Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade.

BACKGROUND: Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing. METHODS: ID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies. RESULTS: Th17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells. CONCLUSIONS: These findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy.

Rotator cuff training with upper extremity blood flow restriction produces favorable adaptations in division IA collegiate pitchers: a randomized trial.

BACKGROUND: Recent evidence indicates that combined upper extremity blood flow restriction (BFR, applied distally to the shoulder) and low-load resistance exercise (LIX) augments clinically meaningful responses in shoulder region tissues proximal to the occlusion site. The purpose of this investigation was to determine the efficacy of BFR-LIX for the shoulder when added to standard offseason training in Division IA collegiate baseball pitchers. We hypothesized that BFR-LIX would augment training-induced increases in shoulder-region lean mass, rotator cuff strength, and endurance. As secondary outcomes, we sought to explore the impact of BFR-LIX rotator cuff training on pitching mechanics. METHODS: Twenty-eight collegiate baseball pitchers were randomized into 2 groups (BFRN = 15 and non-BFR [NOBFR]N = 13) that, in conjunction with offseason training, performed 8 weeks of shoulder LIX (Throwing arm only; 2/week, 4 sets [30/15/15/fatigue], 20% isometric max) using 4 exercises (cable external and internal rotation [ER/IR], dumbbell scaption, and side-lying dumbbell ER). The BFR group also trained with an automated tourniquet on the proximal arm (50% occlusion). Regional lean mass (dual-energy x-ray absorptiometry), rotator cuff strength (dynamometry: IR 0 & 90, ° ER 0 & 90, ° Scaption, Flexion), and fastball biomechanics were assessed pre and post-training. Achievable workload (sets × reps × resistance) was also recorded. An ANCOVA (covaried on baseline measures) repeated on training timepoint was used to detect within-group and between-group differences in outcome measures (α = 0.05). For significant pairwise comparisons, effect size (ES) was calculated using a Cohen's d statistic and interpreted as: 0-0.1, negligible; 0.1-0.3, small; 0.3-0.5, moderate; 0.5-0.7, large; >0.7, and very large (VL). RESULTS: Following training, the BFR group experienced greater increases in shoulder-region lean mass (BFR: ↑ 227 ± 60g, NOBFR: ↑ 75 ± 37g, P = .018, ES = 1.0 VL) and isometric strength for IR 90 ° (↑ 2.4 ± 2.3 kg, P = .041, ES = 0.9VL). The NOBFR group experienced decreased shoulder flexion ↓ 1.6 ± 0.8 kg, P = .007, ES = 1.4VL) and IR at 0 ° ↓ 2.9 ± 1.5 kg, P = .004, ES = 1.1VL). The BFR group had a greater increase in achievable workload for the scaption exercise (BFR: ↑ 190 ± 3.2 kg, NOBFR: ↑ 90 ± 3.3 kg, P = .005, ES = 0.8VL). Only the NOBFR group was observed to experience changes in pitching mechanics following training with increased shoulder external rotation at lead foot contact (↑ 9.0° ± 7.9, P = .028, ES = 0.8VL) as well as reduced forward ↓ 3.6° ± 2.1, P = .001, ES = 1.2VL) and lateral ↓ 4.6° ± 3.4, P = .007, ES = 1.0VL) trunk tilt at ball release. CONCLUSION: BFR-LIX rotator cuff training performed in conjunction with a collegiate offseason program augments increases in shoulder lean mass as well as muscular endurance while maintaining rotator cuff strength and possibly pitching mechanics in a manner that may contribute to favorable outcomes and injury prevention in baseball pitching athletes.

Blood Flow Restriction Training for the Shoulder: A Case for Proximal Benefit.

BACKGROUND: Although blood flow restriction (BFR) is becoming increasingly popular in physical therapy and athletic training settings, little is known about the effects of BFR combined with low-intensity exercise (LIX) on muscles proximal to the site of occlusion. HYPOTHESIS/PURPOSE: Determine whether LIX combined with BFR applied distally to the shoulder on the brachial region of the arm (BFR-LIX) promotes greater increases in shoulder lean mass, rotator cuff strength, endurance, and acute increases in shoulder muscle activation compared with LIX alone. We hypothesized that BFR-LIX would elicit greater increases in rotator cuff strength, endurance, and muscle mass. We also hypothesized that the application of BFR would increase EMG amplitude in the shoulder muscles during acute exercise. STUDY DESIGN: Controlled laboratory study. METHODS: 32 healthy adults were randomized into 2 groups (BFR group, 13 men, 3 women; No-BFR group, 10 men, 6 women) who performed 8 weeks of shoulder LIX (2 times per week; 4 sets [30/15/15/fatigue]; 20% maximum) using common rotator cuff exercises (cable external rotation [ER], cable internal rotation [IR], dumbbell scaption, and side-lying dumbbell ER). The BFR group also trained with an automated tourniquet placed at the proximal arm (50% occlusion). Regional lean mass (dual-energy x-ray absorptiometry), isometric strength, and muscular endurance (repetitions to fatigue [RTF]; 20% maximum; with and without 50% occlusion) were measured before and after training. Electromyographic amplitude (EMGa) was recorded from target shoulder muscles during endurance testing. A mixed-model analysis of covariance (covaried on baseline measures) was used to detect within-group and between-group differences in primary outcome measures (α = .05). RESULTS: The BFR group had greater increases in lean mass in the arm (mean ± 95% CI: BFR, 175 ± 54 g; No BFR, -17 ± 77 g; P < .01) and shoulder (mean ± 95% CI: BFR, 278 ± 90 g; No BFR, 96 ± 61 g; P < .01), isometric IR strength (mean ± 95% CI: BFR, 2.9 ± 1.3 kg; No BFR, 0.1 ± 1.3 kg; P < .01), single-set RTF volume (repetitions × resistance) for IR (~1.7- to 2.1-fold higher; P < .01), and weekly training volume (weeks 4, 6-8, ~5%-22%; P < .05). Acute occlusion (independent of group or timepoint) yielded increases in EMGa during RTF (~10%-20%; P < .05). CONCLUSION: Combined BFR-LIX may yield greater increases in shoulder and arm lean mass, strength, and muscular endurance compared with fatiguing LIX alone during rotator cuff exercises. These findings may be due, in part, to a greater activation of shoulder muscles while using BFR. CLINICAL RELEVANCE: The present study demonstrates that BFR-LIX may be a suitable candidate for augmenting preventive training or rehabilitation outcomes for the shoulder.

Pelvic region bone density, soft tissue mass, and injury frequency in female professional ballet dancers and soccer athletes.

We recently observed a high prevalence of low pelvic bone mineral density (BMD) in female professional ballet performers. Because this population is susceptible to musculoskeletal overuse injuries, we aimed to determine which regions of the pelvis may be at greatest risk compared to general population females (GENPOP) as well as professional female soccer players (SOCCER, a comparison to other elite athletes regularly subjected to high degrees of loading). Three groups of age-matched females [(GENPOP; n = 38, 27±1yrs), (BALLET; single company, n = 36, 26±3yrs), (SOCCER; single NWSL® club, n = 34, 25±1yrs)] consented to have their BMD and body composition assessed (DEXA, GE®). In addition to soft tissue and total and regional BMD analyses, a segmental analysis of the pelvis was performed to determine site-specific BMD for the iliac fossa, iliac fossa/iliac crest/ilium combined, pubic bone, ischium, and sacrum. A mixed-model ANOVA followed by a Tukey's post-hoc test was used to compare the groups (Type-I error; α = 0.05). The BALLET group had lower pelvic BMD for all measures (Avg.%Diff. = 15%-27%, p<0.001) compared to the SOCCER group and for the ischium (Avg.%Diff.= 8%; p=0.007) and sacrum (Avg.%Diff. â€‹= â€‹7%; p = 0.028) compared to the GENPOP group. The BALLET group had lower lean mass for all measures compared to the other groups (Avg.%Diff. = 12%-18%; p < 0.01). Professional ballet performers exhibit reduced pelvic region soft tissue and site-specific BMD not previously detected using standard DEXA analyses. These findings highlight which pelvic regions may benefit from preventative strength training and/or nutritional interventions.

FOREARM POSITION MATTERS DURING ECCENTRIC SHOULDER EXERCISES: AN EMG RECRUITMENT STUDY WITH IMPLICATIONS FOR REHABILITATION.

BACKGROUND: Eccentric exercise has demonstrated great utility in the rehabilitation of various shoulder pathologies. Research on the electromyographic (EMG) activity of the shoulder musculature during these activities is limited, however. Furthermore, no studies have observed how forearm positioning during exercise affects EMG output. PURPOSE/HYPOTHESIS: The purpose was to examine the degree of specific muscle recruitment among commonly used eccentric exercises in rehabilitation of the upper extremity and shoulder. Secondarily, the authors hypothesized that different hand/forearm positions would alter EMG activity within the targeted musculature during a given exercise. STUDY DESIGN: Prospective cross-sectional observation of EMG analysis. METHODS: This study analyzed surface EMG data obtained from 10 healthy individuals during five eccentric exercises of the dominant extremity, performed in a randomized order: side-lying eccentric horizontal abduction (SL ER), half-kneeling weighted ball decelerations (BALL DC), seated eccentric external rotation in scaption (STD ER), standing eccentric external rotation at 0deg (STND ER), supine eccentric external rotation at 90deg (SUP ER). Each exercise was performed with two to three forearm position variants commonly used in clinical environments: neutral, pronation, and/or supination. EMG data were collected from the upper trapezius, infraspinatus, teres minor, latissimus dorsi, and anterior/middle/posterior deltoid. Data were analyzed for each individual exercise and within each muscle using a mixed-model ANOVA repeated across forearm position. Significant interactions were followed by a Bonferroni post-hoc test for pairwise comparisons. Effect size was calculated for all significant pairwise comparisons using a Cohen's d statistic. RESULTS: Significant differences in EMG activity for the selected musculature exist between forearm positions for four of the five exercises and Cohen's d effect sizes 0.178 - 1.159. CONCLUSION: Specific eccentric shoulder exercises activate muscles of the shoulder complex differently based on forearm positioning. LEVEL OF EVIDENCE: Level 2.

Electromyographic Profile of the Shoulder During Stability Exercises With Kettlebells.

CONTEXT: Shoulder rehabilitation can be a difficult task due to the dynamic nature of the joint complex. Various weight training implements, including kettlebells (KB), have been utilized for therapeutic exercise in the rehabilitation setting to improve shoulder girdle strength and motor control. The KBs are unique in that they provide an unstable load and have been purported to promote greater muscle activation versus standard dumbbells. Recent literature has examined the efficacy of KB exercises for global strengthening and aerobic capacity; however, electromyographic data for shoulder-specific activities are lacking. OBJECTIVE: To examine muscle activation patterns about the rotator cuff and scapular musculature during 5 commonly-utilized KB exercises. DESIGN: Cross-sectional analysis of a single group. SETTING: Clinical biomechanics laboratory. PARTICIPANTS: Ten participants performed all exercises in a randomized order. MAIN OUTCOME MEASURES: Mean electromyographic values for each subject were compared between exercises for each target muscle. RESULTS: Significant differences (P < .05) between exercises were observed for all target muscles except for the infraspinatus. CONCLUSIONS: The data in this study indicates that certain KB exercises may elicit activation of the shoulder girdle at different capacities. Physical therapy practitioners, athletic trainers, and other clinical professionals who intend to optimize localized strengthening responses may elect to prescribe certain exercises over others due to the inherent difference in muscular utilization. Ultimately, this data may serve to guide or prioritize exercise selection to achieve higher levels of efficacy for shoulder strength and stability gains.

Building Patient-Physician Trust: A Medical Student Perspective.

Public trust in physicians has declined over the last 50 years. Future physicians will need to mend the patient-physician trust relationship. In conjunction with the American Medical Association's Accelerating Change in Medical Education initiative, the Mayo Clinic Alix School of Medicine implemented the Science of Health Care Delivery (SHCD) curriculum-a 4-year curriculum that emphasizes interdisciplinary training across population-centered care; person-centered care; team-based care; high-value care; leadership; and health policy, economics, and technology-in 2015. In this medical student perspective, the authors highlight how the SHCD curriculum has the potential to address issues that have eroded patient-physician trust. The curriculum reaches this aim through didactic and/or experiential teachings in health equity, cultural humility and competence, shared decision making, patient advocacy, and safety and quality of care. It is the authors' hope that novel medical education programs such as the SHCD curriculum will allow the nation's future physicians to own their role in rebuilding and fostering public trust in physicians and the health care system.

Detection of lipoarabinomannan in urine and serum of HIV-positive and HIV-negative TB suspects using an improved capture-enzyme linked immuno absorbent assay and gas chromatography/mass spectrometry.

TB diagnosis and treatment monitoring in resource limited regions rely heavily on serial sputum smear microscopy and bacterial culture. These microbiological methods are time-consuming, expensive and lack adequate sensitivity. The WHO states that improved TB diagnosis and treatment is imperative to achieve an end to the TB epidemic by 2030. Commercially available lipoarabinomannan (LAM) detection tools perform at low sensitivity that are highly dependent on the underlying immunological status of the patient; those with advanced HIV infection perform well. In this study, we have applied two novel strategies towards the sensitive diagnosis of TB infection based on LAM: Capture ELISA to detect LAM in paired urine and serum samples using murine and human monoclonal antibodies, essentially relying on LAM as an 'immuno-marker'; and, secondly, detection of α-d-arabinofuranose and tuberculostearic acid (TBSA)- 'chemical-markers' unique to mycobacterial cell wall polysaccharides/lipoglycans by our recently developed gas chromatography/mass spectrometry (GC/MS) method. Blinded urine specimens, with microbiologically confirmed active pulmonary TB or non TB (HIV+/HIV-) were tested by the aforementioned assays. LAM in patient urine was detected in a concentration range of 3-28 ng/mL based on GC/MS detection of the two LAM-surrogates, d-arabinose and tuberculostearic acid (TBSA) correctly classifying TB status with sensitivity > 99% and specificity = 84%. The ELISA assay had high sensitivity (98%) and specificity (92%) and the results were in agreement with GC/MS analysis. Both tests performed well in their present form particularly for HIV-negative/TB-positive urine samples. Among the HIV+/TB+ samples, 52% were found to have >10 ng/mL urinary LAM. The detected amounts of LAM present in the urine samples also appears to be associated with the gradation of the sputum smear, linking elevated LAM levels with higher mycobacterial burden (odds ratio = 1.08-1.43; p = 0.002). In this small set, ELISA was also applied to parallel serum samples confirming that serum could be an additional reservoir for developing a LAM-based immunoassay for diagnosis of TB.

IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer.

Ligation of programmed cell death-1 (PD-1) in the tumor microenvironment is known to inhibit effective adaptive antitumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients. PD-1 was recently shown to be expressed on and thereby impair the functions of tumor-infiltrating murine and human myeloid dendritic cells (TIDC) in ovarian cancer. In the present work, we characterize the regulation of PD-1 expression and the effects of PD-1 blockade on TIDC. Treatment of TIDC and bone marrow-derived dendritic cells (DC) with IL10 led to increased PD-1 expression. Both groups of DCs also responded to PD-1 blockade by increasing production of IL10. Similarly, treatment of ovarian tumor-bearing mice with PD-1 blocking antibody resulted in an increase in IL10 levels in both serum and ascites. While PD-1 blockade or IL10 neutralization as monotherapies were inefficient, combination of these two led to improved survival and delayed tumor growth; this was accompanied by augmented antitumor T- and B-cell responses and decreased infiltration of immunosuppressive MDSC. Taken together, our findings implicate compensatory release of IL10 as one of the adaptive resistance mechanisms that undermine the efficacy of anti-PD-1 (or anti-PD-L1) monotherapies and prompt further studies aimed at identifying such resistance mechanisms. Cancer Res; 77(23); 6667-78. ©2017 AACR.