Immunotherapy for Biliary Tract Cancer in the Era of Precision Medicine: Current Knowledge and Future Perspectives

Biliary tract cancers (BTC) represent a heterogeneous and aggressive group of tumors with dismal prognosis. For a long time, BTC has been considered an orphan disease with very limited therapeutic options. In recent years a better understanding of the complex molecular landscape of biology is rapidly changing the therapeutic armamentarium. However, while 40–50% of patients there are molecular drivers susceptible to target therapy, for the remaining population new therapeutic options represent an unsatisfied clinical need. The role of immunotherapy in the continuum of treatment of patients with BTC is still debated. Despite initial signs of antitumor-activity, single-agent immune checkpoint inhibitors (ICIs) demonstrated limited efficacy in an unselected population. Therefore, identifying the best partner to combine ICIs and predictive biomarkers represents a key challenge to optimize the efficacy of immunotherapy. This review provides a critical analysis of completed trials, with an eye on future perspectives and possible biomarkers of response.     

Thermal Effects on the Gas Transmission Properties of Ionomers Used in Food Packaging Applications

Polyethylene-based ionomers, due to the presence of ionic aggregates, display a time-dependent crystalline morphology if submitted to thermal treatments. As a consequence gas permeability, which is strongly affected by physical morphology, is also found to be time dependent in previously thermally treated ionomer samples. The effect of sample exposure at 65°C and of successive ageing at 35°C on gas transmission properties of three different ethylene– acrylic acid ionomers (characterized by a different amount of acrylic acid groups, percentage of neutralization and type of counterions) has been investigated. In particular the changes in oxygen and carbon dioxide permeabilities due to thermal treatments at 65°C and subsequent ageing at 35°C have been monitored. X-Ray diffraction analysis and differential scanning calorimetry have been used to elucidate these changes in transport properties.     

Short-run statistical process control: Q-Chart enhancements and alternative methods

The first two tables in Reference 1 are incorrect. Corrected tables are provided below. The errors do not affect the conclusions or the discussion in that paper.     

SEC23B Loss-of-Function Suppresses Hepcidin Expression by Impairing Glycosylation Pathway in Human Hepatic Cells

Biallelic pathogenic variants in the SEC23B gene cause congenital dyserythropoietic anemia type II (CDA II), a rare hereditary disorder hallmarked by ineffective erythropoiesis, hemolysis, erythroblast morphological abnormalities, and hypo-glycosylation of some red blood cell membrane proteins. Abnormalities in SEC23B, which encodes the homonymous cytoplasmic COPII (coat protein complex II) component, disturb the endoplasmic reticulum to Golgi trafficking and affect different glycosylation pathways. The most harmful complication of CDA II is the severe iron overload. Within our case series (28 CDA II patients), approximately 36% of them exhibit severe iron overload despite mild degree of anemia and slightly increased levels of ERFE (the only erythroid regulator of hepcidin suppression). Thus, we hypothesized a direct role of SEC23B loss-of-function in the pathomechanism of hepatic iron overload. We established a hepatic cell line, HuH7, stably silenced for SEC23B. In silenced cells, we observed significant alterations of the iron status, due to both the alteration in BMP/SMADs pathway effectors and a reduced capability to sense BMP6 stimulus. We demonstrated that the loss-of-function of SEC23B is responsible of the impairment in glycosylation of the membrane proteins involved in the activation of the BMP/SMADs pathway with subsequent hepcidin suppression. Most of these data were confirmed in another hepatic cell line, HepG2, stably silenced for SEC23B. Our findings suggested that the pathogenic mechanism of iron overload in CDA II is associated to both ineffective erythropoiesis and to a specific involvement of SEC23B pathogenic variants at hepatic level. Finally, we demonstrated the ability of SEC23B paralog, i.e., SEC23A, to rescue the hepcidin suppression, highlighting the functional overlap between the two SEC23 paralogs in human hepatic cells.     

Nondegradative additive manufacturing of medical grade copolyesters of high molecular weight and with varied elastic response

Although additive manufacturing through melt extrusion has become increasingly popular as a route to design scaffolds with complex geometries the technique if often limited by the reduction in molecular weight and the viscoelastic response when degradable aliphatic polyesters of high molecular weight are used. Here we use a melt extruder and fused filament fabrication printer to produce a reliable nondegradative route for scaffold fabrication of medical grade copolymers of L-lactide, poly(ε-caprolactone-co-L-lactide), and poly(L-lactide-co-trimethylene carbonate). We show that degradation is avoided using filament extrusion and fused filament fabrication if the process parameters are deliberately chosen based upon the rheological behavior, mechanical properties, and polymer composition. Structural, mechanical, and thermal properties were assessed throughout the process to obtain comprehension of the relationship between the rheological properties and the behavior of the medical grade copolymers in the extruder and printer. Scaffolds with a controlled architecture were achieved using high-molecular-weight polyesters exhibiting a large range in the elastic response causing negligible degradation of the polymers. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48550.     

Inactivation of Staphylococcus aureus by the synergistic action of charged and reactive plasma particles

In this paper, a low-pressure capacitively coupled plasma discharge sustained in an argonoxygen mixture was studied in order to evaluate its properties in terms of inactivation of Staphylococcus aureus. The plasma parameters as electron temperature and plasma density were measured by the Langmuir probe (N_e ≈ 10¹⁵ m⁻³, T_e ≈ 1.5 eV), while the neutral atom density was in the range of 10²¹ m⁻³. In the plasma phase, oxygen radicals were taken as reference of the reactive species with antimicrobial activity, and oxygen spectral lines, over a range of plasma process parameters, were investigated by the optical emission spectroscopy. Optimal plasma conditions were found, and a count reduction of 4 log in a few minutes of the bacterium proves the potentiality of an industrial grade plasma reactor as a sterilization agent.     

Characterization of Gram‐Negative Psychrotrophic Bacteria isolated from Italian Bulk Tank Milk

Eighty psychrotrophic bacterial strains, isolated from different northwest Italian bulk tank milks destined for Grana Padano cheese production, were identified by 16S rRNA gene amplification and partial sequence analysis of the rpoB gene. Pseudomonas spp. were the most commonly occurring contaminants, P. fluorescens being the predominant isolated species, along with Enterobacteriaceae, primarily Serratia marcescens. RAPD‐PCR was used to study genetic variability and distinguish closely related strains; a high degree of genetic heterogeneity among the strains was highlighted. All the strains were characterized for their ability to produce proteases, lipases and lecithinases at different temperatures (7, 22, and 30 °C). Forty‐one of the psychrotrophic strains were positive for all the enzymatic activities. The highest number of positive strains for all the incubation temperatures was found for lipolytic activity (59), followed by proteolytic (31) and lecithinase (28) activities, and the enzymatic traits varied among the Pseudomonas and Enterobacteriaceae strains. The proteolytic psychrotrophic strains were screened for the presence of the aprX gene, coding for a heat‐resistant metalloprotease in Pseudomonas spp. The aprX gene was detected in 19 of 63 Pseudomonas strains, and was widespread in the P. fluorescens strains (14/19).     

Microbiological and Sensorial Quality Assessment of Ready-to-Cook Seafood Products Packaged under Modified Atmosphere

ABSTRACT:  The effects of modified atmosphere packaging (MAP) (30:40:30 O₂:CO₂:N₂ and 5:95 O₂:CO₂) on the quality of 4 ready-to-cook seafood products were studied. In particular, the investigation was carried out on hake fillets, yellow gurnard fillets, chub mackerel fillets, and entire eviscerated cuttlefish. Quality assessment was based on microbiological and sensorial indices determination. Both packaging gas mixtures contributed to a considerable slowing down of the microbial and sensorial quality loss of the investigated seafood products. Results showed that sensorial quality was the subindex that limited their shelf life. In fact, based primarily on microbiological results, samples under MAP remained acceptable up to the end of storage (that is, 14 d), regardless of fish specie. On the other hand, results from sensory analyses showed that chub mackerel fillets in MAP were acceptable up to the 6th storage d, whilst hake fillets, yellow gurnard fillets, and entire cuttlefish became unacceptable after 10 to 11 d. However, compared to control samples, an increase in the sensorial shelf life of MAP samples (ranging from about 95% to 250%) was always recorded.
Practical Application: Modified atmosphere packaging (MAP) is an inexpensive and uncomplicated method of extending shelf life of packed seafood. It could gain great attention from the fish industrial sector due to the fact that MAP is a practical and economic technique, realizable by small technical expedients. Moreover, there is great attention from the food industry and retailers to react to the growing demand for convenience food, thus promoting an increase in the assortments of ready-to-cook seafood products.     

Aerosol Retention in the Vicinity of a Breach in a Tube Bundle: An Experimental Investigation

This article summarizes the main results of a bench-scale program focused on experimentally assessing the aerosol retention near the tube breach in a tube bundle. The major variables investigated were particle nature (polydispersed TiO ₂ agglomerates vs. solid, monodisperse SiO ₂ spheres) and Re _D (0.8?2.7· 10 ⁵ ). In addition, comparisons to other data sets provided insights into the particle aerodynamic size effect on retention efficiency. Results showed that particle nature substantially affects aerosol retention in the tube bundle: mass retention efficiency was low for TiO ₂ agglomerates (less than 30%) whereas it was much higher for SiO ₂ particles (around 85%). Retention efficiency is also affected by Re _D : its sensitivity was found to follow a log-normal behavior with a maximum retention attained at Re _D near 1· 10 ⁵ . This evolution with Re _D was similar for both types of compounds. Particle size also influences retention efficiency: the bigger the TiO₂ agglomerates the lower retention efficiency (no data were available for SiO ₂ ). Among all these variables, particle nature was noted to have a prime importance for in-bundle retention, whereas Re _D and particle aerodynamic size, although also affect retention efficiency, did not play such a key role. In light of the results, the presence of retention-inhibiting mechanisms such as fragmentation, resuspension or bouncing has been discussed. The data recorded will enhance the overall understanding of the governing mechanisms involved and will serve as a database against which compare model predictions. Nevertheless, further experimental data would be desirable to set up a sound database.     

Water governance and scalar politics across multiple-boundary river basins: states,catchments and regional powers in the Iberian Peninsula

Karezes (qanats), historically vital sources of water for multiple uses in the driest parts of the world, have been deteriorating over the past five decades. This paper provides a review of the global literature on the status and potential of karezes, and offers country case studies for Afghanistan, Iran, Pakistan, and Kingdom of Saudi Arabia. It offers syntheses of key issues, lessons, options and proposed interventions for re-vitalizing the karez systems. The paper identifies criteria for prioritizing karez systems for rehabilitation and outlines key conditions for their effective functioning and sustainability. The paper suggests that the benefits of restoring karez systems to local communities are large and some systems, such as the Ain Zubaida in the Makkah Al-Mukaramah Region, are of global importance.