Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials.

Importance: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective: To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants: The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions: Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures: The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results: At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance: Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration: ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.

A 24-Week, Phase IIa, Randomized, Double-Blind, Placebo-Controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis.

OBJECTIVE: We undertook this study to explore the efficacy, safety, and tolerability of ziritaxestat, a selective autotaxin inhibitor, in patients with early diffuse cutaneous systemic sclerosis (dcSSc). METHODS: NOVESA was a 24-week, multicenter, phase IIa, double-blind, placebo-controlled study. Adults with dcSSc were randomized to oral ziritaxestat 600 mg once daily or matching placebo. The primary efficacy end point was change from baseline in modified Rodnan skin score (MRSS) at week 24. Secondary end points assessed safety and tolerability; other end points included assessment of skin and blood biomarkers. Patients in NOVESA could enter a 104-week open-label extension (OLE). RESULTS: Patients were randomized to ziritaxestat (n = 21) or placebo (n = 12). Reduction in MRSS was significantly greater in the ziritaxestat group versus the placebo group (-8.9 versus -6.0 units, respectively; P = 0.0411). Placebo patients switching to ziritaxestat in the OLE showed similar reductions in MRSS to those observed for ziritaxestat patients in the parent study. Ziritaxestat was well tolerated; the most frequent treatment-related treatment-emergent adverse events were headache and diarrhea. Circulating lysophosphatidic acid (LPA) C18:2 was significantly reduced, demonstrating ziritaxestat target engagement, and levels of fibrosis biomarkers were reduced in the blood. No differentially expressed genes were identified in skin biopsies. Significant changes in 109 genes were identified in blood samples. CONCLUSION: Ziritaxestat resulted in significantly greater reduction in MRSS at week 24 than placebo; no new safety signals emerged. Biomarker analysis suggests ziritaxestat may reduce fibrosis. Modulation of the autotaxin/LPA pathway could improve skin involvement in patients with dcSSc. A plain language summary is provided in the Supplementary Material, available on the Arthritis & Rheumatology website at https://onlinelibrary.wiley.com/doi/10.1002/art.42477.

Autotaxin facilitates selective LPA receptor signaling.

Autotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA1-3) and P2Y (LPA4-6) G protein-coupled receptors. ATX/LPA promotes several (patho)physiological processes, including in pulmonary fibrosis, thus serving as an attractive drug target. However, it remains unclear if clinical outcome depends on how different types of ATX inhibitors modulate the ATX/LPA signaling axis. Here, we show that the ATX "tunnel" is crucial for conferring key aspects of ATX/LPA signaling and dictates cellular responses independent of ATX catalytic activity, with a preference for activation of P2Y LPA receptors. The efficacy of the ATX/LPA signaling responses are abrogated more efficiently by tunnel-binding inhibitors, such as ziritaxestat (GLPG1690), compared with inhibitors that exclusively target the active site, as shown in primary lung fibroblasts and a murine model of radiation-induced pulmonary fibrosis. Our results uncover a receptor-selective signaling mechanism for ATX, implying clinical benefit for tunnel-targeting ATX inhibitors.

GLPG1205 for idiopathic pulmonary fibrosis: a phase 2 randomised placebo-controlled trial.

BACKGROUND: GLPG1205 is a selective functional antagonist of G-protein-coupled receptor 84, which plays an important role in fibrotic processes. This study assessed the efficacy, safety and tolerability of GLPG1205 for treatment of idiopathic pulmonary fibrosis (IPF). METHODS: PINTA (ClinicalTrials.gov: NCT03725852) was a phase 2, randomised, double-blind, placebo-controlled, proof-of-concept trial. Patients with IPF were randomised 2:1 to once-daily oral GLPG1205 100 mg or placebo for 26 weeks and stratified to receive GLPG1205 alone or with local standard of care (nintedanib or pirfenidone). The primary end-point was change from baseline in forced vital capacity (FVC); other end-points were safety and tolerability, and lung volumes measured by imaging (high-resolution computed tomography). The study was not powered for statistical significance. RESULTS: In total, 68 patients received study medication. Least squares mean change from baseline in FVC at week 26 was -33.68 (95% CI -112.0-44.68) mL with GLPG1205 and -76.00 (95% CI -170.7-18.71) mL with placebo (least squares mean difference 42.33 (95% CI -81.84-166.5) mL; p=0.50). Lung volumes by imaging declined -58.30 versus -262.72 mL (whole lung) and -33.68 versus -135.48 mL (lower lobes) with GLPG1205 versus placebo, respectively. Treatment with GLPG1205 versus placebo resulted in higher proportions of serious and severe treatment-emergent adverse events and treatment-emergent discontinuations, most apparent with nintedanib. CONCLUSIONS: Treatment with GLPG1205 did not result in a significant difference in FVC decline versus placebo. GLPG1205 demonstrated a poorer safety and tolerability profile than placebo.

A Case Report of Severe Factor XI Deficiency during Cardiac Surgery: Less Can Be More.

Severe congenital Factor XI (FXI) deficiency (<20% normal activity) can be associated with significant bleeding disorders, and there has been great concern for severe bleeding following cardiac surgery requiring cardiopulmonary bypass (CPB) in this patient population. Over the past four decades remarkably different approaches to this problem have been taken, including the administration of blood volumes of fresh frozen plasma, administration of activated recombinant Factor VII, and diminutive administration of heparin. We describe a case wherein the patient was assessed in the perioperative period with a point-of-care, viscoelastic hemostasis device (ROTEM), with changes in the intrinsic/Factor XII-dependent coagulation pathway determined before, during, and after CPB. Fresh frozen plasma was administered in small amounts (5−7.5 mL/kg) just before surgery began and just before cessation of CPB. Administering fresh frozen plasma to the patient to nearly normalize in vitro ROTEM hemostasis values at times when hemostasis was needed resulted in no important bleeding occurring or need of further transfusion of other blood products. In conclusion, by using small amounts of fresh frozen plasma guided by ROTEM, an evidenced-based, precision medicine approach resulted in optimized patient care and outcome.

Patient Perceptions of FDA Approval: Gaps in Education or Variation in Values?

OBJECTIVE: To assess perceptions and opinions about the Food and Drug Administration (FDA) approval process for disease-modifying therapies (DMT) in people living with multiple sclerosis (MS). METHODS: People living with MS were invited to complete a web-based survey of their perceptions of the FDA role and process for approval of MS medications. The survey asked about the role of the FDA, factors involved in the approval process, which voices should represent those with MS in deliberations about drug approval, and the level of comfort with uncertain safety of newly approved therapies. RESULTS: Three thousand thirty-three respondents met inclusion criteria for data analysis. Most respondents seemed to understand the role of the FDA, although only half understood a fundamental FDA role: balancing the risks and benefits when considering drug approval. Significant differences were observed in many areas between those who have and have not tried DMTs. Comfort with uncertainty was associated with several factors relating to side effects and benefits believed important for the FDA to consider. Most respondents reported that people who participated in the medication's clinical trial were particularly able to represent people living with MS. CONCLUSION: Perceptions regarding the FDA and views of who should represent people living with MS varied between those who have and have not tried DMT. There is variability in personal values that should be recognized and taken into account when considering regulatory responsibilities. Interventions are needed to address educational gaps regarding the mission and trustworthiness of the FDA as an oversight body.

Changes in Patients' Desired Control of Their Deep Brain Stimulation and Subjective Global Control Over the Course of Deep Brain Stimulation.

Objective: To examine changes in patients' desired control of the deep brain stimulator (DBS) and perception of global life control throughout DBS. Methods: A consecutive cohort of 52 patients with Parkinson's disease (PD) was recruited to participate in a prospective longitudinal study over three assessment points (pre-surgery, post-surgery months 3 and 6). Semi-structured interviews assessing participants' desire for stimulation control and perception of global control were conducted at all three points. Qualitative data were coded using content analysis. Visual analog scales were embedded in the interviews to quantify participants' perceptions of control over time. Results: Participants reported significant increases in their perception of global control over time and significant declines in their desired control of the stimulation. These changes were unrelated to improvements in motor symptoms. Improvements in global control were negatively correlated with a decline in desired stimulation control. Qualitative data indicate that participants have changed, nuanced levels of desired control over their stimulators. Increased global life control following DBS may be attributed to increased control over PD symptoms, increased ability to engage in valued activities, and increased overall self-regulation, while other domains related to global control remained unaffected by DBS. Conclusions: There are few empirical data documenting patients' desire for stimulation control throughout neuromodulation and how stimulation control is related to other aspects of control despite the growing application of neuromodulation devices to treat a variety of disorders. Our data highlight distinctions in different types of control and have implications for the development of patient-controlled neurostimulation devices.

Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis.

Galectin (Gal)-3 is a profibrotic ß-galactoside-binding lectin that plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and IPF exacerbations. TD139 is a novel and potent small-molecule inhibitor of Gal-3.A randomised, double-blind, multicentre, placebo-controlled, phase 1/2a study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled TD139 in 36 healthy subjects and 24 patients with IPF. Six dose cohorts of six healthy subjects were evaluated (4:2 TD139:placebo ratio) with single doses of TD139 (0.15-50 mg) and three dose cohorts of eight patients with IPF (5:3 TD139:placebo ratio) with once-daily doses of TD139 (0.3-10 mg) for 14 days.Inhaled TD139 was well tolerated with no significant treatment-related side-effects. TD139 was rapidly absorbed, with mean time taken to reach maximum plasma concentration (C max) values ranging from 0.6 to 3 h and a plasma half-life (T 1/2) of 8 h. The concentration of TD139 in the lung was >567-fold higher than in the blood, with systemic exposure predicting exposure in the target compartment. Gal-3 expression on alveolar macrophages was reduced in the 3 and 10 mg dose groups compared with placebo, with a concentration-dependent inhibition demonstrated. Inhibition of Gal-3 expression in the lung was associated with reductions in plasma biomarkers centrally relevant to IPF pathobiology (platelet-derived growth factor-BB, plasminogen activator inhibitor-1, Gal-3, CCL18 and YKL-40).TD139 is safe and well tolerated in healthy subjects and IPF patients. It was shown to suppress Gal-3 expression on bronchoalveolar lavage macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression.

The autotaxin-lysophosphatidic acid pathway mediates mesenchymal cell recruitment and fibrotic contraction in lung transplant fibrosis.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the leading cause of mortality in lung transplant recipients. CLAD is characterized by respiratory failure owing to the accumulation of fibrotic cells in small airways and alveoli, inducing tissue contraction and architectural destruction. However, the source of the fibroblastic cells and the mechanism(s) underlying the accumulation and activation remain unexplained. Mesenchymal stromal cells (MSCs) are multipotent progenitors that are normally located in the lung tissue but can be isolated from the alveolar space in lung transplant recipients, where they have a profibrotic phenotype. Our objective was to identify the mediator(s) inducing migration and contractile differentiation of lung tissue MSCs. METHODS: Bronchoalveolar lavage (BAL) (7 healthy controls and 21 lung transplant recipients), CCL2, HGF, TGFB, EGF, and PDGF-BB and autotaxin were measured by enzyme-linked immunosorbent assay. BAL (7 healthy controls and 31 lung transplant recipients) lysophosphatidic acid (LPA) (16:0, 18:0, 18:1, 22:4) was measured by liquid chromatography with tandem mass spectrometry. The effect of inhibition of candidate mediators on BAL-mediated chemoattraction of MSCs and contraction of MSC-spiked collagen gel assays was assessed. BAL cells from a lung transplant recipient with CLAD were analyzed by single-cell RNA sequencing. RESULTS: We first demonstrate that BAL fluid from lung transplant recipients and particularly those with CLAD is potently chemoattractive to human lung tissue‒derived MSCs and induces a contractile phenotype. After excluding several candidate mediators, we show that LPA blockade completely abrogated transplant recipient BAL‒mediated chemoattraction of MSCs and contraction of MSC-spiked collagen gels. Furthermore, LPA levels were enriched in transplant recipient BAL, and LPA replicated the observed in vitro profibrotic effects of transplant recipient BAL. Finally, we identify BAL monocyte‒derived macrophages with autotaxin (ENPP2) and fibrotic transcriptional signature. CONCLUSIONS: Autotaxin-expressing alveolar macrophages are present in CLAD BAL. These cells potentially provide a local source of autotaxin/LPA that drives MSC recruitment and tissue contraction in CLAD. These cells are analogous to an aberrant macrophage population recently identified in idiopathic pulmonary fibrosis, suggesting an overlap in pathogenesis between CLAD and other forms of lung fibrosis.

Standardization of the 6-min walk test in clinical trials of idiopathic pulmonary fibrosis.

The 6-min walk test (6MWT) is an important measure of functional capacity in idiopathic pulmonary fibrosis (IPF) and has been an endpoint of several IPF clinical trials. However, current guidance for the 6MWT offers insufficient advice on standardization, particularly oxygen supplementation, for clinical trials. Three physicians experienced with the 6MWT and IPF developed a standardized protocol for the 6MWT based on existing clinical guidelines and published literature. The protocol comprises guidance on test conditions, pre-defined parameters to measure at specified timepoints, and step-by-step instructions on conducting the test. The standardized test will be evaluated in the large-scale phase 3 ISABELA trials (NCT03711162; NCT03733444). The test is conducted indoors, using standardized equipment, along a flat, straight, 30-m unobstructed corridor; tests for each individual are performed by the same administrators at the same time of day; warm-up prior to testing is prohibited; supplemental oxygen tanks are permitted and moved by the patient in the same manner for each test; precise wording is used to instruct and encourage patients. Contraindications and stopping criteria are specified. Key assessments include: 6-min walk distance, distance walked at 1 and 3 min, the Borg CR10 scale, heart rate, blood pressure, and oxygen desaturation levels. A standardized 6MWT for IPF will enable more reliable comparisons between clinical trials and limit variability, optimizing use as an endpoint. Application of the standardized 6MWT in the ISABELA program will allow its correlation with other clinically important endpoints and may lead to novel composite endpoints for use in future trials. Submission category: Study Design, Statistical Design, Study Protocols. Submission classifications: Clinical study methodology; Clinical trial design; Clinical trials; Pulmonary disease; Pulmonary disease clinical trial; Respiratory medicine.

Modelling Forced Vital Capacity in Idiopathic Pulmonary Fibrosis: Optimising Trial Design.

INTRODUCTION: Forced vital capacity is the only registrational endpoint in idiopathic pulmonary fibrosis clinical trials. As most new treatments will be administered on top of standard of care, estimating treatment response will become more challenging. We developed a simulation model to quantify variability associated with forced vital capacity decline. METHODS: The model is based on publicly available clinical trial summary and home spirometry data. A single, illustrative trial setting is reported. Model assumptions are 400 subjects randomised 1:1 to investigational drug or placebo over 52 weeks, 50% of each group receiving standard of care (all-comer population), and a 90-mL treatment difference in annual forced vital capacity decline. Longitudinal profiles were simulated and the impact of varying clinical scenarios evaluated. RESULTS: Power to detect a significant treatment difference was 87-97%, depending on the analysis method. Repeated measures analysis generally outperformed analysis of covariance and mixed linear models, particularly with missing data (as simulated data were non-linear). A 15% yearly random dropout rate led to 0.6-5% power loss. Forced vital capacity decline-related dropout introduced greater power loss (up to 12%), as did subjects starting/stopping standard of care or investigational drug. Power was substantially lower for a 26-week trial due to the smaller assumed treatment effect at week 26 (sample size would need doubling to reach a power similar to that of a 52-week trial). CONCLUSIONS: Our model quantifies forced vital capacity decline and associated variability, with all the caveats of background therapy, permitting robust power calculations to inform future idiopathic pulmonary fibrosis clinical trial design. FUNDING: Galapagos NV (Mechelen, Belgium).

Ethical Challenges of Risk, Informed Consent, and Posttrial Responsibilities in Human Research With Neural Devices: A Review.

Importance: Developing more and better diagnostic and therapeutic tools for central nervous system disorders is an ethical imperative. Human research with neural devices is important to this effort and a critical focus of the National Institutes of Health Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Despite regulations and standard practices for conducting ethical research, researchers and others seek more guidance on how to ethically conduct neural device studies. This article draws on, reviews, specifies, and interprets existing ethical frameworks, literature, and subject matter expertise to address 3 specific ethical challenges in neural devices research: analysis of risk, informed consent, and posttrial responsibilities to research participants. Observations: Research with humans proceeds after careful assessment of the risks and benefits. In assessing whether risks are justified by potential benefits in both invasive and noninvasive neural device research, the following categories of potential risks should be considered: those related to surgery, hardware, stimulation, research itself, privacy and security, and financial burdens. All 3 of the standard pillars of informed consent-disclosure, capacity, and voluntariness-raise challenges in neural device research. Among these challenges are the need to plan for appropriate disclosure of information about atypical and emerging risks of neural devices, a structured evaluation of capacity when that is in doubt, and preventing patients from feeling unduly pressured to participate. Researchers and funders should anticipate participants' posttrial needs linked to study participation and take reasonable steps to facilitate continued access to neural devices that benefit participants. Possible mechanisms for doing so are explored here. Depending on the study, researchers and funders may have further posttrial responsibilities. Conclusions and Relevance: This ethical analysis and points to consider may assist researchers, institutional review boards, funders, and others engaged in human neural device research.

Rationale, design and objectives of two phase III, randomised, placebo-controlled studies of GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis (ISABELA 1 and 2).

Introduction: While current standard of care (SOC) for idiopathic pulmonary fibrosis (IPF) slows disease progression, prognosis remains poor. Therefore, an unmet need exists for novel, well-tolerated agents that reduce lung function decline and improve quality of life. Here we report the design of two phase III studies of the novel IPF therapy, GLPG1690. Methods and analysis: Two identically designed, phase III, international, randomised, double-blind, placebo-controlled, parallel-group, multicentre studies (ISABELA 1 and 2) were initiated in November 2018. It is planned that, in each study, 750 subjects with IPF will be randomised 1:1:1 to receive oral GLPG1690 600 mg, GLPG1690 200 mg or placebo, once daily, on top of local SOC, for at least 52 weeks. The primary endpoint is rate of decline of forced vital capacity (FVC) over 52 weeks. Key secondary endpoints are week 52 composite endpoint of disease progression or all-cause mortality (defined as composite endpoint of first occurrence of ≥10% absolute decline in per cent predicted FVC or all-cause mortality at week 52); time to first respiratory-related hospitalisation until end of study; and week 52 change from baseline in the St George's Respiratory Questionnaire total score (a quality-of-life measure). Ethics and dissemination: Studies will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication. Trial registration numbers: NCT03711162; NCT03733444.

A survey of risk tolerance to multiple sclerosis therapies.

OBJECTIVE: To determine tolerance to various risk scenarios associated with current multiple sclerosis (MS) therapies. METHODS: People with MS from the North American Research Committee on Multiple Sclerosis Registry's online cohort and the National Multiple Sclerosis Society were invited to complete a questionnaire on tolerance to real-world risks associated with a hypothetical therapy. Multiple risks levels were presented, including skin rash, infection, kidney injury, thyroid injury, liver injury, and progressive multifocal leukoencephalopathy (PML). RESULTS: Both PML and kidney injury had the lowest risk tolerance (RT) at 1:1,000,000, and thyroid and infection risks had the highest tolerance at 1:1,000. Men, younger individuals, and participants with greater disability reported a higher tolerance to all risk scenarios. Those who were currently taking an MS therapy reported higher tolerance than those not taking any therapy. Participants taking infusion therapies reported high tolerance to all risks, and those taking injectables reported a lower tolerance. CONCLUSION: People with MS displayed a wide range of RT for MS therapies. Our study identified sex, age, disability, and current disease-modifying therapy use to be associated with RT.

An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade.

A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a ß-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non-small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3-/- mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3-/- mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8+ T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNγ, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers. SIGNIFICANCE: A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1480/F1.large.jpg.

Cinnamon - Differentiation of Four Species by Linking Classical Botany to an Automated Chromatographic Authentication System.

One of the world's oldest spices, cinnamon is also one of the most popular. Species of the genus Cinnamomum offer a variety of extractable oils with aroma and flavor characteristics of importance to the flavor industry, so differentiating cinnamon samples for culinary-based applications is very important. Cinnamon also has reported health benefits associated with specific phytochemical constituents, but its composition can vary greatly depending on species and source region. A substantial amount of the research reported on cinnamon does not provide thorough documentation of the source and taxonomic identification of the study material, a very common issue with studies of food and medicinal plants. In the interest of providing some clarity to the discussion of the health benefits and culinary attributes of the different cinnamon types in the marketplace, we offer the results of a long-term chemotaxonomic study of cinnamon samples sourced from different regions of the world and link those chemical data to classical taxonomic identification of the source plants. We provide details of the effective use of an automated chemotaxonomic analytical method to differentiate cinnamons from various geographic regions. Also included are chromatographic data for the polyphenolic/procyanidin fractions of each species, as cinnamon type-A procyanidins are often the purported source of biological activity in cinnamon and cinnamon extracts.

Piper nigrum Oil - Determination of Selected Terpenes for Quality Evaluation.

The growing demand and commercial value of black pepper (Piper nigrum) has resulted in considerable interest in developing suitable and cost-effective methods for chemical characterization and quality evaluation purposes. In the current study, an extensive set of oil samples (n = 23) that were extracted by steam distillation from black pepper seeds was investigated to compare the chemical profiles of samples originating from nine major producing countries, as well as to identify potential chemical markers for quality evaluation. The twenty-two most abundant volatile compounds, mainly terpenes, in these oils were determined by conventional GC/MS analysis. Principal component analysis with this set of data revealed distinct clusters for samples that originated from China and Malaysia. Relatively low concentrations of sabinene (< 0.2%) and high concentrations of 3-carene (10.9 - 21.1%) were observed in these samples, respectively, compared to oil samples from other countries. The enantiomeric distributions of key terpene markers, viz., ß-pinene, sabinene, limonene, and terpinen-4-ol, were determined by chiral GC/MS analysis. Interestingly, for these four monoterpenes, levo-isomers were found to be predominant, emphasizing the highly conserved enzymatic processes occurring in P. nigrum. Moreover, consistent enantiomeric ratios ((-) isomer/(+) isomer) of 92.2 ± 3.0% for ß-pinene, 94.8 ± 2.8% for sabinene, 60.7 ± 1.1% for limonene, and 78.3 ± 1.3% for terpinen-4-ol were observed, independent of geographical location. These results demonstrate the potential of using stereospecific compositions as chiral signatures for establishing the authenticity and quality of black pepper oil.