An inflammation based score can optimize the selection of patients with advanced cancer considered for early phase clinical trials.

Background: Adequate organ function and good performance status (PS) are common eligibility criteria for phase I trials. As inflammation is pathogenic and prognostic in cancer we investigated the prognostic performance of inflammation-based indices including the neutrophil (NLR) and platelet to lymphocyte ratio (PLR). Methods: We studied inflammatory scores in 118 unselected referrals. NLR normalization was recalculated at disease reassessment. Each variable was assessed for progression-free (PFS) and overall survival (OS) on uni- and multivariate analyses and tested for 90 days survival (90DS) prediction using receiving operator curves (ROC). Results: We included 118 patients with median OS 4.4 months, 23% PS>1. LDH 65450 and NLR 655 were multivariate predictors of OS (p<0.001). NLR normalization predicted for longer OS (p<0.001) and PFS (p<0.05). PS and NLR ranked as most accurate predictors of both 90DS with area under ROC values of 0.66 and 0.64, and OS with c-score of 0.69 and 0.60. The combination of NLR+PS increased prognostic accuracy to 0.72. The NLR was externally validated in a cohort of 126 subjects. Conclusions: We identified the NLR as a validated and objective index to improve patient selection for experimental therapies, with its normalization following treatment predicting for a survival benefit of 7 months. Prospective validation of the NLR is warranted. Copyright: \ua9 2014 Pinato et al

Do Soldiers Get a Say? Soldiers’ Views and Public Support for Military Operations in Four Democracies

When deciding whether to support a military operation, do citizens in democracies weigh whether soldiers themselves support the operation? Recent research has concluded that, in the United States, public support for military operations rests in part on people’s beliefs that soldiers favor their own deployment. However, it is not known whether this finding extends beyond the United States to democracies with diverse national citizenship discourses and threat profiles, and its theoretical basis is not well understood. This article addresses both these gaps. Using novel survey data and an experiment in four democracies with divergent citizenship traditions—France, Israel, the United Kingdom, and the United States—we show that, in all four nations, support for military operations depends significantly on whether people believe that soldiers themselves favor the operation. We highlight two reasons: (1) battlefield performance (respondents think that soldiers who favor their mission fight better), and (2) soldier consent (humans’ capacity for empathy makes them sensitive to whether soldiers are willingly sent into harm’s way). This article has significant implications for debates on public support for the use of military force, the nature of citizenship in modern democracies, and contemporary militarism.<br/

Citizenship Traditions and Cultures of Military Service:Patriotism and Paychecks in Five Democracies

Why do people think that soldiers and officers join the military? In this article, we report and explain unique survey results of nationally representative populations in five democracies—France, Germany, Israel, the United Kingdom, and the United States. Beliefs about motivations for military service vary significantly by nation. In Israel and France, large majorities endorse intrinsic accounts of service motivations—that is, those centering on patriotism and good citizenship. The U.S. population is nearly evenly split between extrinsic accounts—ascribing service to the pay and benefits received or to the desire to escape desperate circumstances—and intrinsic ones. A large majority of U.K. and Germany-based respondents hew to extrinsic service accounts. We argue that the most plausible explanation lies with prevailing national citizenship discourses, in combination with the military’s operational tempo. This research has implications for public support for military recruitment, the use of force, and democratic civil–military relations.<br/

Citizenship Traditions and Cultures of Military Service:Patriotism and Paychecks in Five Democracies

Why do people think that soldiers and officers join the military? In this article, we report and explain unique survey results of nationally representative populations in five democracies—France, Germany, Israel, the United Kingdom, and the United States. Beliefs about motivations for military service vary significantly by nation. In Israel and France, large majorities endorse intrinsic accounts of service motivations—that is, those centering on patriotism and good citizenship. The U.S. population is nearly evenly split between extrinsic accounts—ascribing service to the pay and benefits received or to the desire to escape desperate circumstances—and intrinsic ones. A large majority of U.K. and Germany-based respondents hew to extrinsic service accounts. We argue that the most plausible explanation lies with prevailing national citizenship discourses, in combination with the military’s operational tempo. This research has implications for public support for military recruitment, the use of force, and democratic civil–military relations.<br/

Polymorphism in sulfadimidine/4- aminosalicylic acid cocrystals: solid-state characterization and physicochemical properties

YesPolymorphism of crystalline drugs is a common phenomenon. However, the number of reported polymorphic cocrystals is very limited. In this work, the synthesis and solid state characterisation of a polymorphic cocrystal composed of sulfadimidine (SD) and 4- aminosalicylic acid (4-ASA) is reported for the first time. By liquid-assisted milling, the SD:4-ASA 1:1 form I cocrystal, the structure of which has been previously reported, was formed. By spray drying, a new polymorphic form (form II) of the SD:4-ASA 1:1 cocrystal was discovered which could also be obtained by solvent evaporation from ethanol and acetone. Structure determination of the form II cocrystal was calculated using high resolution X-ray powder diffraction. The solubility of the SD:4-ASA 1:1 cocrystal was dependent on the pH and predicted by a model established for a two amphoteric component cocrystal. The form I cocrystal was found to be thermodynamically more stable in aqueous solution than form II, which showed transformation to form I. Dissolution studies revealed that the dissolution rate of SD from both cocrystals was enhanced when compared to a physical equimolar mixture and pure SD.Science Foundation Ireland (SFI) under Grant Number 07/SRC/B1158 and SFI/12/RC/2275

A longitudinal study of muscle strength and function in patients with cancer cachexia

Purpose Patients with cancer frequently experience an involuntary loss of weight (in particular loss of muscle mass), defined as cachexia, with profound implications for independence and quality of life. The rate at which such patients’ physical performance declines has not been well established. The aim of this study was to determine the change in muscle strength and function over 8 weeks in patients with already established cancer cachexia, to help inform the design and duration of physical activity interventions applicable to this patient group. Methods Patients with thoracic and gastrointestinal cancer, with unintentional weight loss of >5% in 6 months or BMI < 20 plus 2% weight loss were included. Physical and functional assessments (baseline, 4 weeks, 8 weeks) included: isometric quadriceps and hamstring strength, handgrip, standing balance, 10m walk time and timed up and go. Results Fifty patients (32 male), mean ±SD age 65 ±10 years and BMI 24.9 ±4.3kg/m2 were recruited. Thoracic cancer patients had lower muscle strength and function (p0.05). Baseline variables did not differentiate between completers and non-completers (p>0.05). Conclusions More than a third of patients with established cancer cachexia in our study were stable over 8 weeks, suggesting a subgroup who may benefit from targeted interventions of reasonable duration. Better understanding the physical performance parameters which characterize and differentiate these patients has important clinical implications for cancer multidisciplinary team practice

A phase 1b, multicentre, dose escalation, safety and pharmacokinetics study of tilvestamab (BGB149) in relapsed, platinum-resistant, high-grade serous ovarian cancer (PROC) patients: Translational Therapeutics

Background: Tilvestamab is a highly selective humanised immunoglobulin G1 anti-AXL monoclonal antibody. This phase 1 study evaluated its optimal dose, safety, tolerability, immunogenicity and pharmacokinetics (PK) in relapsed platinum-resistant HGSOC patients. Methods: Patients received tilvestamab in three dose levels (1 mg/kg, 3 mg/kg and 5 mg/kg) via IV infusion every 2 weeks. Primary objectives included safety, tolerability and PK. Exploratory objectives included overall response, progression-free survival (PFS) and quality-of-life measures. Pharmacodynamic included AXL expression, gene and protein changes by transcriptomic and proteomic analysis. Results: Between 25 February 2021 and 4 February 2022, 16 patients were enroled across 8 sites in Singapore, Korea, United Kingdom, and Norway. Median treatment duration was 6.1 weeks. Grade 3 or higher treatment-emergent adverse events occurred in 62.5% patients, but none were tilvestamab-related. Common events included fatigue (38%), anorexia (38%) infections (31%), anaemia (25%) and dyspnoea (25%). No objective responses were observed, but 7 (44%) had stable disease at 6 weeks. PK showed dose-proportional exposure and steady-state by the second dose. Pharmacodynamic analyses revealed reduced fibrosis-related gene signatures and AXL protein expression. Epithelial-mesenchymal transition reversal was seen in 2 patients. Conclusion: Tilvestamab was well-tolerated and further studies to examine the efficacy of AXL inhibition in other indications are required. Clinical trial registration: This trial is registered at https://clinicaltrials.gov. Registration number: NCT04893551. EudraCT Number: 2020-001382-3

A Phase IB open-label, dose-escalation study of NUC 1031 in combination with carboplatin for recurrent ovarian cancer

Funding: The study was funded and the investigational drug NUC-1031 was supplied by NuCana plc.Purpose: NUC-1031 is a first-in-class ProTide modification of gemcitabine. In PRO-002, NUC‑1031 was combined with carboplatin in recurrent ovarian cancer (OC). Experimental Design: NUC-1031 was administered on days 1 & 8 with carboplatin on day 1 every 3 weeks for up to 6 cycles. Four dose cohorts of NUC-1031 (500, 625 and 750 mg/m2) with carboplatin (AUC4 or 5) were investigated. Primary endpoint was RP2CD. Secondary endpoints included safety, investigator-assessed objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS) and pharmacokinetics (PK). Results: 25 women with recurrent OC, a mean of 3.8 prior lines of chemotherapy and a median platinum-free interval (PFI) of 5 months (range: 7 - 451 days) were enrolled, 15/25 (60%) platinum-resistant; 9 (36%) partially platinum-sensitive and 1 (4%) platinum-sensitive. Of the 23 response-evaluable: there was 1 confirmed complete response (CR, 4%), 5 partial responses (PR, 17%) and 8 (35%) stable disease (SD). The ORR was 26% and CBR was 74% across all doses and 100% in the RP2CD cohort. Median PFS was 27.1 weeks. NUC-1031 was stable in the plasma and rapidly generated high intracellular dFdCTP levels that were unaffected by carboplatin. Conclusions: NUC-1031 combined with carboplatin is well tolerated in recurrent OC. Highest efficacy was observed at the RP2CD of 500 mg/m2 NUC-1031 on days 1 & 8 with AUC5 carboplatin day 1, every 3 weeks for 6 cycles. The ability to deliver carboplatin at AUC5 and the efficacy of this schedule even in patients with platinum-resistant disease makes this an attractive therapeutic combination.PostprintPeer reviewe

The RNA binding protein Larp1 regulates cell division, apoptosis and cell migration.

The RNA binding protein Larp1 was originally shown to be involved in spermatogenesis, embryogenesis and cell-cycle progression in Drosophila. Our data show that mammalian Larp1 is found in a complex with poly A binding protein and eukaryote initiation factor 4E and is associated with 60S and 80S ribosomal subunits. A reduction in Larp1 expression by siRNA inhibits global protein synthesis rates and results in mitotic arrest and delayed cell migration. Consistent with these data we show that Larp1 protein is present at the leading edge of migrating cells and interacts directly with cytoskeletal components. Taken together, these data suggest a role for Larp1 in facilitating the synthesis of proteins required for cellular remodelling and migration