High-grade mesenchymal pancreatic ductal adenocarcinoma drives stromal deactivation through CSF-1.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundance of stroma. Multiple molecular classification efforts have identified a mesenchymal tumor subtype that is consistently characterized by high-grade growth and poor clinical outcome. The relation between PDAC stroma and tumor subtypes is still unclear. Here, we aimed to identify how PDAC cells instruct the main cellular component of stroma, the pancreatic stellate cells (PSCs). We found in primary tissue that high-grade PDAC had reduced collagen deposition compared to low-grade PDAC. Xenografts and organotypic co-cultures established from mesenchymal-like PDAC cells featured reduced collagen and activated PSC content. Medium transfer experiments using a large set of PDAC cell lines revealed that mesenchymal-like PDAC cells consistently downregulated ACTA2 and COL1A1 expression in PSCs and reduced proliferation. We identified colony-stimulating factor 1 as the mesenchymal PDAC-derived ligand that deactivates PSCs, and inhibition of its receptor CSF1R was able to counteract this effect. In conclusion, high-grade PDAC features stroma that is low in collagen and activated PSC content, and targeting CSF1R offers direct options to maintain a tumor-restricting microenvironment.

A Biofouling Resistant Zwitterionic Polysulfone Membrane Prepared by a Dual-Bath Procedure.

This study introduces a zwitterionic material to modify polysulfone (PSf) membranes formed by a dual bath procedure, in view of reducing their fouling propensity. The zwitterionic copolymer, derived from a random polymer of styrene and 4-vinylpyrridine and referred to as zP(S-r-4VP), was incorporated to the PSf solution without any supplementary pore-forming additive to study the effect of the sole copolymer on membrane-structuring, chemical, and arising properties. XPS and mapping FT-IR provided evidence of the modification. Macrovoids appeared and then disappeared as the copolymer content increased in the range 1-4 wt%. The copolymer has hydrophilic units and its addition increases the casting solution viscosity. Both effects play an opposite role on transfers, and so on the growth of macrovoids. Biofouling tests demonstrated the efficiency of the copolymer to mitigate biofouling with a reduction in bacterial and blood cell attachment by more than 85%. Filtration tests revealed that the permeability increased by a twofold factor, the flux recovery ratio was augmented from 40% to 63% after water/BSA cycles, and irreversible fouling was reduced by 1/3. Although improvements are needed, these zwitterionic PSf membranes could be used in biomedical applications where resistance to biofouling by cells is a requirement.

Associations of waking cortisol with DHEA and testosterone across the pubertal transition: Effects of threat-related early life stress.

Atypical regulation of the hypothalamic-pituitary-adrenal (HPA) axis is a putative mechanism underlying the association between exposure to early life stress (ELS) and the subsequent development of mental and physical health difficulties. Recent research indicates that puberty is a period of HPA-axis plasticity during which the effects of exposure to ELS on cortisol regulation may change. In particular, increases in the sex hormones that drive pubertal maturation, including dehydroepiandrosterone (DHEA) and testosterone, may be implicated in pubertal recalibration of cortisol regulation. In the current study, we examined the associations among levels of objectively-rated threat-related ELS and salivary waking cortisol, DHEA, and testosterone in a sample of 178 adolescents (55 % female) who were in early puberty at baseline (Tanner stages 1-3; mean Tanner stage[SD] = 1.93[0.64]; mean age[SD] = 11.42[1.04]) and were followed up approximately two years later (mean Tanner stage[SD] = 3.46[0.86]; mean age[SD] = 13.38[1.06]). Using multi-level modeling, we disaggregated the effects of between-individual levels and within-individual increases in pubertal stage and sex hormones on change in cortisol. Controlling for between-individual differences in average pubertal stage, the association between levels of cortisol and DHEA was more strongly positive among adolescents who evidenced greater within-individual increases in pubertal stage across time. Both higher average levels and greater within-individual increases in DHEA and testosterone were associated with increases in cortisol across time, indicating positive coupling of developmental changes in these hormones; however, coupling was attenuated in adolescents who were exposed to more severe threat-related ELS prior to puberty. These findings advance our understanding of the development of the HPA-axis and its association with childhood environmental risk during puberty.

Clinical Trials Targeting the Stroma in Pancreatic Cancer: A Systematic Review and Meta-Analysis.

The tumor microenvironment plays an important role in the initiation and progression of pancreatic adenocarcinoma (PDAC). In this systematic review, we provide an overview of clinical trials with stroma-targeting agents. We systematically searched MEDLINE/PubMed and the EMBASE database, using the PRISMA guidelines, for eligible clinical trials. In total, 2330 records were screened, from which we have included 106 articles. A meta-analysis could be performed on 51 articles which describe the targeting of the vascular endothelial growth factor (VEGF) pathway, and three articles which describe the targeting of hyaluronic acid. Anti-VEGF therapies did not show an increase in median overall survival (OS) with combined hazard ratios (HRs) of 1.01 (95% confidence interval (CI) 0.90-1.13). Treatment with hyaluronidase PEGPH20 showed promising results, but, thus far, only in combination with gemcitabine and nab-paclitaxel in selected patients with hyaluronic acid (HA)high tumors: An increase in median progression free survival (PFS) of 2.9 months, as well as a HR of 0.51 (95% CI 0.26-1.00). In conclusion, we found that anti-angiogenic therapies did not show an increased benefit in median OS or PFS in contrast to promising results with anti-hyaluronic acid treatment in combination with gemcitabine and nab-paclitaxel. The PEGPH20 clinical trials used patient selection to determine eligibility based on tumor biology, which underlines the importance to personalize treatment for pancreatic cancer patients.

Exercise increases the lung clearance of inhaled technetium-99m DTPA.

The regional lung clearance of a deposited aerosol of [99mTc] diethylenetriaminepentaacetic acid was successively computed at rest and at exercise in seven nonsmoking volunteers in upright posture. The subjects were seated on a bicycle with their backs against a gamma camera. At rest there was a gradient of clearance from the apex to the base of the lung, the apical clearance being significantly higher. At exercise this regional gradient was enhanced by a large and significant increase of the apical clearances (3.40 +/- 0.63% min-1 s.d. compared with 1.82 +/- 0.75% min-1 s.d. at rest, n = 7, p less than 0.01). By contrast the changes of the basal clearances were slight and unsignificant (1.46 +/- 0.71% min-1 s.d. compared with 1.40 +/- 0.82% min-1 s.d.). This increase of the apical lung clearance could be attributed primarily to the increase of apical blood flow induced by exercise and to the subsequent increase of the permeability surface area product.

Ion microscopy, a method for imaging the distribution of trace elements in the lung.

Analytical ion microscopy, a method of surface microanalysis, is applied to the detection of trace elements in the lung. With this method it is possible to obtain images of the distribution of any element in lung tissue sections with a resolution of 0.5 micron and with very high sensitivity (of an order of magnitude 3 or 4 times greater than with X-ray microanalysis). Under these conditions it is possible to study at the microscopic level the penetration into the lung cells of mineral materials administered in physiological amounts. The images are formed by ion microscopy of atoms sputtered as charged particles from the specimen, and these atoms are selected by mass spectrometry. This technique has been applied to the detection of aerosols (diam. less than 1 micron) of rare earths (thulium or cerium chloride), inhaled in very small amounts (20-50 micrograms), in cells from the lung of a rat. Images of the distribution of these elements were obtained in a few seconds or minutes, when X-ray microanalysis gave either a weak signal or none at all. Their behaviour in the lung could be easily studied several weeks after the end of the inhalation.

[Particles. Aerosols. Dust (author's transl)]. / Particules. Aérosols. Poussières.

After a few definitions and generalities about aerosols, the main physical properties of aerosols are reviewed: sedimentation, diffusion, coagulation, optical and electrical properties. The properties of atmospheric aerosol are also summarized.

[Intrapulmonary deposition of inframicron particles during inspiratory apnea (author's transl)]. / Déposition intrapoulmonaire des particules inframicroniques au cours de l'apnée inspiratoire.

An experimental approach of the intrapulmonary deposition of particles with a diameter below 1 micron, suspended in the surrounding atmosphere, was done on two normal subjects during inspiratory apnea with a Whitby impactor. The first results seem to agree with those of literature and confirm the importance of pulmonary morphometric factors in the deposition processes. Numerous methodological problems remain, but it appears that the technique would be useful to evaluate the likelyhood of deposition of submicron particles which are presently known to be pathogenic.