Johnson, Bruce D.

The remarkable success of cancer immunotherapies has provided new hope to cancer patients. Unfortunately, a significant proportion of patients remain unable to respond to immunotherapy or maintain durable clinical responses. The lack of objective responses likely results from profound immune dysfunction often observed in patients with cancer. There is substantial evidence that exercise and physical activity can reduce incidence and improve outcomes in cancer patients. As the immune system is highly responsive to exercise, one potential avenue to improve immune function is through exercise and physical activity. A single event of dynamic exercise results in the substantial mobilization of leukocytes with increased functional capacities into the circulation. Chronic, or long-term, exercise leads to higher physical fitness in terms of greater cardiorespiratory function and/or muscle strength and endurance. High aerobic capacity, as measured by maximal oxygen uptake, has been associated with the reduction of dysfunctional T cells and improvements in the abundance of some T cell populations. To be sure, however, the mechanisms of exercise-mediated immune changes are both extensive and diverse. Here, we examine the evidence and theorize how acute and chronic exercise could be used to improve responses to cancer immunotherapies including immune checkpoint inhibitors, dendritic cell vaccines, natural killer cell therapies, and adoptive T cell therapies such as chimeric antigen receptor (CAR) T cells. Although the parameters of optimal exercise to yield defined outcomes remain to be determined, the available current data provide a compelling justification for additional human studies and clinical trials investigating the adjuvant use of exercise in immuno-oncology.

Growing evidence suggests that the larger conducting airways are smaller in women than men; however, evidence of this sex‐difference in airway geometry is yet to be demonstrated in a large cohort of adult, healthy non‐smokers. Furthermore, it is not known whether these sex differences persist after airway size is adjusted for its allometric relationship with absolute lung size. Purpose We examined the effect of sex on airway size in a large cohort of non‐smoking healthy adults after adjusting for the possible confounding effect of absolute lung size. Methods A total of 133 (75 men; 58 women) non‐smoking adults (50 ± 18 yrs) with normal pulmonary function (>80% pred.) participated in this study. Full thoracic CT scans were obtained in each participant during a breath‐hold at full inflation. Commercial software was used to automatically segment airways and assign 32 anatomical labels ranging from the 0 th to the 5 th generation. Intraluminal hydraulic diameters ( D h ) were obtained for each airway. An allometric relationship was assumed between D h and absolute lung size, as given by: D h = TLV β · e k , where TLV is the total lung volume at full inflation, β is the allometric scaling exponent, and k allowed for proportional effects of confounding variables. This allometric equation was log‐log transformed such that it could be examined using linear regression: e.g., ln( D h ) = β ·ln(TLV) + k . Sex, age and their interaction were allowed to contribute to both β and k as covariates. The model also included a term for reconstructed voxel size. Model averaging was used to provide parameter estimates of the log‐log transformed allometric equation. Results The allometric exponent, β , assigned to TLV was significant for all 32 anatomically labelled airways ( P < 0.05); neither sex nor age affected β . On the other hand, sex and age were significant mediators of k for the extra‐parenchymal airways only (Trachea, RMB, LMB, BronInt, see Figure 1, P < 0.05). Conclusions Our findings indicate that sex differences in D h remain present despite accounting for the allometric relationship between airway and lung size (see Figure 1). Importantly, however, this sex‐difference in airway size is seemingly confined to the extra‐parenchymal airways. Support or Funding Information This work was supported by NIH Grant HL71478. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

The classic method for determining alveolar‐capillary membrane conductance (D M ) and pulmonary capillary blood volume (V C ) involves measurement of lung diffusing capacity for carbon monoxide (D LCO ) at multiple inspired O 2 tensions (F I O 2 ). Recently, the technique has been simplified by simultaneously measuring D LNO (nitric oxide) to determine values at a single F I O 2 . Controversy exists over equations for calculation of θ CO (reaction rate of CO with Hgb) and the correct diffusion ratio for NO and CO (α) in the calculation of D MCO . The purpose of this study was to investigate how various published equations and ratios influence D M & V C using both the multiple and single F I O 2 methods. Eight healthy males were studied. D LCO & D LNO were measured using the rebreathe method (inspired vol. ~75% of inspiratory capacity, F I O 2 18, 35, & 55%). D M & V C were first calculated using five reported equations for θ CO . Once D M & V C were optimized based on reported predicted values, the D LNO method was compared using a range of α values. Using the multiple F I O 2 method, depending on the equation for θ CO , D M ranged from 47 to 103 ml/min/mmHg, and V C from 74 to 102 ml. For the calculation of D M & V C using the D LNO method, α ranged from 1.5 to 4.0 in order to optimize D M & V C values to the classic method. The determination of D M & V C is critically dependent on the equations used for θ CO which in turn affects the optimal ratio used to correct the D LNO method. NIH HL71478

The aim of this study was to determine if left ventricular (LV) diastolic function influences pulmonary function (PF) in healthy subjects and to determine if they are independently related after accounting for age, gender, BMI and blood pressure (BP). Echocardiograms and PF tests were performed in 103 healthy subjects (22‐76 yr). The ratio of peak early (E) and late (A) mitral inflow velocities and the ratio of peak early (E') and late (A') mitral annular velocities were obtained by pulsed wave Doppler and tissue Doppler imaging. The first stage of diastolic dysfunction, often observed in healthy aging, is characterized by reduced E and E', and greater A and A' resulting in a reversal of E/A and E'/A'. PF measures included forced vital capacity (FVC), carbon monoxide diffusing capacity (DL CO ) and forced mid‐expiratory flow (FEF 25‐75 ). Age, gender and BMI accounted for >60% of the interindividual variation between diastolic function and PF. After accounting for age, gender, BMI and BP, E' was positively associated with FVC (additional R 2 =0.03 , P <0.01). A was negatively and A' positively associated with DL CO (additional R 2 =0.03, R 2 =0.01, P <0.05) and FVC (additional R 2 =0.03, R 2 =0.03, P <0.01). E/A was positively associated with DL CO (additional R 2 =0.02, P <0.01). In conclusion, LV diastolic function may influence PF in healthy subjects, with the greatest interactions being observed in older males. NIH HL71478

Pulmonary function (PF) may be influenced by a deterioration of cardiac function. As such, resting measures of PF may be prognostically useful in heart failure patients (HF). This study examined the prognostic value of resting PF in a cohort of HF. This included 113 patients (enrolled 1999‐2005, EF=28±11%; age=55±12yr; 62% male) followed for 64±34mo with death confirmed via the SSI & Mayo Clinic registry. PF included, forced vital capacity, FVC; diffusing capacity, DLCO; forced expiratory volume, FEV1; alveolar volume, VA. Patients were divided in tertiles according to PF with survival analysis via Log‐rank Mantel‐Cox Test with Chi squared analysis (Chi‐sq). Groups for FVC: 1)=80, 2)81‐97, 3)=98, %pre (Chi‐sq 21.5, p<0.01). Bonferonni correction (BC) suggested differences (diff) between groups 1 & 2 and 1 & 3 (p=0.01) with no diff (ND) between 2 & 3 (p=0.62). Groups for FEV1: 1)=77, 2)78‐95, 3)=96, %pre (Chi‐sq 16.3, p<0.01). BC suggested diff between groups 1 & 2 (p=0.02) and 1 & 3 (p<0.01). Groups for DLCO: 1)=75, 2)76‐90, 3)=91, %pre (Chi‐sq=8.2, p=0.02). BC suggested diff between groups 1 & 3 (p=0.003) with ND between 1 & 2 or 2 & 3 (p>0.05). Groups for VA: 1)=87, 2)88‐97, 3)=98, %pre (Chi‐sq=8.9, p=0.01). BC suggested diff between 1 & 3 (p<0.01) with ND between 1 & 2 or 2 & 3 (p>0.05). In a well defined cohort of HF patients, resting measures of PF appear to be predictive of all cause mortality. NIH HL71478

Reduced partial pressures of inspired O 2 may influence the bronchial circulation through a number of mechanisms (e.g. altered pulmonary and systemic vascular pressures, lung fluid regulation, airway cooling & drying from increased ventilation). The present study examined the impact of acute, graded hypoxia on bronchial blood flow (Q aw ) in eight healthy adults (28 ± 9 years). Subjects were exposed to inspired O 2 levels resulting in arterial O 2 saturation (SaO 2 ) values of 90% and 80% for 15 min each. To control for the mild hyperventilation that accompanies hypoxia, subjects then mimicked the 80% SaO 2 ventilation (V E ) rate with 21% FIO 2 and again with CO 2 added to the inspirate to maintain normocapnia. Q aw and cardiac output (CO) were measured using soluble gas techniques. Also measured were alveolar‐capillary conductance (D m , index of lung fluid balance), pulmonary capillary blood volume (V c ), and systemic mean (MAP) and pulmonary arterial pressures (PAP). Hypoxia resulted in minimal change in MAP, a small rise in PAP, minimal change in CO and V c , and a rise in D m . There was also a non significant decrease in Q aw with hypoxia. Mild hyperventilation resulted in a significant fall in Q aw , but when normocapnia was maintained, Q aw returned to baseline values. These data suggest that acute, graded hypoxic exposure does not significantly impact Q aw , however, the hypocapnia associated with mild hyperventilation reduces Q aw .

Heart failure (HF) patients have reduced cardiac reserve and increased work of breathing (WOB)., Increased demand for locomotor muscle blood flow (i.e. activities of daily living) may result in competition between respiratory and locomotor vascular beds. We hypothesized that HF patients would demonstrate improved locomotor blood flow with respiratory muscle unloading during moderate activity. We studied 10 HF patients (EF=30±8%) and 10 controls during two 10 min. cycling sessions at 60% VO 2 max. Session 1 (S1): 5 min of normal breathing (NB) and 5 min respiratory muscle unloading with a ventilator. Session 2 (S2): 5 min NB and 5 min of respiratory muscle loading with inspiratory resistance. Measurements included: leg blood flow (LBF), cardiac output (CO), and inspiratory pleural pressure time integral as an index of the WOB. During S1, WOB was reduced similarly in both groups (HF: 50±60%; CTL: 50±56%, p<0.05 for both). In HF, CO was reduced (9.6±1.4 vs 8.2±2.1 L/min, p<0.05) and LBF increased (4.9±2.6 vs 6.2±2.9 L/min, p<0.01). In CTL, there was no change in CO (14.7±3.1 vs 14.8±5.0 L/min) or LBF (10.9±5.6 vs 10.3±5.2 L/min). During S2, WOB was increased similarly in both groups (HF: 111±75%, CTL: 110±85%, p<0.01 for both). In HF, there was no change in CO (10.0±1.3 vs 10.3±2.5 L/min) or LBF (5.0±1.8 vs 4.9±1.4 L/min). In CTL, CO increased (15.4±4.3 vs 16.9±4.7 L/min, p<0.01) with no change in LBF (10.7±5.3 vs 10.3±5.6 L/min). These data suggest that the respiratory muscles of HF patients preferentially recruit blood flow away from the locomotor muscles during moderate intensity, whole body exercise.