CA, USA.

Real-time molecular imaging to guide curative cancer surgeries is critical to ensure removal of all tumor cells; however, visualization of microscopic tumor foci remains challenging. Wide variation in both imager instrumentation and molecular labeling agents demands a common metric conveying the ability of a system to identify tumor cells. Microscopic disease, comprised of a small number of tumor cells, has a signal on par with the background, making the use of signal (or tumor) to background ratio inapplicable in this critical regime. Therefore, a metric that incorporates the ability to subtract out background, evaluating the signal itself relative to the sources of uncertainty, or noise is required. Here we introduce the signal to noise ratio (SNR) to characterize the ultimate sensitivity of an imaging system and optimize factors such as pixel size. Variation in the background (noise) is due to electronic sources, optical sources, and spatial sources (heterogeneity in tumor marker expression, fluorophore binding, and diffusion). Here, we investigate the impact of these noise sources and ways to limit its effect on SNR. We use empirical tumor and noise measurements to procedurally generate tumor images and run a Monte Carlo simulation of microscopic disease imaging to optimize parameters such as pixel size.
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http://dx.doi.org/10.1177/1536012120913693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139168PMC
April 2020

Loss of Endothelial Endoglin Promotes High-Output Heart Failure Through Peripheral Arteriovenous Shunting Driven by VEGF Signaling.

Circ Res 2020 01 6;126(2):243-257. Epub 2019 Dec 6.

From the Biosciences Institute (S.T.-C., R.E.R., E.S., B.D., C.P., H.L., H.M.A.), Faculty of Medical Sciences, Newcastle University, United Kingdom.

Rationale: ENG (endoglin) is a coreceptor for BMP (bone morphogenetic protein) 9/10 and is strongly expressed in endothelial cells. Mutations in lead to the inherited vascular disorder hereditary hemorrhagic telangiectasia characterized by local telangiectases and larger arteriovenous malformations (AVMs); but how ENG functions to regulate the adult vasculature is not understood.

Objective: The goal of the work was to determine how ENG maintains vessel caliber in adult life to prevent AVM formation and thereby protect heart function.

Methods And Results: Genetic depletion of endothelial in adult mice led to a significant reduction in mean aortic blood pressure. There was no evidence of hemorrhage, anemia, or AVMs in major organs to explain the reduced aortic pressure. However, large AVMs developed in the peripheral vasculature intimately associated with the pelvic cartilaginous symphysis-a noncapsulated cartilage with a naturally high endogenous expression of VEGF (vascular endothelial growth factor). The increased blood flow through these peripheral AVMs explained the drop in aortic blood pressure and led to increased cardiac preload, and high stroke volumes, ultimately resulting in high-output heart failure. Development of pelvic AVMs in this region of high VEGF expression occurred because loss of ENG in endothelial cells leads to increased sensitivity to VEGF and a hyperproliferative response. Development of AVMs and associated progression to high-output heart failure in the absence of endothelial ENG was attenuated by targeting VEGF signaling with an anti-VEGFR2 (VEGF receptor 2) antibody.

Conclusions: ENG promotes the normal balance of VEGF signaling in quiescent endothelial cells to maintain vessel caliber-an essential function in conditions of increased VEGF expression such as local hypoxia or inflammation. In the absence of endothelial ENG, increased sensitivity to VEGF drives abnormal endothelial proliferation in local regions of high VEGF expression, leading to AVM formation and a rapid injurious impact on heart function.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970547PMC
January 2020

Radiotherapy Utilization for Patients Over Age 60 With Early Stage Breast Cancer.

Clin Breast Cancer 2020 04 25;20(2):168-173. Epub 2019 Oct 25.

Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA.

Introduction: Recent studies have questioned the relative benefit of radiotherapy (RT) for older patients with favorable breast cancer given the lack of survival benefit and marginal local control benefit. Despite the 2004 National Comprehensive Cancer Network (NCCN) guidelines advocating for the option of hormonal therapy alone, trends in utilization rates of RT in this group are not well-documented. We analyzed our institutional experience with implementation of the guidelines over time.

Material And Methods: We identified 564 patients aged ≥ 60 years with favorable breast cancer treated with breast conserving surgery from 2000 to 2017. Patients met criteria for Cancer and Leukemia Group B (CALGB) 9343, Postoperative Radiotherapy in Minimum Risk Elderly (PRIME II), or the very-low risk cohort identified in the Toronto-British Columbia study. Multivariable logistic regression analysis was performed to assess the magnitude of association between omission status, grade, and tumor size while controlling for age and year of diagnosis.

Results: Overall RT omission rates were 17.6% prior to the 2004 NCCN update and 45% after the publication of the 10-year CALGB data in 2013. The overall RT omission rate was 29%. Patients with grade 1 to 2 histology (odds ratio, 3.2; 95% confidence interval, 1.3-7.7; P = .01) and tumors < 1 cm (odds ratio, 1.60; 95% confidence interval, 0.4-0.9; P = .007) were more likely to omit RT than those with higher grade or larger tumors.

Conclusions: We observed a slight decrease in the use of RT over time, suggesting a move towards adoption of the NCCN guidelines. There remains a fundamental need to continue to individualize breast cancer care based on risk stratification and make evidenced-based treatment recommendations with equitable use of health care resources.
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http://dx.doi.org/10.1016/j.clbc.2019.10.005DOI Listing
April 2020

Examinations in Radiation Oncology: Listening, Learning, and Looking Forward Together.

Int J Radiat Oncol Biol Phys 2020 01 21;106(1):29-31. Epub 2019 Oct 21.

John Hopkins School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1016/j.ijrobp.2019.10.012DOI Listing
January 2020

Translating the Hypoxic Response-the Role of HIF Protein Translation in the Cellular Response to Low Oxygen.

Cells 2019 02 1;8(2). Epub 2019 Feb 1.

Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

Hypoxia-Inducible Factors (HIFs) play essential roles in the physiological response to low oxygen in all multicellular organisms, while their deregulation is associated with human diseases. HIF levels and activity are primarily controlled by the availability of the oxygen-sensitive HIFα subunits, which is mediated by rapid alterations to the rates of HIFα protein production and degradation. While the pathways that control HIFα degradation are understood in great detail, much less is known about the targeted control of HIFα protein synthesis and what role this has in controlling HIF activity during the hypoxic response. This review will focus on the signalling pathways and RNA binding proteins that modulate HIFα mRNA half-life and/or translation rate, and their contribution to hypoxia-associated diseases.
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http://dx.doi.org/10.3390/cells8020114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406544PMC
February 2019

Radiographic findings in young adults with asymmetric sensorineural hearing loss.

Am J Otolaryngol 2019 Jan - Feb;40(1):78-82. Epub 2018 Oct 11.

Department of Otolaryngology, Naval Medical Center Portsmouth, Portsmouth, VA, United States of America. Electronic address:

Purpose: To evaluate radiographic findings in US Navy recruits found to have asymmetric sensorineural hearing loss (ASNHL) during routine medical screening.

Materials And Methods: Retrospective analysis of US Navy recruits receiving screening audiometry and medical suitability evaluation from January 2011 to October 2016. Single-institution, institutional review board-approved study of US Navy recruits screened for hearing loss over a six-year period. All recruits with ASNHL were evaluated by an otolaryngologist and received diagnostic radiographic evaluation. Audiometric and imaging results were retrospectively reviewed for this population and compared to common screening criteria.

Results: ASNHL was identified in 674 of 228,504 total recruits screened. This population was 91% male and between 17 and 29 years old (mean age 21.1). Six-hundred fifty-three (97%) met criteria for further ASNHL evaluation. Subjective hearing loss was reported in only 6% of patients. Six-hundred sixty-one (99%) received magnetic resonance imaging of the internal auditory canals. Intracranial pathology was identified in 43 (6.3%) patients and 2 (0.3%) had a causative intracranial lesion corresponding to ASNHL. No patients were found to have a vestibular schwannoma.

Conclusions: In a population of healthy young adults with audiometric proven ASNHL, 0.3% had radiographic proven intracranial pathology explaining the hearing loss. Intracranial masses may be less likely to cause ASNHL in this population; further research is needed to determine appropriate MRI screening methods for young adults with ASNHL.
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http://dx.doi.org/10.1016/j.amjoto.2018.10.003DOI Listing
April 2019

A Molecular Imaging "Skin A Time-resolving Intraoperative Imager for Microscopic Residual Cancer Detection Using Enhanced Upconverting Nanoparticles.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:1-4

Optimal cancer therapy requires targeted and individualized treatment of all tumor cells, including both gross and microscopic disease. Intraoperatively hard to visualize and often left behind, microscopic foci of residual cancer cells significantly increase the risk of cancer recurrence and treatment failure rates. Fluorescently-tagged targeted molecular labels are employed to guide surgery, but conventional fluorescent intraoperative imagers suffer from lack of sensitivity and maneuverability, limiting practicality in small tumor cavities owing to their cumbersome sizes driven by optics. This work does away with conventional lenses and filters and introduces an optics-free molecular imaging "skin" consisting of only a $25\mu \mathrm{m}$ thin CMOS contact imager that synergistically integrates the long emission lifetimes of upconverting nanoparticles (UCNP) combined with upconversion to use a time domain approach to acquire the image coupled with infrared illumination allowing deep tissue penetration and elimination of autofluorescence. Using this strategy, we are able to visualize UCNPs at fluences (W/cm) compatible with intraoperative use, opening the door to visualize targeted areas with microscopic sensitivity and facilitate residual microscopic disease detection during surgery, and laying the groundwork for precision post-operative radiation.
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http://dx.doi.org/10.1109/EMBC.2018.8512947DOI Listing
July 2018

Imaging of IR700DX Labeled Mouse Breast Tumor Using a Custom Angle-Selective Fluorescence Contact Imaging System.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:1-4

Cancer treatment faces the challenge of identifying small clusters of residual tumor cells in the resection cavity after the gross section of tumor is surgically removed. Despite the introduction of targeted fluorescent probes to guide cancer surgeries, large, bulky, optical components restrict the ability of fluorescence imaging devices to detect small clusters of tumor cells in the complex surgical cavity. We have developed a small size-scale contact fluorescence image sensor that incorporates angle-selective gratings and a thin 15 m amorphous silicon optical wavelength filter for detecting residual cancer tissue in vivo. Using a custom fluorescent probe combining a fluorescent dye, IR700DX, with a targeted antibody, Trastuzumab, we label and visualize breast tissue in in vivo mouse models of breast cancer. When imaging tumorbearing mice injected with the probe, HER2+ breast cancer tissue intensity is 3.80.8 times brighter than other tissue. Excised cancer tumors and residual cancer attached to healthy tissue are imaged using the custom image sensor. Residual cancer tissue can be detected in real-time and is imaged with a high SNR of 45 dB using an integration time of only 40 ms.
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http://dx.doi.org/10.1109/EMBC.2018.8512568DOI Listing
July 2018

Real-time cancer detection with an integrated lensless fluorescence contact imager.

Biomed Opt Express 2018 Aug 9;9(8):3607-3623. Epub 2018 Jul 9.

Department of Radiation Oncology, University of California, San Francisco, California 94158, USA.

Microscopic tumor cell foci left in a patient after surgery significantly increase the chance of cancer recurrence. However, fluorescence microscopes used for intraoperative navigation lack the necessary sensitivity for imaging microscopic disease and are too bulky to maneuver within the resection cavity. We have developed a scalable chip-scale fluorescence contact imager for detecting microscopic cancer and in real-time. The imager has been characterized under simulated conditions using samples, providing strong evidence that our device can be used . Angle-selective gratings enhance the resolution of the imager without impacting its physical size. We demonstrate detection of cancer cell clusters containing as few as 25 HCC1569 breast cancer cells and 400 LNCaP prostate cancer cells with integration times of only 50 ms and 70 ms, respectively. A cell cluster recognition algorithm is used to achieve both a sensitivity and specificity of 92 % for HCC1569 cell samples, indicating the reliability of the imager. The signal-to-noise ratio (SNR) degradation with increased separation is only 1.5 dB at 250 μm. Blood scattering and absorption reduce the SNR by less than 2 dB for typical concentrations. Moreover, HER2+ breast cancer tissue taken from a patient is distinguished from normal breast tissue with an integration time of only 75 ms.
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http://dx.doi.org/10.1364/BOE.9.003607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191610PMC
August 2018

xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction.

Oncotarget 2018 Aug 17;9(64):32280-32297. Epub 2018 Aug 17.

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.

About 3 million US cancer patients and 1.7 million EU cancer patients received multiple doses of radiation therapy (RT) in 2012, with treatment duration limited by normal adjacent tissue damage. Tumor-specific sensitization could allow treatment with lower radiation doses, reducing normal tissue damage. This is a longstanding, largely unrealized therapeutic goal. The cystine:glutamate exchanger xCT is expressed on poor prognosis subsets of most solid tumors, but not on most normal cells. xCT provides cells with environmental cystine for enhanced glutathione synthesis. Glutathione is used to control reactive oxygen species (ROS), which are therapeutic effectors of RT. We tested whether xCT inhibition would sensitize xCT tumor cells to ionizing radiation. We found that pretreatment with the xCT inhibitor erastin potently sensitized xCT but not xCT cells, and in xenograft. Similarly, targeted gene inactivation also sensitized cells, and both modes of sensitization were overcome by glutathione supplementation. Sensitization prolongs DNA damage signaling, increases genome instability, and enhances cell death, revealing an unforeseen role for cysteine in genome integrity maintenance. We conclude that an xCT-specific therapeutic would provide tumor-specific sensitization to RT, allowing treatment with lower radiation doses, and producing far fewer side effects than other proposed sensitizers. Our data speaks to the need for the rapid development of such a drug.
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http://dx.doi.org/10.18632/oncotarget.25794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122354PMC
August 2018

Disseminated histoplasmosis in pediatric kidney transplant recipients-A report of six cases and review of the literature.

Pediatr Transplant 2018 11 3;22(7):e13274. Epub 2018 Aug 3.

Department of Pediatrics, Division of General Pediatrics, Le Bonheur Children's Hospital, University of Tennessee Health Sciences Center, Memphis, Tennessee.

Background: We report a case series of histoplasmosis in KTx patients in a children's hospital in an endemic area.

Methods: All KTx cases from January 1, 2002, to August 31, 2016, were reviewed to identify those with disseminated histoplasmosis.

Results: The attack rate of histoplasmosis among our KTx patients was 6.9 per 100 cases. The median age at the time of diagnosis was 16 years (11-18). Comorbidities included glomerulosclerosis (3), medullary cystic disease (1), and obstructive uropathy (2) and HIV (1). There were 5 deceased and 1 living-related donor transplants, and no patient had a history of rejection prior to histoplasmosis. Median time from transplant to histoplasmosis was 14.8 months (IQR 2.2-38.3) and 33% occurred in the first year after transplant. Urine and/or serum antigens were positive in all patients. They were either treated with amphotericin B and transitioned to an azole or received azole monotherapy. Most (83%) received chronic suppression with itraconazole. No patients died and relapse occurred in 1 patient after repeat transplant.

Conclusions: KTx patients in endemic areas are at risk for disseminated histoplasmosis. Further study is needed to determine which factors portend the need for fungal prophylaxis in this subset of patients.
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http://dx.doi.org/10.1111/petr.13274DOI Listing
November 2018

Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase.

Blood Adv 2018 05;2(10):1157-1169

Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.

The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression. When administered in combination with gemcitabine, an inhibitor of the M1 RNR subunit, the ATR inhibitor VX-970, eradicated disseminated leukemia in an orthotopic mouse model, eliciting long-term survival and effective cure. These data identify a synergistic interaction between ATR inhibition and RNR loss that will inform the deployment of small molecule inhibitors for the treatment of AML and other hematologic malignancies.
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http://dx.doi.org/10.1182/bloodadvances.2017015214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965047PMC
May 2018

PERK/eIF2α signaling inhibits HIF-induced gene expression during the unfolded protein response via YB1-dependent regulation of HIF1α translation.

Nucleic Acids Res 2018 05;46(8):3878-3890

Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

HIF1α (hypoxia inducible factor 1α) is the central regulator of the cellular response to low oxygen and its activity is deregulated in multiple human pathologies. Consequently, given the importance of HIF signaling in disease, there is considerable interest in developing strategies to modulate HIF1α activity and down-stream signaling events. In the present study we find that under hypoxic conditions, activation of the PERK branch of the unfolded protein response (UPR) can suppress the levels and activity of HIF1α by preventing efficient HIF1α translation. Activation of PERK inhibits de novo HIF1α protein synthesis by preventing the RNA-binding protein, YB-1, from interacting with the HIF1α mRNA 5'UTR. Our data indicate that activation of the UPR can sensitise tumor cells to hypoxic stress, indicating that chemical activation of the UPR could be a strategy to target hypoxic malignant cancer cells.
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http://dx.doi.org/10.1093/nar/gky127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934640PMC
May 2018

Angle-insensitive amorphous silicon optical filter for fluorescence contact imaging.

Opt Lett 2018 Feb;43(3):354-357

We introduce a novel amorphous silicon absorption filter that has high rejection for all angles of incident light for wavelengths below approximately 700 nm. This filter is used for microscopic cancer tissue detection in a small intraoperative contact fluorescence imaging system that requires excitation light at oblique angles. Our 15 μm thick filter presents over five orders of magnitude rejection at 633 nm, making it compatible with several clinically tested fluorophores, including IR700DX. We have demonstrated imaging of fluorescently labeled human epidermal growth factor receptor 2+ breast cancer tissue using the filter, and we can reliably detect microscopic clusters of breast cancer cells with only a 75 ms integration time.
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http://dx.doi.org/10.1364/OL.43.000354DOI Listing
February 2018

Features of MRI stromal enhancement with neoadjuvant chemotherapy: a subgroup analysis of the ACRIN 6657/I-SPY TRIAL.

J Med Imaging (Bellingham) 2018 01 23;5(1):011014. Epub 2017 Dec 23.

University of California San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, United States.

Although the role of cancer-activated stroma in malignant progression has been well investigated, the influence of an activated stroma in therapy response is not well understood. Using retrospective pilot cohorts, we previously observed that MRI detected stromal contrast enhancement was associated with proximity to the tumor and was predictive for relapse-free survival in patients with breast cancer receiving neoadjuvant chemotherapy. Here, to evaluate the association of stromal contrast enhancement to therapy, we applied an advanced tissue mapping technique to evaluate stromal enhancement patterns within 71 patients enrolled in the I-SPY 1 neoadjuvant breast cancer trial. We correlated MR stromal measurements with stromal protein levels involved in tumor progression processes. We found that stromal percent enhancement values decrease with distance from the tumor edge with the estimated mean change ranging [Formula: see text] to [Formula: see text] ([Formula: see text]) for time points T2 through T4. While not statistically significant, we found a decreasing trend in global stromal signal enhancement ratio values with the use of chemotherapy. There were no statistically significant differences between MR enhancement measurements and stromal protein levels. Findings from this study indicate that stromal features characterized by MRI are impacted by chemotherapy and may have predictive value in a larger study.
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http://dx.doi.org/10.1117/1.JMI.5.1.011014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741993PMC
January 2018

The Future of Radiobiology.

J Natl Cancer Inst 2018 04;110(4):329-340

Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Innovation and progress in radiation oncology depend on discovery and insights realized through research in radiation biology. Radiobiology research has led to fundamental scientific insights, from the discovery of stem/progenitor cells to the definition of signal transduction pathways activated by ionizing radiation that are now recognized as integral to the DNA damage response (DDR). Radiobiological discoveries are guiding clinical trials that test radiation therapy combined with inhibitors of the DDR kinases DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM), ataxia telangiectasia related (ATR), and immune or cell cycle checkpoint inhibitors. To maintain scientific and clinical relevance, the field of radiation biology must overcome challenges in research workforce, training, and funding. The National Cancer Institute convened a workshop to discuss the role of radiobiology research and radiation biologists in the future scientific enterprise. Here, we review the discussions of current radiation oncology research approaches and areas of scientific focus considered important for rapid progress in radiation sciences and the continued contribution of radiobiology to radiation oncology and the broader biomedical research community.
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http://dx.doi.org/10.1093/jnci/djx231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928778PMC
April 2018

Cross-activating c-Met/β1 integrin complex drives metastasis and invasive resistance in cancer.

Proc Natl Acad Sci U S A 2017 10 26;114(41):E8685-E8694. Epub 2017 Sep 26.

Department of Neurosurgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143;

The molecular underpinnings of invasion, a hallmark of cancer, have been defined in terms of individual mediators but crucial interactions between these mediators remain undefined. In xenograft models and patient specimens, we identified a c-Met/β1 integrin complex that formed during significant invasive oncologic processes: breast cancer metastases and glioblastoma invasive resistance to antiangiogenic VEGF neutralizing antibody, bevacizumab. Inducing c-Met/β1 complex formation through an engineered inducible heterodimerization system promoted features crucial to overcoming stressors during metastases or antiangiogenic therapy: migration in the primary site, survival under hypoxia, and extravasation out of circulation. c-Met/β1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and β1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/β1 complex to maintain the high-affinity β1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/β1 binding of amino acids predicted by crystallography to mediate their extracellular interaction. Far-Western blotting and sequential immunoprecipitation revealed that c-Met displaced α5 integrin from β1 integrin, creating a complex with much greater affinity for fibronectin (FN) than α5β1. Thus, tumor cells adapt to microenvironmental stressors induced by metastases or bevacizumab by coopting receptors, which normally promote both cell migration modes: chemotaxis, movement toward concentrations of environmental chemoattractants, and haptotaxis, movement controlled by the relative strengths of peripheral adhesions. Tumor cells then redirect these receptors away from their conventional binding partners, forming a powerful structural c-Met/β1 complex whose ligand-independent cross-activation and robust affinity for FN drive invasive oncologic processes.
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http://dx.doi.org/10.1073/pnas.1701821114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642678PMC
October 2017