In younger adults (i.e., those < 40 years of age) a walking cadence of 100 steps/min is a consistently supported threshold indicative of absolutely-defined moderate intensity ambulation (i.e., ≥ 3 ...metabolic equivalents; METs). Less is known about the cadence-intensity relationship in adults of middle-age.
To establish heuristic (i.e., evidence-based, practical, rounded) cadence thresholds for absolutely-defined moderate (3 METs) and vigorous (6 METs) intensity in adults 41 to 60 years of age.
In this cross-sectional study, 80 healthy adults of middle-age (10 men and 10 women representing each 5-year age-group between 41 to 60 years; body mass index = 26.0 ± 4.0 kg/m
) walked on a treadmill for 5-min bouts beginning at 0.5 mph and increasing in 0.5 mph increments. Performance termination criteria included: 1) transitioning to running, 2) reaching 75% of age-predicted maximum heart rate, or 3) reporting a Borg rating of perceived exertion > 13. Cadence was directly observed (i.e., hand tallied). Intensity (i.e., oxygen uptake VO
mL/kg/min) was assessed with an indirect calorimeter and converted to METs (1 MET = 3.5 mL/kg/min). A combination of segmented regression and Receiver Operating Characteristic (ROC) modeling approaches was used to identify optimal cadence thresholds. Final heuristic thresholds were determined based on an evaluation of classification accuracy (sensitivity, specificity, positive and negative predictive value, overall accuracy).
The regression model identified 101.7 (95% Predictive Interval PI: 54.9-110.6) and 132.1 (95% PI: 122.0-142.2) steps/min as optimal cadence thresholds for 3 METs and 6 METs, respectively. Corresponding values based on ROC models were 98.5 (95% Confidence Intervals CI: 97.1-104.9) and 117.3 (95% CI: 113.1-126.1) steps/min. Considering both modeling approaches, the selected heuristic thresholds for moderate and vigorous intensity were 100 and 130 steps/min, respectively.
Consistent with our previous report in 21 to 40-year-old adults, cadence thresholds of 100 and 130 steps/min emerged as heuristic values associated with 3 and 6 METs, respectively, in 41 to 60-year-old adults. These values were selected based on their utility for public health messaging and on the trade-offs in classification accuracy parameters from both statistical methods. Findings will need to be confirmed in older adults and in free-living settings.
Heuristic (i.e., evidence-based, rounded) cadences of ≥100 and ≥ 130 steps/min have consistently corresponded with absolutely-defined moderate (3 metabolic equivalents METs) and vigorous (6 METs) ...physical activity intensity, respectively, in adults 21-60 years of age. There is no consensus regarding similar thresholds in older adults.
To provide heuristic cadence thresholds for 3, 4, 5, and 6 METs in 61-85-year-old adults.
Ninety-eight community-dwelling ambulatory and ostensibly healthy older adults (age = 72.6 ± 6.9 years; 49% women) walked on a treadmill for a series of 5-min bouts (beginning at 0.5 mph with 0.5 mph increments) in this laboratory-based cross-sectional study until: 1) transitioning to running, 2) reaching ≥75% of their age-predicted maximum heart rate, or 3) reporting a Borg rating of perceived exertion > 13. Cadence was directly observed and hand-tallied. Intensity (oxygen uptake VO
mL/kg/min) was assessed with indirect calorimetry and converted to METs (1 MET = 3.5 mL/kg/min). Cadence thresholds were identified via segmented mixed effects model regression and using Receiver Operating Characteristic (ROC) curves. Final heuristic cadence thresholds represented an analytical compromise based on classification accuracy (sensitivity, specificity, positive and negative predictive value, and overall accuracy).
Cadences of 103.1 (95% Prediction Interval: 70.0-114.2), 116.4 (105.3-127.4), 129.6 (118.6-140.7), and 142.9 steps/min (131.8-148.4) were identified for 3, 4, 5, and 6 METs, respectively, based on the segmented regression. Comparable values based on ROC analysis were 100.3 (95% Confidence Intervals: 95.7-103.1), 111.5 (106.1-112.9), 116.0 (112.4-120.2), and 128.6 steps/min (128.3-136.4). Heuristic cadence thresholds of 100, 110, and 120 were associated with 3, 4, and 5 METs. Data to inform a threshold for ≥6 METs was limited, as only 6/98 (6.0%) participants achieved this intensity.
Consistent with previous data collected from 21-40 and 41-60-year-old adults, heuristic cadence thresholds of 100, 110, and 120 steps/min were associated with 3, 4, and 5 METs, respectively, in 61-85-year-old adults. Most older adults tested did not achieve the intensity of ≥6 METs; therefore, our data do not support establishing thresholds corresponding with this intensity level.
Clinicaltrials.gov NCT02650258 . Registered 24 December 2015.
Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic ...antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.
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•Solid cancers overexpress NQO1, with low catalase levels, reverse of normal tissue•β-Lapachone kills independent of oncogenic driver or passenger mutations•Synergy with PARP inhibitors and β-lapachone is NQO1 dependent•PARP inhibitors + β-lap induce DNA lesions, block repair, and cause apoptosis
Huang et al. show that combination treatment with NQO1 bioactivatible β-lapachone and a PARP inhibitor causes unrepaired DNA damage and induces apoptosis, and that the combination treatment has a synergistic therapeutic effect in orthotopic pancreatic and non-small-cell lung cancer models.
Standardized validation indices (i.e., accuracy, bias, and precision) provide a comprehensive comparison of step counting wearable technologies. To expand a previously published child/youth catalog ...of validity indices to include adults (21-40, 41-60 and 61-85 years of age) assessed across a range of treadmill speeds (slow 0.8-3.2 km/h, normal 4.0-6.4 km/h, fast 7.2-8.0 km/h) and device wear locations (ankle, thigh, waist, and wrist). Two hundred fifty-eight adults (52.5 + or - 18.7 years, 49.6% female) participated in this laboratory-based study and performed a series of 5-min treadmill bouts while wearing multiple devices; 21 devices in total were evaluated over the course of this multi-year cross-sectional study (2015-2019). The criterion measure was directly observed steps. Computed validity indices included accuracy (mean absolute percentage error, MAPE), bias (mean percentage error, MPE), and precision (correlation coefficient, r; standard deviation, SD; coefficient of variation, CoV). Over the range of normal speeds, 15 devices (Actical, waist-worn ActiGraph GT9X, activPAL, Apple Watch Series 1, Fitbit Ionic, Fitbit One, Fitbit Zip, Garmin vivoactive 3, Garmin vivofit 3, waist-worn GENEActiv, NL-1000, PiezoRx, Samsung Gear Fit2, Samsung Gear Fit2 Pro, and StepWatch) performed at < 5% MAPE. The wrist-worn ActiGraph GT9X displayed the worst accuracy across normal speeds (MAPE = 52%). On average, accuracy was compromised across slow walking speeds for all wearable technologies (MAPE = 40%) while all performed best across normal speeds (MAPE = 7%). When analyzing the data by wear locations, the ankle and thigh demonstrated the best accuracy (both MAPE = 1%), followed by the waist (3%) and the wrist (15%) across normal speeds. There were significant effects of speed, wear location, and age group on accuracy and bias (both p < 0.001) and precision (p less than or equai to 0.045). Standardized validation indices cataloged by speed, wear location, and age group across the adult lifespan facilitate selecting, evaluating, or comparing performance of step counting wearable technologies. Speed, wear location, and age displayed a significant effect on accuracy, bias, and precision. Overall, reduced performance was associated with very slow walking speeds (0.8 to 3.2 km/h). Ankle- and thigh-located devices logged the highest accuracy, while those located at the wrist reported the worst accuracy.
We previously demonstrated that a heuristic (i.e., evidence-based, rounded yet practical) cadence threshold of ≥ 100 steps/min was associated with absolutely-defined moderate intensity physical ...activity (i.e., ≥ 3 metabolic equivalents METs) in older adults 61-85 years of age. Although it was difficult to ascertain achievement of absolutely-defined vigorous (6 METs) intensity, ≥ 130 steps/min was identified as a defensible threshold for this population. However, little evidence exists regarding cadence thresholds and relatively-defined moderate intensity indicators, including ≥ 64% heart rate HR maximum HR
= 220-age, ≥ 40% HR reserve HRR = HR
-HR
, and ≥ 12 Borg Scale Rating of Perceived Exertion RPE; or vigorous intensity indicators including ≥ 77%HR
, ≥ 60%HRR, and ≥ 14 RPE.
To analyze the relationship between cadence and relatively-defined physical activity intensity and identify relatively-defined moderate and vigorous heuristic cadence thresholds for older adults 61-85 years of age.
Ninety-seven ostensibly healthy adults (72.7 ± 6.9 years; 49.5% women) completed up to nine 5-min treadmill walking bouts beginning at 0.5 mph (0.8 km/h) and progressing by 0.5 mph speed increments (with 2-min rest between bouts). Directly-observed (and video-recorded) steps were hand-counted, HR was measured using a chest-strapped monitor, and in the final minute of each bout, participants self-reported RPE. Segmented mixed model regression and Receiver Operating Characteristic (ROC) curve analyses identified optimal cadence thresholds associated with relatively-defined moderate (≥ 64%HR
, ≥ 40%HRR, and ≥ 12 RPE) and vigorous (≥ 77%HR
, ≥ 60%HRR, and ≥ 14 RPE) intensities. A compromise between the two analytical methods, including Youden's Index (a sum of sensitivity and specificity), positive and negative predictive values, and overall accuracy, yielded final heuristic cadences.
Across all relatively-defined moderate intensity indicators, segmented regression models and ROC curve analyses identified optimal cadence thresholds ranging from 105.9 to 112.8 steps/min and 102.0-104.3 steps/min, respectively. Comparable values for vigorous intensity indicators ranged between126.1-132.1 steps/min and 106.7-116.0 steps/min, respectively. Regardless of the relatively-defined intensity indicator, the overall best heuristic cadence threshold aligned with moderate intensity was ≥ 105 steps/min. Vigorous intensity varied between ≥ 115 (greater sensitivity) or ≥ 120 (greater specificity) steps/min.
Heuristic cadence thresholds align with relatively-defined intensity indicators and can be useful for studying and prescribing older adults' physiological response to, and/or perceived experience of, ambulatory physical activity.
Clinicaltrials.gov NCT02650258. Registered 24 December 2015.
Wearable technologies play an important role in measuring physical activity (PA) and promoting health. Standardized validation indices (i.e., accuracy, bias, and precision) compare performance of ...step counting wearable technologies in young people.
To produce a catalog of validity indices for step counting wearable technologies assessed during different treadmill speeds (slow 0.8-3.2 km/h, normal 4.0-6.4 km/h, fast 7.2-8.0 km/h), wear locations (waist, wrist/arm, thigh, and ankle), and age groups (children, 6-12 years; adolescents, 13-17 years; young adults, 18-20 years).
One hundred seventeen individuals (13.1 ± 4.2 years, 50.4% female) participated in this cross-sectional study and completed 5-min treadmill bouts (0.8 km/h to 8.0 km/h) while wearing eight devices (Waist: Actical, ActiGraph GT3X+, NL-1000, SW-200; Wrist: ActiGraph GT3X+; Arm: SenseWear; Thigh: activPAL; Ankle: StepWatch). Directly observed steps served as the criterion measure. Accuracy (mean absolute percentage error, MAPE), bias (mean percentage error, MPE), and precision (correlation coefficient, r; standard deviation, SD; coefficient of variation, CoV) were computed.
Five of the eight tested wearable technologies (i.e., Actical, waist-worn ActiGraph GT3X+, activPAL, StepWatch, and SW-200) performed at < 5% MAPE over the range of normal speeds. More generally, waist (MAPE = 4%), thigh (4%) and ankle (5%) locations displayed higher accuracy than the wrist location (23%) at normal speeds. On average, all wearable technologies displayed the lowest accuracy across slow speeds (MAPE = 50.1 ± 35.5%), and the highest accuracy across normal speeds (MAPE = 15.9 ± 21.7%). Speed and wear location had a significant effect on accuracy and bias (P < 0.001), but not on precision (P > 0.05). Age did not have any effect (P > 0.05).
Standardized validation indices focused on accuracy, bias, and precision were cataloged by speed, wear location, and age group to serve as important reference points when selecting and/or evaluating device performance in young people moving forward. Reduced performance can be expected at very slow walking speeds (0.8 to 3.2 km/h) for all devices. Ankle-worn and thigh-worn devices demonstrated the highest accuracy. Speed and wear location had a significant effect on accuracy and bias, but not precision.
Clinicaltrials.gov NCT01989104 . Registered November 14, 2013.
•In a randomized trial of nintedanib for the treatment of radiation pneumonitis, serum biomarkers were longitudinally assessed.•Network analysis identified a module of ten cytokines correlated with ...pulmonary exacerbations from radiation pneumonitis.•Two individual cytokines in the module (IL-5 and TNFSF12) were correlated with decreased acute pulmonary exacerbations.
Radiation pneumonitis (RP) is a common side effect of thoracic radiotherapy and often has a long course characterized by acute exacerbations and progression to permanent lung fibrosis. There are no validated biomarkers of prognosis in patients diagnosed with RP.
We analyzed a time course of serum chemokines, cytokines, and other proteins from patients with grade 2+ RP in a randomized clinical trial of a steroid taper plus nintedanib, a multiple tyrosine kinase inhibitor, versus placebo plus a steroid taper for the treatment of RP. Weighted gene correlation network analysis (WGCNA) and univariable zero inflated Poisson models were used to identify groups of correlated analytes and their associations with clinical outcomes.
Thirty enrolled patients had biomarker data available, and 17 patients had enough analytes tested for network analysis. WGNCA identified ten analytes, including transforming growth factor beta-1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1), and platelet-derived growth factor (PDGF), that in aggregate were correlated with the occurrence of pulmonary exacerbations (p = 0.008), the total number of acute pulmonary exacerbations (p = 0.002), and treatment arm (p = 0.036). By univariable analysis, an increase in rate of change of two components of the RP module were associated with an increased incidence rate of pulmonary exacerbations: interleukin 5 (IL-5, incidence rate ratio (IRR) 1.02, 95% CI 1.01–1.04, p = 0.002), and tumor necrosis factor superfamily 12 (TNFSF12, IRR 1.06, CI 1–1.11, p = 0.036). An increased slope of epidermal growth factor (EGF) was associated with a decreased incidence rate of exacerbations (IRR 0.94, CI 0.89–1, p = 0.036).
We identified a panel of serum biomarkers that showed association with nintedanib treatment and acute pulmonary exacerbations in patients with RP. A confirmatory study will be needed to validate this panel for use as a prognostic tool in patients with RP.
Heuristic cadence (steps/min) thresholds of ≥100 and ≥ 130 steps/min correspond with absolutely-defined moderate (3 metabolic equivalents METs; 1 MET = 3.5 mL O
·kg
·min
) and vigorous (6 METs) ...intensity, respectively. Scarce evidence informs cadence thresholds for relatively-defined moderate (≥ 64% heart rate maximum HR
= 220-age, ≥ 40%HR reserve HRR = HR
-HR
, and ≥ 12 Rating of Perceived Exertion RPE); or vigorous intensity (≥ 77%HR
, ≥ 60%HRR, and ≥ 14 RPE).
To identify heuristic cadence thresholds corresponding with relatively-defined moderate and vigorous intensity in 21-60-year-olds.
In this cross-sectional study, 157 adults (40.4 ± 11.5 years; 50.6% men) completed up to twelve 5-min treadmill bouts, beginning at 0.5 mph and increasing by 0.5 mph. Steps were directly observed, HR was measured with chest-worn monitors, and RPE was queried in the final minute of each bout. Segmented mixed model regression and Receiver Operating Characteristic (ROC) curve analyses identified optimal cadence thresholds, stratified by age (21-30, 31-40, 41-50, and 51-60 years). Reconciliation of the two analytical models, including trade-offs between sensitivity, specificity, positive and negative predictive values, and overall accuracy, yielded final heuristic cadences.
Across all moderate intensity indicators, the segmented regression models estimated optimal cadence thresholds ranging from 123.8-127.5 (ages 21-30), 121.3-126.0 (ages 31-40), 117.7-122.7 (ages 41-50), and 113.3-116.1 steps/min (ages 51-60). Corresponding values for vigorous intensity were 140.3-144.1, 140.2-142.6, 139.3-143.6, and 131.6-132.8 steps/min, respectively. ROC analysis estimated chronologically-arranged age groups' cadence thresholds ranging from 114.5-118, 113.5-114.5, 104.6-112.9, and 103.6-106.0 across all moderate intensity indicators, and 127.5, 121.5, 117.2-123.2, and 113.0 steps/min, respectively, for vigorous intensity.
Heuristic cadence thresholds corresponding to relatively-defined moderate intensity for the chronologically-arranged age groups were ≥ 120, 120, 115, and 105 steps/min, regardless of the intensity indicator (i.e., % HR
, %HRR, or RPE). Corresponding heuristic values for vigorous intensity indicators were ≥ 135, 130, 125, and 120 steps/min. These cadences are useful for predicting/programming intensity aligned with age-associated differences in physiological response to, and perceived experiences of, moderate and/or vigorous intensity.
Clinicaltrials.gov NCT02650258 . Registered 24 December 2015.
Elevated oxidative stress is an aberration seen in many solid tumors, and exploiting this biochemical difference has the potential to enhance the efficacy of anticancer agents. Homeostasis of ...reactive oxygen species (ROS) is important for normal cell function, but excessive production of ROS can result in cellular toxicity, and therefore ROS levels must be balanced finely. Here, we highlight the relationship between the extracellular matrix and ROS production by reporting a novel function of the matricellular protein Fibulin-5 (Fbln5). We used genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDAC) and found that mutation of the integrin-binding domain of Fbln5 led to decreased tumor growth, increased survival, and enhanced chemoresponse to standard PDAC therapies. Through mechanistic investigations, we found that improved survival was due to increased levels of oxidative stress in Fbln5-mutant tumors. Furthermore, loss of the Fbln5-integrin interaction augmented fibronectin signaling, driving integrin-induced ROS production in a 5-lipooxygenase-dependent manner. These data indicate that Fbln5 promotes PDAC progression by functioning as a molecular rheostat that modulates cell-ECM interactions to reduce ROS production, and thus tip the balance in favor of tumor cell survival and treatment-refractory disease.
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