Citations

Background and Purpose― We aimed to determine whether low-frequency electric field navigated repetitive transcranial magnetic stimulation to noninjured motor cortex versus sham repetitive transcranial magnetic stimulation avoiding motor cortex could improve arm motor function in hemiplegic stroke patients when combined with motor training. Methods― Twelve outpatient US rehabilitation centers enrolled participants between May 2014 and December 2015. We delivered 1 Hz active or sham repetitive transcranial magnetic stimulation to noninjured motor cortex before each of eighteen 60-minute therapy sessions over a 6-week period, with outcomes measured at 1 week and 1, 3, and 6 months after end of treatment. The primary end point was the percentage of participants improving ≥5 points on upper extremity Fugl-Meyer score 6 months after end of treatment. Secondary analyses assessed changes on the upper extremity Fugl-Meyer and Action Research Arm Test and Wolf Motor Function Test and safety. Results― Of 199 participants, 167 completed treatment and follow-up because of early discontinuation of data collection. Upper extremity Fugl-Meyer gains were significant for experimental ( P <0.001) and sham groups ( P <0.001). Sixty-seven percent of the experimental group (95% CI, 58%–75%) and 65% of sham group (95% CI, 52%–76%) improved ≥5 points on 6-month upper extremity Fugl-Meyer ( P =0.76). There was also no difference between experimental and sham groups in the Action Research Arm Test ( P =0.80) or the Wolf Motor Function Test ( P =0.55). A total of 26 serious adverse events occurred in 18 participants, with none related to the study or device, and with no difference between groups. Conclusions― Among patients 3 to 12 months poststroke, goal-oriented motor rehabilitation improved motor function 6 months after end of treatment. There was no difference between the active and sham repetitive transcranial magnetic stimulation trial arms. Clinical Trial Registration― URL: https://www.clinicaltrials.gov . Unique identifier: NCT02089464.

Abstract Introduction: Defining the histologic correlates of mammographic breast density (MD) may provide insights into why elevated MD is related to increased breast cancer risk. Studies suggest that reduced terminal ductal lobular (TDLU) involution is associated with elevated MD, and both are independent breast cancer risk factors among women who have undergone a biopsy for benign breast disease (BBD). Prior digital histologic analyses of normal breast tissues revealed epithelial nuclear density (END) and TDLU involution are correlated. Accordingly, we examined associations of END with TDLU involution and MD in clinical biopsies. Methods: We analyzed 262 image-guided breast biopsies diagnosed as BBD from 224 women. TDLU involution was visually assessed as TDLU count/mm2 and TDLU span (inversely related to level of involution) in background normal tissue, evaluated using digitized images. The Genie Classifier (Aperio) was applied to images to estimate nuclei count per unit epithelial area, (END). Single X-ray Absorptiometry of pre-biopsy craniocaudal digital mammograms was applied to measure global MD (percent fibroglandular volume (%FGV)). Analysis of covariance, adjusted for age and body mass index, examined mean END differences across tertiles of TDLU/MD measures. Analyses were conducted at the biopsy level using SAS PROC GENMOD to account for within-woman correlations. All tests were two-tailed. Results: Overall, 67% of BBD biopsies were proliferative. Higher END was observed among proliferative than non-proliferative BBD (median END: 10,187 vs. 9,953 respectively; p=0.04). Among all women, END significantly increased with increasing tertiles of TDLU measures (p-trends: TDLU count/100mm2=0.0001, TDLU span=0.046). Whereas TDLU metrics were positively associated with %FGV, no relationship was observed between END and %FGV. In analyses stratified by BBD severity, however, END and %FGV were positively associated among women with non-proliferative disease (p-trend=0.04), findings not observed with proliferative disease. Conclusions: Automated END and visually assessed TDLU involution metrics were positively associated with each other and with MD. However, associations were diluted for proliferative lesions, suggesting that applying automated digital pathology tools to unsegmented digital images of whole sections of BBD biopsies does not demonstrate the same associations with MD as visual assessment of TDLU involution. Citation Format: Maeve Mullooly, Samantha Puvanesarajah, Shaoqi Fan, Ruth M. Pfeiffer, Linnea Olsson, Manila Hada, Erin L. Kirk, Pamela M. Vacek, Donald L. Weaver, John A. Shepherd, Amir P. Mahmoudzadeh, Jeff Wang, Stephen M. Hewitt, Sally D. Herschorn, Mark E. Sherman, Melissa A. Troester, Gretchen L. Gierach. Utilizing digital pathology to understand breast epithelial characteristics of benign breast disease among women undergoing diagnostic image-guided breast biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3260.

Abstract Purpose: Volumetric breast density and body mass index (BMI) are increasingly used for breast cancer risk stratification. We examine if the effect of volumetric breast density on breast cancer risk increases with increasing BMI. Methods: Participants were from two case-control studies within mammography practices, the San Francisco Mammography Registry and the Mayo Clinic Rochester, Breast Screening Practice. Breast cancers were included if diagnosed between January 2007 and 2015 and with a screening full-field digital mammogram at least 6 months prior to diagnosis; the earliest mammogram within 5 years of diagnosis was selected. Up to three controls were matched to each case on age, race, date, mammography machine, and state of residence. Volumetric percent density (VPD), dense volume (DV) and non-dense volume (NDV) were measured using VolparaTM software. Breast cancer risk was assessed using logistic regression stratified by menopause status and adjusted for matching factors, family history of breast cancer, parity/age at first birth, and postmenopausal hormone therapy. Models for DV were additionally adjusted for NDV, and NDV models for DV. Multiplicative interactions were fit between BMI categories [&lt;25 (underweight), 25-30 (normal weight) and &gt;30 (overweight/obese) kg/m2] and VPD, DV, and NDV, and trend tests assessed for increasing odds ratios (OR) with increasing BMI. Results: A total of 781 premenopausal and 1850 postmenopausal breast cancers and 3535 controls were included in the analysis. Median age of premenopausal women was 45 years (IQR: 6.1) and 63.3 years (IQR: 14) for postmenopausal women. Cases vs. controls had greater VPD and DV for both premenopausal (VPD: 14.9% vs. 12.0%, DV: 74.1 cm3 vs. 64.4 cm3) and postmenopausal women (VPD: 6.8% vs. 6.1%, DV: 53.4 cm3 vs. 48.0 cm3)(all p's&lt;0.001). Trends between increasing BMI and VPD were evident for both pre (ptrend=0.0007) and postmenopausal (ptrend=0.0005) women. Among premenopausal women, the odds ratio (OR) for breast cancer associated with a 10% increase in VPD was of 1.39, 2.19 and 2.88 for BMI &lt;25, 25-30 and &gt;30 kg/m2 (p-trend=0.0007), respectively. For DV, OR's were 1.39, 1.33 and 1.51 for a 1 SD increase in DV, respectively, though the interaction with DV was not significant (ptrend=0.68). Among postmenopausal women, a 10% increase in VPD was associated with OR's of 1.35, 2.03, 3.6 for BMI &lt;25, 25-29, &gt;30-kg/m2 (ptrend =0.0001), respectively, and 1.31, 1.34 and 1.65 for a 1 SD increase in DV (ptrend =0.01), respectively. Associations between NDV and breast cancer risk did not differ by BMI category for premenopausal (ptrend =0.52) or postmenopausal (ptrend =0.07) women. Conclusions: The effect of VPD on breast cancer risk is strongest in overweight/obese women. As volumetric breast density and BMI are commonly used in clinical risk stratification, these differences in risk have high clinical relevance for informing prevention decisions. Citation Format: Natalie J. Engmann, Christopher G. Scott, Matthew R. Jensen, Stacey J. Winham, Lin Ma, Kathleen R. Brandt, Amir Mahmoudzadeh, Serghei Malkov, Dana Whaley, Carrie Hruska, Fang Fang Wu, Diana L. Miglioretti, Aaron D. Norman, John Heine, John Shepherd, Vernon S. Pankratz, Celine M. Vachon, Karla Kerlikowske. Overweight and obese women with high volumetric breast density at high breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3226.

Abstract BACKGROUND: A GWAS for the MA.27 aromatase inhibitors (AIs) adjuvant trial (4,406 controls and 252 cases) identified variant (V) SNPs in a long noncoding (lnc) RNA, MIR2052HG, that were associated with longer breast cancer free interval (HR= 0.37, P= 2.15E-07). V SNPs (MAF= 0.32 to 0.42) were associated with lower MIR2052HG and ERα expression in the presence of AIs. MIR2052HG maintained ERα both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated ERα degradation. (Cancer Res 76:7012-23, 2016). Our goal was to further elucidate MIR2052HG's mechanism of action. METHODS: RNA-Binding Protein Immunoprecipitation (RBPI) assays were performed to demonstrate that the transcription factor, early growth response protein 1 (EGR1), worked together with MIR2052HG to regulate lemur tyrosine kinase-3 (LMTK3) transcription in MCF7/AC1 and CAMA-1 cells. The location of EGR1 on the LMTK3 gene locus was mapped using chromatin immunoprecipitation (ChIP) assays. The co-localization of MIR2052HG RNA and the LMTK3 gene locus was determined using RNA-DNA dual fluorescent in situ hybridization (FISH). SNP effects were evaluated using a panel of human lymphoblastoid cell lines. RESULTS: TCGA analysis revealed LMTK3 and MIR2052HG expression were highly correlated in ERα-positive breast cancer patients. We found that the MIR2052HG transcript was located in the LMTK3 gene locus by RNA-DNA FISH. Among all of the 12 potential LMTK3 transcription factors identified in the Encode database that were examined by RBPI, only EGR1 showed an interaction with MIR2052HG. CHIP assays confirmed EGR1 binding to the two putative EGR1 binding sites in LMTK3 gene.Depletion of MIR2052HG reduced the binding of EGR1 to the LMTK3 promoter and decreased LMTK3 expression, suggesting that it might function as a scaffold. Mechanistically, decreased LMTK3 levels further increased protein kinase C (PKC) activity and downstream AKT activity, leading to reduced ESR1 mRNA levels via increased pFOXO3. At the protein level, in MIR2052HG depleted cells, increased PKC activity increased the phosphorylation of MEK, ERK, and RSK1, leading to increased ERα phosphorylation at Ser167 and increased ERα degradation. Conversely, overexpression of LMTK3 in MIR2052HG depleted cells reversed these phenotypes. MIR2052HG regulated LMTK3 and ERα expression in a SNP- dependent fashion: the MIR2052HG V SNP, relative to wild-type (WT) genotype, increased LMTK3/ERα expression in response to androstenedione due to increased binding between EGR1 and the LMTK3 promoter in LCLs. However, AI treatment reduced this binding in MIR2052HG variant cells but increased binding in WT cells, resulting in decreased LMTK3/ERα in V cells and increased expression in WT cells. CONCLUSIONS: Our findings support a model in which the protective MIR2052HG variant genotype regulates LMTK3 via MIR2052HG/EGR1, and LMTK3 regulates ERα stability via the PKC/MEK/ERK/RSK1 axis. This regulation may explain the effect of the MIR2052HG variant genotype on cell proliferation and response to AIs in MA.27. These findings provide new insight into the mechanism of action of MIR2052HG and suggest that LMTK3 may be a new therapeutic target in ERα-positive breast cancer patients treated with AIs. Citation Format: Cairns J, Ingle JN, Shepherd LE, Kubo M, Goetz MP, Weinshilboum RM, Kalari KR, Wang L. LncRNA MIR2052HG regulates ERα level and endocrine resistance through LMTK3 by recruiting early growth response protein 1 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-07-01.

Abstract Background Celecoxib and low-dose aspirin might decrease risk of breast cancer recurrence. Methods In the Canadian Cancer Trials Group MA.27, postmenopausal hormone receptor–positive breast cancer patients were randomly assigned (2 × 2) to adjuvant exemestane or anastrozole, and celecoxib or placebo. Low-dose aspirin of 81 mg or less was a stratification factor. Due to concerns about cardiac toxicity, celecoxib use was stopped in December 2004, while stratification by aspirin use was removed through protocol amendment. We examined the effects of celecoxib and low-dose aspirin on event-free survival (EFS), defined as time from random assignment to time of locoregional or distant disease recurrence, new primary breast cancer, or death from any cause; distant disease–free survival (DDFS); and overall survival (OS). All statistical tests were two-sided. Results Random assignment to celecoxib (n = 811, 50.0%) or placebo (n = 811, 50.0%) was discontinued after 18 months (n = 1622). At a median of 4.1 years’ follow-up, among 1622 patients, 186 (11.5%) patients had an EFS event: 80 (4.9%) had distant relapse, and 125 (7.7%) died from any cause. Celecoxib did not statistically significantly impact EFS, DDFS, or OS in univariate analysis (respectively, P = .92, P = .55, and P = .56) or multivariable analysis (respectively, P = .74, P = .60, and P = .76). Low-dose aspirin use (aspirin users n = 476, 21.5%; non–aspirin users n = 1733, 78.5%) was associated in univariate analyses with worse EFS (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.12 to 1.96, P = 0.006) and worse OS (HR = 1.87, 95% CI = 1.35 to 2.61, P < .001). After adjusting for baseline characteristics and treatment arm, aspirin use showed no statistical association with EFS (P = .08) and DDFS (P = .82), but was associated with statistically worse OS (HR = 1.67, 95% CI = 1.13 to 2.49, P = .01). Conclusion Random assignment to short-term (≤18 months) celecoxib as well as use of low-dose aspirin showed no effect on DDFS and EFS in multivariable analysis. Low-dose aspirin increased “all-cause” mortality, presumably because of higher preexisting cardiovascular risks.

In studies on six experienced subjects lying supine, cardiac output and oxygen content of femoral venous blood were measured with the subject at rest, during the increase in muscle blood flow caused by intravenous infusion of epinephrine, during mild leg exercise, and during identical exercise combined with an infusion. The oxygen content of the blood from the exercising limb was much higher (average, 50%) during an infusion than when no infusion was given (average, 32%). The mean increase in cardiac output during the combined maneuver (8.2 liters/min) almost equaled the sum of the increases during the separate infusion (3.7 liters) and during exercise (4.7 liters). All individual studies showed approximately this same result. Thus, the additional blood supplied to the leg muscles by the infusion did not appear to be used for metabolic purposes during exercise. cardiac output; muscle blood flow Submitted on March 22, 1963

Normal subjects have been studied to assess the response of the capacitance vessels in the forearm during supine leg exercise. Measurements were made of changes in forearm volume (strain-gauge and water-filled plethysmographs) at a given pressure in the large forearm veins, of changes in pressure in the forearm veins with the circulation to the forearm arrested and in “isolated” vein segments. The results were consistent and demonstrated that exercise with a work load of 270–810 kg/min caused constriction of forearm capacitance vessels via the sympathetic nerves proportional to the severity of the exercise. Venoconstriction also occurred in the hand, and in the calf during arm exercise. Local exercise of the forearm muscles during supine leg exercise, which increased forearm blood flow by dilating the resistance vessels, did not prevent the increase in venous tone in the forearm. Thus a reflex increase in tone in the limb veins, both in the exercising and in the nonexercising parts, contributes to the cardiovascular adaptation to exercise. venoconstriction in exercising and nonexercising limbs; reflex venoconstriction with exercise graded to severity of work; reflex venoconstriction with exercise mediated through sympathetic nerves Submitted on June 15, 1964