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The selective adenosine A2A receptor (A2AR) agonist regadenoson reduces inflammation due to lung ischemia-reperfusion injury (IRI). The objective of this study was to investigate molecular and cellular mechanisms by which regadenoson reduces IRI in lung transplant recipients. Fourteen human lung transplant recipients were infused for 12 hours with regadenoson and 7 more served as untreated controls. Plasma levels of high mobility group box 1 and its soluble receptor for advanced glycation end-products (sRAGE) were measured by Luminex. Matrix metalloproteinase (MMP) 2 and 9 were measured by gelatin zymography. Tissue inhibitor of metalloproteinase 1 was measured by mass spectroscopy. A2AR expression on leukocytes was analyzed by flow cytometry. MMP-9–mediated cleavage of RAGE was evaluated using cultured macrophages in vitro. Regadenoson treatment during lung transplantation significantly reduced levels of MMP-9 (P <.05), but not MMP-2, and elevated levels of tissue inhibitor of metalloproteinase 1 (P <.05), an endogenous selective inhibitor of MMP-9. Regadenoson infusion significantly reduced plasma levels of sRAGE (P <.05) during lung reperfusion compared with control subjects. A2AR expression was highest on invariant natural killer T cells and higher on monocytes than other circulating immune cells (P <.05). The shedding of RAGE from cultured monocytes/macrophages was increased by MMP-9 stimulation and reduced by an MMP inhibitor or by A2AR agonists, regadenoson or ATL146e. In vivo and in vitro studies suggest that A2AR activation reduces sRAGE in part by inhibiting MMP-9 production by monocytes/macrophages. These results suggest a novel molecular mechanism by which A2AR agonists reduce primary graft dysfunction. [ABSTRACT FROM AUTHOR]

Rhinovirus frequently causes asthma exacerbations among children and young adults who are allergic. The interaction between allergen and rhinovirus-induced symptoms and inflammation over time is unclear. Our aim was to compare the response to an experimental inoculation with rhinovirus-16 in allergic asthmatics with the response in healthy controls and to evaluate the effects of administrating omalizumab before and during the infection. Two clinical trials were run in parallel. In one of these trials, the response to an experimental inoculation with rhinovirus-16 among asthmatics with high levels of total IgE was compared to the response in healthy controls. The other trial compared the effects of administering omalizumab versus placebo to asthmatics in a randomized, double-blind placebo-controlled investigation. The primary outcome for both trials compared lower respiratory tract symptoms (LRTSs) between study groups over the first 4 days of infection. Frequent comparisons of symptoms, lung function, and blood eosinophil counts revealed differences that were more pronounced among allergic asthmatics than among controls by days 2 and 3 after virus inoculation. Additionally, an augmentation of upper respiratory tract symptom scores and LRTS scores occurred among the atopic asthmatics versus the controls during the resolution of symptoms (P <.01 for upper respiratory symptom tract scores and P <.001 for LRTS scores). The beneficial effects of administering omalizumab on reducing LRTSs and improving lung function were strongest over the first 4 days. LRTSs and blood eosinophil counts were augmented and lung function was reduced among allergic asthmatics early after rhinovirus inoculation but increased late in the infection during symptom resolution. The effect of administering omalizumab on the response to rhinovirus was most pronounced during the early/innate phase of the infection. [ABSTRACT FROM AUTHOR]

Objective: To assess the method and time to stand from supine and the time to run 10 m for normal young children. Study design: Three hundred twenty-one normal children aged 2.8-7.8 years were recruited from primary schools. After standardization, each test was carried out twice, timed, and videoed. The influence of age, sex, height, weight, body mass index (BMI), and method of standing were analyzed. Charts for time to stand and running time were produced and assessment of reproducibility performed. Results: For the time to stand from supine and the method used, there was a significant correlation with age. More than 50% of young children took >2 seconds. There was no significant association with BMI. Method of standing was associated with standing time in boys but not in girls. A Bland-Altman plot of standing times by 2 observers showed good reproducibility with no clinically significant difference. For the 10-m running test, there was a significant negative correlation with age, height, weight, and BMI. Conclusion: There is considerable variability in the method used and time taken to stand from supine in young children. These change with age, permitting the creation of charts showing age-related normal values. [ABSTRACT FROM AUTHOR]

Background: The beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitors (statins) in patients undergoing coronary artery bypass grafting have been recognized. Reduced mortality rates and clinical events have been demonstrated. These outcomes were examined in patients taking statins who underwent cardiac valve operations. Methods: This retrospective study included 447 consecutive patients undergoing valve operations between July 2004 and February 2006; 203 patients (45.6%) received statins preoperatively and postoperatively vs 244 who did not. Preoperative risk factors and outcome data for both cohorts were compared. Primary outcomes included 30-day mortality, renal failure, and postoperative stroke. Results: The statin group had more comorbidities. Although they had increased risk factors, including previous stroke (30 of 203 vs 16 of 244, p = 0.004), diabetes (66 of 203 vs 32 of 244, p < 0.0001), cerebrovascular disease (45 of 203 vs 24 of 244, p = 0.003), and dyslipidemia (191 of 203 vs 63 of 244, p < 0.0001), they had better outcomes. The unadjusted odds ratio (OR) for the composite end point of death/stroke/renal failure was 1.90 (95% confidence interval [CI], 0.95 to 3.76; p = 0.068) favoring the statin group. By univariate analysis, the adjusted OR for the composite end point demonstrated a benefit with statin therapy: diabetes, 2.29 (95% CI, 1.16 to 4.71; p = 0.024); stroke, 2.15 (95% CI, 1.06 to 4.35; p = 0.034); and renal dysfunction, 2.05 (95% CI, 1.02 to 4.13; p = 0.045). Conclusions: Statin therapy in this population undergoing cardiac valve procedures was associated with decreased postoperative morbidity and death. The mechanism may be independent of statins'' lipid-lowering effects. A prospective, randomized-control trial of statin therapy in this population is warranted. [Copyright &y& Elsevier]

Abstract: This retrospective study examined the influence of hemoglobin (Hb) on the outcomes of 184 acute inpatient rehabilitation patients admitted to a single university-based inpatient rehabilitation facility after primary total knee arthroplasty between 2001 and 2003. Patient function was measured using the Functional Independence Measure (FIM) instrument. Average length of stay was 9.4 days. Total FIM score increased from 81.5 to 110.8. Mean baseline Hb was 10.5 g/dL. Multivariate analyses demonstrated that a higher Hb at baseline was associated with significantly shorter length of stay (P = .004) and greater FIM efficiency (change in total FIM score/length of stay) (P = .04). Hemoglobin is associated with rehabilitation outcomes after total knee arthroplasty; additional research into the influence of blood management strategies on rehabilitation outcomes is warranted. [Copyright &y& Elsevier]

Background: This study evaluated the efficacy and the complications associated with the use of the covered Wallstent in the setting of unresectable malignant biliary obstruction. Methods: Between March 2001 and January 2003, all patients with distal malignant biliary obstruction that required drainage were treated with a covered Wallstent. Every 2 months, the patients were evaluated clinically and biochemical tests of liver function were obtained. Data were recorded for the following variables: early complications (within 30 days of stent placement), early and late stent occlusion, duration of stent patency, need for subsequent biliary intervention, and patient survival. Results: A total of 88 covered Wallstents were inserted in 80 patients. Stent patency rates at 3, 6, and 12 months were 90%, 82%, and 78%, respectively. Complications included stent migration (5), stent occlusion (12), episodes of cholecystitis (3), and episodes of post-ERCP pancreatitis (5). Biliary intervention was required in 9 patients subsequent to placement of the initial covered Wallstent. Conclusions: Deployment of a covered Wallstent is safe and relatively easy. It achieves biliary drainage with an acceptable risk to benefit ratio in the majority of patients with distal malignant biliary obstruction. [Copyright &y& Elsevier]

Tumor-associated tertiary lymphoid structures (TA-TLS) are associated with enhanced patient survival and responsiveness to cancer therapies, but the mechanisms underlying their development are unknown. We show here that TA-TLS development in murine melanoma is orchestrated by cancer-associated fibroblasts (CAF) with characteristics of lymphoid tissue organizer cells that are induced by tumor necrosis factor receptor signaling. CAF organization into reticular networks is mediated by CD8 T cells, while CAF accumulation and TA-TLS expansion depend on CXCL13-mediated recruitment of B cells expressing lymphotoxin-α 1 β 2. Some of these elements are also overrepresented in human TA-TLS. Additionally, we demonstrate that immunotherapy induces more and larger TA-TLS that are more often organized with discrete T and B cell zones, and that TA-TLS presence, number, and size are correlated with reduced tumor size and overall response to checkpoint immunotherapy. This work provides a platform for manipulating TA-TLS development as a cancer immunotherapy strategy. [Display omitted] • Cancer-associated fibroblasts orchestrate tertiary lymphoid structures in tumors • CD8 T cells and B cells drive tertiary lymphoid structure development via fibroblasts • Tertiary lymphoid structure development is mediated by TNF and lymphotoxin receptors • Checkpoint blockade alters tertiary lymphoid structures together with tumor control Rodriguez et al. describe the cellular and molecular mechanisms driving development of tumor-associated tertiary lymphoid structures and the importance of these structures as mediators of anti-tumor immunity and response to checkpoint immunotherapy. [ABSTRACT FROM AUTHOR]

Long-term estrogen deprivation causes hypersensitivity of MCF-7 cells to the mitogenic effect of estradiol (E2) which is associated with activation of mitogen-activated protein kinase (MAPK). However, several lines of evidence indicate that MAPK activation is not the exclusive mechanism for E2 hypersensitivity and multiple signal pathways might be involved. The current study explores the possible role of the PI3 kinase (PI3K) pathway in development of E2 hypersensitivity. Basal PI3K activity in long-term estrogen deprived MCF-7 cells (LTED) was elevated as evidenced by increased phosphorylation of three downstream effectors, Akt, p70 S6 kinase, and eukaryotic initiation factor-4E binding protein (4E-BP1), which was blocked by the specific inhibitor of PI3K, LY294002. Dual blockade of both MAPK and PI3K completely reversed E2 hypersensitivity of LTED cells. Enhancement in aromatase activity is another phenomenon accompanied with E2 hypersensitivity. In aromatase over-expressing MCF-7 cells, aromatase activity was reduced by inhibitors of MAPK and PI3K suggesting the involvement of protein phosphorylation in the regulation of aromatase activity. Our data suggest that in addition to the MAP kinase pathway, activation of the PI3 kinase pathway is involved in E2 hypersensitivity, which develops during adaptation of MCF-7 cells to the low estrogen environment. [Copyright &y& Elsevier]

Operating characteristics for proposed clinical trial designs provide insight into performance regarding safety and accuracy, allowing the study team and review entities to determine the design's suitability to achieve the study's proposed objectives. Advances in cancer therapeutics have augmented the needs of early phase clinical trial design. Additionally, advances in research on early-phase trial design have led to the availability of a wide range of methods that show vast improvement over outdated approaches. Three trials utilizing variations of the 3 + 3 decision rule are discussed. The protocols lacked detail, including operating characteristics and guidance for decision-making that deviated from the 3 + 3 decision rule and MTD determination. We provide a discussion of the statistical issues associated with each design and operating characteristics for the proposed design compared to alternatives better suited to achieve the aims of each trial. Our results illustrate how operating characteristics inform a design's safety and accuracy. Operating characteristics can unmask poor behavior, such as a high percentage of particiapnts exposed to overly toxic doses, a low probability of correctly identifying the MTD, and inappropriate early study termination. Selection of early-phase trial design has significant implications on a trial's ability to meet its objectives. Operating characteristics are a necessary component in the design and review of a protocol, determining if the study's objectives can be achieved and documenting the study's scientific validity. Continued use of outdated approaches due to historical acceptance hinders scientific rigor and the effort to move effective agents through the drug development process. [ABSTRACT FROM AUTHOR]

Currently, there are no clinically approved treatments for ischemia-reperfusion injury after lung transplantation. Pre-clinical animal models have demonstrated a promising efficacy of adenosine 2A receptor (A 2A R) agonists as a treatment option for reducing ischemia-reperfusion injury. The purpose of this human study, is to conduct a Phase I clinical trial for evaluating the safety of continuous infusion of an A 2A R agonist in lung transplant recipients. An adaptive, two-stage continual reassessment trial was designed to evaluate the safety of regadenoson (A 2A R agonist) in the setting of lung transplantation. Continuous infusion of regadenoson was administered to lung transplant recipients that was started at the time of skin incision. Adverse events and dose-limiting toxicities, as pre-determined by a study team and assessed by a clinical team and an independent safety monitor, were the primary end-points for safety in this trial. Between January 2018 and March 2019, 14 recipients were enrolled in the trial. Of these, 10 received the maximum infused dose of 1.44 µg/kg/min for 12 hours. No dose-limiting toxicities were observed. The steady-state plasma regadenoson levels sampled before the reperfusion of the first lung were 0.98 ± 0.46 ng/ml. There were no mortalities within 30 days. Regadenoson, an A 2A R agonist, can be safely infused in the setting of lung transplantation with no dose-limiting toxicities or drug-related mortality. Although not powered for the evaluation of secondary end-points, the results of this trial and the outcome of pre-clinical studies warrant further investigation with a Phase II randomized controlled trial. [ABSTRACT FROM AUTHOR]

Abstract: Therapies targeting oncogenic drivers rapidly induce compensatory adaptive responses that blunt drug effectiveness, contributing to therapeutic resistance. Adaptive responses are characteristic of robust cell signaling networks, and thus there is increasing interest in drug combinations that co-target the driver and the adaptive response. An alternative approach to co-inhibiting oncogenic and adaptive targets is to identify a critical node where the activities of these targets converge. Nodes of convergence between signaling modules represent potential therapeutic vulnerabilities because their inhibition could result in the collapse of the network, leading to enhanced cytotoxicity. In this report we demonstrate that p70S6 kinase (p70S6K) can function as a critical node linking HER-family and phosphoinositide-3-kinase (PI3K) pathway signaling. We used high-throughput combinatorial drug screening to identify adaptive survival responses to targeted therapies, and found that HER-family and PI3K represented compensatory signaling pathways. Co-targeting these pathways with drug combinations caused synergistic cytotoxicity in cases where inhibition of neither target was effective as a monotherapy. We utilized Reverse Phase Protein Arrays and determined that phosphorylation of ribosomal protein S6 was synergistically down-regulated upon HER-family and PI3K/mammalian target of rapamycin (mTOR) co-inhibition. Expression of constitutively active p70S6K protected against apoptosis induced by combined HER-family and PI3K/mTOR inhibition. Direct inhibition of p70S6K with small molecule inhibitors phenocopied HER-family and PI3K/mTOR co-inhibition. These data implicate p70S6K as a critical node in the HER-family/PI3K signaling network. The ability of direct inhibitors of p70S6K to phenocopy co-inhibition of two upstream signaling targets indicates that identification and targeting of critical nodes can overcome adaptive resistance to targeted therapies. [Copyright &y& Elsevier]

Abstract: Objective: To evaluate program and health care costs of a lifestyle intervention in a high-risk obese population. Design: Twelve-month randomized controlled trial comparing lifestyle case management to usual care. Subjects/setting: Health plan members (n=147) with obesity (body mass index ≥27) and type 2 diabetes. Intervention: Lifestyle case management entailed individual and group education, support, and referrals by registered dietitians. Those in the usual-care group received educational material. Main outcome measures: Medical and pharmaceutical health care costs reimbursed by the participant’s primary insurance company. Statistical analysis: Total costs were modeled using the four-equation model using previous year cost as a predictor. Results: Net cost of the intervention was $328 per person per year. After incorporating program costs, mean health plan costs were $3,586 (95% confidence interval [CI]: −$8,036, −$25, P<0.05) lower in case management compared to usual care. The difference was driven by group differences in medical (−$3,316, 95% CI: −$7,829 to −$320, P<0.05) but not pharmaceutical costs (−$239, 95% CI: −$870 to $280, not statistically significant), with fewer inpatient admissions and costs among case management compared with usual care (admission prevalence: 2.8% vs 22.5% respectively, P<0.001). Conclusion: Addition of a modest-cost, registered dietitian–led lifestyle case-management intervention to usual medical care did not increase health care costs and suggested modest cost savings among obese patients with type 2 diabetes. Larger trials are needed to determine whether these results can be replicated in a broader population. The findings can be judiciously applied to support that the addition of a registered dietitian–led lifestyle case-management program to medical care does not increase health care costs. [Copyright &y& Elsevier]