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Background Navafenterol (AZD8871) is a dual-pharmacology muscarinic antagonist β 2− agonist (MABA) molecule in development for the treatment of chronic obstructive pulmonary disease (COPD). The pharmacodynamics, safety and tolerability of single doses of navafenterol were investigated in patients with moderate to severe COPD. Methods This was a randomized, five-way complete cross-over study. Patients received single doses of navafenterol 400 μg, navafenterol 1800 μg and placebo (all double-blind) and indacaterol 150 μg and tiotropium 18 μg (both open-label active comparators). The primary pharmacodynamic endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV 1 ) on day 2. Safety and tolerability were monitored throughout. Results Thirty-eight patients were randomized and 28 (73.7%) completed the study. Navafenterol 400 μg and 1800 μg demonstrated statistically significant improvements vs placebo in change from baseline in trough FEV 1 (least squares mean [95% confidence interval]: 0.111 [0.059, 0.163] L and 0.210 [0.156, 0.264] L, respectively, both P  < .0001). The changes were significantly greater with navafenterol 1800 μg vs the active comparators (least squares mean treatment difference: 0.065–0.069 L, both P  < .05). The frequency of treatment-emergent adverse events was similar for placebo and the active comparators (range 34.4–37.5%), slightly higher for navafenterol 400 μg (52.9%), and lowest for navafenterol 1800 μg (22.6%). Conclusions Both doses of navafenterol demonstrated sustained bronchodilation over 24 h. Navafenterol was well tolerated and no safety concerns were raised. Trial registry ClinicalTrials.gov ; No.: NCT02573155 ; URL: www.clinicaltrials.gov . Registered 9th October, 2015.

Background Navafenterol (AZD8871) is a novel, long-acting, dual-pharmacology (muscarinic receptor antagonist and β 2− adrenoceptor agonist) molecule in development for chronic obstructive pulmonary disease and asthma. Methods These two phase I, randomised, single-blind, multiple-ascending-dose studies evaluated inhaled navafenterol and placebo (3:1 ratio) in healthy, male, non-Japanese (study A; NCT02814656) and Japanese (study B; NCT03159442) volunteers. In each study, volunteers were dosed in three cohorts, allowing gradual dose escalation from 300 μg to 600 μg to 900 μg. The primary objective was to investigate the safety and tolerability of navafenterol at steady state. Pharmacokinetics were also assessed. Results Twenty-four volunteers completed each study (navafenterol, n  = 6; placebo, n  = 2 in each cohort). There were no deaths, serious adverse events (AEs) or treatment-emergent AEs (TEAEs) leading to discontinuation of navafenterol. The most frequent TEAEs were vessel puncture-site bruise (placebo, n = 2; navafenterol 900 μg; n  = 3) in study A and diarrhoea (placebo, n  = 1; navafenterol 300 μg, n = 2; navafenterol 900 μg, n = 3) in study B. No dose-response relationship was observed for TEAEs. There was a dose-dependent increase in mean heart rate on day 16 in both studies. The pharmacokinetics of navafenterol were similar between non-Japanese and Japanese volunteers. Conclusions Multiple ascending doses of navafenterol were well-tolerated and the safety and pharmacokinetics of navafenterol were similar in non-Japanese and Japanese volunteers. The findings support navafenterol clinical development. Trial registration ClinicalTrials.gov ; Nos.: NCT02814656 and NCT03159442; URL: www.clinicaltrials.gov .

[...]once-daily doses of the MABA AZD8871 in patients with COPD delivered significant bronchodilation and clinically meaningful improvement of symptoms. Author Contributions: D.S. is the overall guarantor of this report and takes responsibility for the content, including the data and analysis; L.J., U.W.H., A.J., M.-P.M., V.B., A.L., A.A., C.A., and I.P. contributed to the study design, concept, and/or interpretation; D.S. and R.F. contributed to data acquisition; A.J. and M.-P.M. performed the statistical analyses; and all authors critically revised the manuscript and approved the submitted version. Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, et at Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary.

The purpose of this study was to examine the use of lean manufacturing practices and how the utilization of this strategy has helped to improve operational performance in the areas of service, quality, productivity, and flexibility in the electronics and medical devices industries in Puerto Rico. The study also examined the impact transactional and transformational leadership style had in the implementation level of lean manufacturing practices. Two Likert type surveys were used: (a) a survey consisting of a series of questions pertaining to organization demographics, lean practices and organizational performance developed by Shah and (b) the Multifactor Leadership Questionnaire (MLQ 5X-Short) developed by Avolio and Bass. A one-Sample T test was conducted to compare the implementation level of lean manufacturing and service, quality, productivity and flexibility in the electronics and medical devices operations in Puerto Rico. While examining the p-value to determine whether a comparison existed between the implementation of lean manufacturing practices and productivity and the implementation of lean manufacturing practices and flexibility the researcher found a calculated p-value of .034 and .077 respectively. This was much lower than the .10 significant level required for the study. Thus, the test statistic failed to support the null hypothesis, concluding that implementation of lean manufacturing practices result in improvement in productivity and flexibility.

Chimeric antigen receptor (CAR) T‐cell therapy is a promising treatment option for relapsed or refractory (R/R) large B‐cell lymphoma (LBCL). However, only a subset of patients will present long‐term benefit. In this study, we explored the potential of PET‐based radiomics to predict treatment outcomes with the aim of improving patient selection for CAR T‐cell therapy. We conducted a single‐center study including 93 consecutive R/R LBCL patients who received a CAR T‐cell infusion from 2018 to 2021, split in training set (73 patients) and test set (20 patients). Radiomics features were extracted from baseline PET scans and clinical benefit was defined based on median progression‐free survival (PFS). Cox regression models including the radiomics signature, conventional PET biomarkers and clinical variables were performed for most relevant outcomes. A radiomics signature including 4 PET‐based parameters achieved an AUC = 0.73 for predicting clinical benefit in the test set, outperforming the predictive value of conventional PET biomarkers (total metabolic tumor volume [TMTV]: AUC = 0.66 and maximum standardized uptake value [SUV max ]: AUC = 0.59). A high radiomics score was also associated with longer PFS and OS in the multivariable analysis. In conclusion, the PET‐based radiomics signature predicted efficacy of CAR T‐cell therapy and outperformed conventional PET biomarkers in our cohort of LBCL patients.

BackgroundThe gut microbiota, composed by several species of microorganisms, works to preserve the liver–gut homeostasis and plays an important role during digestion and absorption of nutrients, and in the immune response of the host. In this review, we analyzed the influence of microbiota in patients with cholangiocarcinoma (CCA) who were candidates for elective surgery.MethodsA literature review was conducted to identify papers that provided empiric evidence to support that the altered microbiota composition (dysbiosis) is related also to CCA development.ResultsBacteria such as Helicobacter pylori, Helicobacter hepaticus, and Opisthorchis viverrini increase the risk of CCA. The most abundant genera were Enterococcus, Streptococcus, Bacteroides, Klebsiella, and Pyramidobacter in CCA’s biliary microbiota. Additionally, levels of Bacteroides, Geobacillus, Meiothermus, and Anoxybacillus genera were significantly higher. An enrichment of Bifidobacteriaceae, Enterobacteriaceae, and Enterococcaceae families has also been observed in CCA tumor tissue. Microbiota is related to postoperative outcomes in abdominal surgery. The combination of caloric restriction diets in liver cancer or CCA increases the effect of the chemotherapy treatment.ConclusionThe correct use of nutrition for microbiota modulation according to each patient’s needs could be a therapeutic tool in combination with elective surgery and chemotherapy to diminish side effects and improve prognosis. Further investigations are needed to fully understand the mechanisms by which they are related.

Organ-on-a-chip (OOC) devices offer new approaches for metabolic disease modeling and drug discovery by providing biologically relevant models of tissues and organs in vitro with a high degree of control over experimental variables for high-content screening applications. Yet, to fully exploit the potential of these platforms, there is a need to interface them with integrated non-labeled sensing modules, capable of monitoring, in situ, their biochemical response to external stimuli, such as stress or drugs. In order to meet this need, we aim here to develop an integrated technology based on coupling a localized surface plasmon resonance (LSPR) sensing module to an OOC device to monitor the insulin in situ secretion in pancreatic islets, a key physiological event that is usually perturbed in metabolic diseases such as type 2 diabetes (T2D). As a proof of concept, we developed a biomimetic islet-on-a-chip (IOC) device composed of mouse pancreatic islets hosted in a cellulose-based scaffold as a novel approach. The IOC was interfaced with a state-of-the-art on-chip LSPR sensing platform to monitor the in situ insulin secretion. The developed platform offers a powerful tool to enable the in situ response study of microtissues to external stimuli for applications such as a drug-screening platform for human models, bypassing animal testing.

Purpose We aimed to expand and refine the experimental models for pediatric-type diffuse high grade gliomas (pHGG) and the methods to follow up disease progression in mouse pHGG xenografts. Methods Using whole exome sequencing and immunoassays we characterized pHGG primary cultures and xenografts established at hospital SJD Barcelona. We obtained tumor samples and serial CSF samples from mouse xenografts. To assess tumor progression, we evaluated: (1) mouse weight, (2) human cell counts in brain paraffin sections, and (3) tumor DNA amount, quantified through droplet digital polymerase chain reaction (ddPCR) in paraffin sections and cerebrospinal fluid (CSF). Results We established 15 experimental models of three pHGG subclasses, four of which engrafted in mice. Xenografts HSJD-DIPG-007 and HSJD-DMG-005 are diffuse midline glioma (DMG) H3 K27-altered, HSJD-GBM-002 is an H3 G34-mutant diffuse hemispheric glioma, and HSJD-GBM-001 is an H3-wildtype and IDH-wildtype pHGG. ddPCR quantification of human H3F3A K27M, H3F3A G34R, and ACVR1 R206H in paraffin samples is linear and sufficiently sensitive. We required a preamplification step to detect H3F3A K27M in CSF. In HSJD-DIPG-007 xenografts, human cell counts correlated with H3F3A amounts in paraffin for the whole engraftment period. Weight loss correlated with human cell counts and H3F3A amounts in paraffin. Serial collection of CSF was feasible, but H3F3A amounts in the CSF correlated only with weight loss. Conclusion The developed methods contribute to the preclinical field of pHGG and introduce for the first time the concept of liquid biopsy in mice, which still needs improvement regarding its use as a preclinical biomarker.

BackgroundThe selection of patients for genetic testing to rule out Lynch syndrome is currently based on fulfilment of at least one of the revised Bethesda criteria followed by mismatch repair (MMR) status analysis. A study was undertaken to compare the present approach with universal MMR study-based strategies to detect Lynch syndrome in a large series of patients with colorectal cancer (CRC).Methods2093 patients with CRC from the EPICOLON I and II cohorts were included. Immunohistochemistry for MMR proteins and/or microsatellite instability (MSI) analysis was performed in tumour tissue. Germline MLH1 and MSH2 mutation analysis was performed in patients whose tumours showed loss of MLH1 or MSH2 staining, respectively. MSH6 genetic testing was done in patients whose tumours showed lack of MSH6 expression or a combined lack of MSH2 and MSH6 expression but did not have MSH2 mutations. PMS2 genetic testing was performed in patients showing isolated loss of PMS2 expression. In patients with MSI tumours and normal or not available MMR protein expression, all four MMR genes were studied.ResultsA total of 180 patients (8.6%) showed loss of expression of some of the MMR proteins and/or MSI. Four hundred and eighty-six patients (23.2%) met some of the revised Bethesda criteria. Of the 14 (0.7%) patients who had a MMR gene mutation, 12 fulfilled at least one of the revised Bethesda criteria and two (14.3%) did not.ConclusionsRoutine molecular screening of patients with CRC for Lynch syndrome using immunohistochemistry or MSI has better sensitivity for detecting mutation carriers than the Bethesda guidelines.