Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade.

CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors.

Is career adaptability a double-edged sword? The impact of work social support and career adaptability on turnover intentions during the COVID-19 pandemic.

During the COVID-19 pandemic, many hospitality organizations are trying to help their employees overcome various challenges. Career adaptability has proven to be useful in helping employees handle challenges, while proactive personality is a critical factor affecting the formation of career adaptability. However, career adaptability can be a double-edged sword, and it is unclear how it may impact employees' turnover intentions. Drawing on social exchange theory, the current study reconciles mixed findings in the literature by proposing a moderated mediation model suggesting that work social support moderates the indirect relationship between proactive personality and turnover intentions through career adaptability. Results based on data collected from 339 hotel employees in the United States indicate that proactive personality is positively associated with employees' career adaptability. More importantly, work social support significantly moderates the relationship between career adaptability and turnover intentions. Theoretical and managerial implications are discussed.

The Effect of Coupling Agents and Graphene on the Mechanical Properties of Film-Based Post-Consumer Recycled Plastic.

This study aims to improve the mechanical properties of post-consumer recycled (PCR) plastic composed primarily of polypropylene (PP) and polyethylene (PE), which generally exhibit poor miscibility, by applying coupling agents and graphene. Here, we compare a commercially available coupling agent with a directly synthesized maleic anhydride (MA) coupling agent. When applied to a 5:5 blend of recycled PP and PE, an optimum tensile strength was achieved at a 3 wt% coupling agent concentration, with the MA coupling agent outperforming the commercial one. Characterization through Fourier transform infrared spectroscopy (FT-IR) and thermogravimetry analysis (TGA) revealed a PP:PE ratio of approximately 3:7 in the PCR plastics, with 4.86% heterogeneous materials present. Applying 3 wt% of the commercial and MA coupling agents to the PCR plastics resulted in a significant 53.9% increase in the tensile strength, reaching 11.25 MPa, and a remarkable 421.54% increase in the melt flow index (MFI), reaching 25.66 g/10 min. Furthermore, incorporating 5 wt% graphene led to a notable 64.84% increase in the tensile strength. In addition, the application of MA coupling agents and graphene improved the thermal stability of the PCR plastics. These findings show significant promise for addressing environmental concerns associated with plastic waste by facilitating the recycling of PCR plastics into new products. The utilization of coupling agents and graphene offers a viable approach to enhance the mechanical properties of PCR plastics, paving the way for sustainable and environmentally friendly solutions.

3-Pentadecylphenol (PDP) as a Novel Compatibilizer for Simultaneous Toughened and Reinforced PA10,12 Composites.

The utilization of polyamide 10,12 (PA10,12) composites in various industries has been limited constrained by their inherent low toughness, making it a challenge to achieve a balance between toughness and structural integrity through conventional elastomer addition strategies. Herein, we introduce a straightforward method for the concurrent toughening and reinforcement of PA10,12 composites. This is accomplished by blending polyolefin elastomer (POE) and 3-pentadecylphenol (PDP) with the PA10,12 matrix. The incorporation of 5 wt% PDP effectively blurred the PA10,12/POE interface due to PDP's role as a compatibilizer. This phenomenon is attributed to the formation of intermolecular hydrogen bonds, as evidenced by Fourier Transform Infrared Spectroscopy (FTIR) analysis. Further investigation, using differential scanning calorimetry (DSC), elucidated the crystallization thermodynamics and kinetics of the resulting binary PA10,12/POE and ternary PA10,12/POE/PDP composites. Notably, the crystallization temperature (Tc) was observed to decrease from 163.1 °C in the binary composite to 161.5 °C upon the addition of PDP. Increasing the PDP content to 10% led to a further reduction in Tc to 159.5 °C due to PDP's capacity to slow down crystallization. Consequently, the ternary composite of PA10,12/POE/PDP (92/3/5 wt%) demonstrated a synergistic improvement in mechanical properties, with an elongation at break of 579% and a notch impact strength of 61.54 kJ/m2. This represents an approximately eightfold increase over the impact strength of unmodified PA10,12. Therefore, our work provides the potential of PDP as a compatibilizer to develop nylon composites with enhanced stiffness and toughness.

Recyclability of Post-Consumer Polystyrene at Pilot Scale: Comparison of Mechanical and Solvent-Based Recycling Approaches.

Solvent-based and mechanical recycling technology approaches were compared with respect to each process's decontamination efficiency. Herein, post-consumer polystyrene (PS) feedstock was recycled by both technologies, yielding recycled PS resins (rPS). The process feedstock was subjected to four recycling cycles in succession to assess the technology perennity. The physico-chemical and mechanical properties of the rPS were then evaluated to discern the advantages and drawbacks of each recycling approach. The molecular weight of the mechanically recycled resin was found to decrease by 30% over the reprocessing cycles. In contrast, the solvent-base recycling technology yielded a similar molecular weight regarding the feedstock. This consistency in the rPS product is critical for consumer applications. Further qualitative and quantitative analyses on residual organic compounds and inorganic and particulate contaminants were investigated. It was found that the solvent-based technology is very efficient for purifying deeply contaminated feedstock in comparison to mechanical recycling, which is limited to well-cleaned and niche feedstocks.

Generation of Tough, Stiff Polylactide Nanocomposites through the In Situ Nanofibrillation of Thermoplastic Elastomer.

Polylactide (PLA) resins are among the most desirable biopolymers due to their biobased and compostable nature, excellent stiffness, and tensile strength. However, the widespread application of PLA has long been hindered by its inherent brittleness. While multiple routes have been successfully developed for the toughening of PLA, this toughening has always come at the cost of compromising the stiffness and strength of the matrix. In this work, we report a robust and scalable method for the development of PLA nanocomposites with an unprecedented combination of stiffness and toughness. Using the in situ nanofibrillation technique, we generated PLA composites containing nanofibrils of thermoplastic polyester elastomer (TPEE). Due to the high aspect ratio of these nanofibrils, they form physically percolated networks at low weight fractions (∼2.8 wt %) which dramatically change the mechanical behavior of the material. We found that, upon network formation, the material transitions from brittle to ductile behavior, dramatically increasing its toughness with only a marginal decrease in Young's modulus. We investigate the peculiar rheological behavior and crystallization kinetics of these blends, and propose an extension of the critical ligament thickness mechanism, wherein intrinsic toughening arises at the fiber-matrix interface in the presence of entangled elastomer networks.

Controlling stereocomplex crystal morphology in poly(lactide) through chain alignment.

The incorporation of poly(d-lactide) (PDLA) to form stereocomplex crystallites (SCs) within a poly(l-lactide) (PLLA) matrix is among the most effective strategies in overcoming PLLA's numerous drawbacks. However, high concentrations of PDLA (>3 wt%) are required to improve PLLA's crystallization kinetics and melt strength, which is undesirable owing to PDLA's high cost. In this study, we use chain alignment as a levier to tune stereocomplex superstructure morphology to overcome these limitations. Herein, PLLA/PDLA blends were manufactured using an environmentally friendly and low-cost single step spunbond fibrillation process, yielding microfibers stretched to diameters of 5-20 µm. During this stretching process, PLLA and PDLA chains are aligned along the flow direction. SCs subsequently formed in situ upon heating, dramatically improving crystallization kinetics, melt elasticity, and tensile performance compared with neat PLLA and non-stretched blend analogues, even with low PDLA content (<3 wt%). These improvements were attributed to topological variations in SC superstructures caused by alignment of PLLA and PDLA chains. The application of chain alignment in tuning SC superstructure morphology is ubiquitous in fibrillation processes.

Tailoring Multifunctional and Lightweight Hierarchical Hybrid Graphene Nanoplatelet and Glass Fiber Composites.

In this work, hybrid polypropylene (PP)-based composites reinforced with graphene nanoplatelets (GnPs) and glass fiber (GF) were fabricated by injection molding to elucidate how the hybrid approach can produce synergistic effects capable of achieving properties and functionalities not possible in biphasic composites. Synergism between the reinforcements translated to improved mechanical performance, which was attributed to the chemically and/or electrostatically assembled hierarchical structure that facilitates load transfer at the interface while simultaneously tailoring the crystalline microstructure of the matrix by inducing transcrystallization and ß-crystal formation. It was demonstrated that there exists an optimal concentration of 0.5 wt % GnP, producing the greatest mechanical properties and synergistic effect, corresponding to the highest degree of crystallinity (∼6% greater than Neat PP) and peak formation of ß-crystals within the PP matrix. The greatest synergistic effect was found to be ∼52 and ∼39% for the specific tensile strength and flexural strength, respectively. The same optimal concentration of GnPs was found to produce the highest synergistic effect for thermal conductivity of ∼68% due to the volume exclusion effect induced by the GFs combined with the higher crystallinity of the microstructure, promoting the formation of thermally conductive pathways. Ultimately, the mechanisms contributing to the synergistic effect presented in this work can be used to maximize the performance of hybrid composite systems, giving them the potential to be tailored for a variety of high-performance industrial applications to meet the rising demands for ultra-strong, thermally conductive, and lightweight materials.

Determination of CO2 solubility in semi-crystalline polylactic acid with consideration of rigid amorphous fraction.

Due to phase heterogeneity in semi-crystalline polymers, accurate determination of gas solubility has been a challenge. In this regard, PLA/CO2 was used as a case study to investigate the parameters governing formation of the rigid amorphous fraction (RAF) and its effect on the gas sorption behavior of the polymer. Six samples with different degrees of RAF were prepared through varying PLA tacticity and thermal history. Then, a gravimetric method involving a magnetic suspension balance and an in-house PVT visualization system was employed to experimentally determine the CO2 solubility at 70 °C under a pressure of 4.5 MPa. Furthermore, a theoretical CO2 solubility was calculated based on the Simha-Somcynski equation of state and was used in conjunction with the two-phase and three-phase models to describe the phase dependency of the gas solubility. The conventional two-phase model that considered the bulk amorphous phase consistently over-approximated the CO2 solubility compared to the measured data. On the other hand, the three-phase model that distinguished the rigid and the mobile amorphous phases well represented the experimental result. The analysis yielded CO2 solubility coefficients of 0.0375 ggas/gpoly for the RAF and 0.0817 ggas/gpoly for the mobile counterpart.

Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma.

Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC.

Telavancin versus vancomycin for hospital-acquired pneumonia due to gram-positive pathogens.

BACKGROUND: Telavancin is a lipoglycopeptide bactericidal against gram-positive pathogens. METHODS: Two methodologically identical, double-blind studies (0015 and 0019) were conducted involving patients with hospital-acquired pneumonia (HAP) due to gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA). Patients were randomized 1:1 to telavancin (10 mg/kg every 24 h) or vancomycin (1 g every 12 h) for 7-21 days. The primary end point was clinical response at follow-up/test-of-cure visit. RESULTS: A total of 1503 patients were randomized and received study medication (the all-treated population). In the pooled all-treated population, cure rates with telavancin versus vancomycin were 58.9% versus 59.5% (95% confidence interval [CI] for the difference, -5.6% to 4.3%). In the pooled clinically evaluable population (n = 654), cure rates were 82.4% with telavancin and 80.7% with vancomycin (95% CI for the difference, -4.3% to 7.7%). Treatment with telavancin achieved higher cure rates in patients with monomicrobial S. aureus infection and comparable cure rates in patients with MRSA infection; in patients with mixed gram-positive/gram-negative infections, cure rates were higher in the vancomycin group. Incidence and types of adverse events were comparable between the treatment groups. Mortality rates for telavancin-treated versus vancomycin-treated patients were 21.5% versus 16.6% (95% CI for the difference, -0.7% to 10.6%) for study 0015 and 18.5% versus 20.6% (95% CI for the difference, -7.8% to 3.5%) for study 0019. Increases in serum creatinine level were more common in the telavancin group (16% vs 10%). CONCLUSIONS: The primary end point of the studies was met, indicating that telavancin is noninferior to vancomycin on the basis of clinical response in the treatment of HAP due to gram-positive pathogens.

Two-Dimensional Correlation Analysis of iPP Bead Foaming Thermal Features Modeled by Fast Scanning Calorimetry.

The bead foaming of semicrystalline polymers is a complex thermal process involving the formation of multiple crystalline populations, which serve the dual purposes of ensuring the structural integrity of beads while also allowing bead sintering at the interface. The quality of this "double melting peak" structure is determined by the temperature and duration of the isothermal treatment of the beads as well as the quenching rate following the isotherm. Currently, the intricacies of the quenching process are not very well-known due to the challenge of replicating these rapid cooling rates in a laboratory setting. Fast-scanning calorimetry was used to reproduce these conditions for isotactic polypropylene (iPP), revealing optimal quenching rates for the bead foaming of iPP. We further probed these thermal features using two-dimensional correlation analysis as a tool to understand the dynamics, interdependence, and relative contributions of multiple thermal events such as glass transition, mesophase formation, cold crystallization, and melting in response to the perturbation of the quenching rate.

Targeting the Fibroblast Growth Factor Receptor (FGFR) in Advanced Cholangiocarcinoma: Clinical Trial Progress and Future Considerations.

Landmark molecular profiling efforts have identified multiple targetable alterations in cholangiocarcinoma. Among the molecular-driven subsets of cholangiocarcinoma, targeting the fibroblast growth factor receptor (FGFR) has shown promise and represents the first targeted therapy to be approved in treatment-refractory, advanced cholangiocarcinoma. In this review, we provide an up-to-date overview of the clinical development of FGFR inhibitors in advanced cholangiocarcinoma. We review the FGFR pathway and discuss emerging issues including resistance to FGFR inhibitors. We end with a discussion on future considerations to optimize the potential of this class of therapeutics in advanced cholangiocarcinoma.

Improved Cell Morphology and Surface Roughness in High-Temperature Foam Injection Molding Using a Long-Chain Branched Polypropylene.

Long-chain branched polypropylene (LCB PP) has been used extensively to improve cell morphologies in foaming applications. However, most research focuses on low melt flow rate (MFR) resins, whereas foam production methods such as mold-opening foam injection molding (MO-FIM) require high-MFR resins to improve processability. A systematic study was conducted comparing a conventional linear PP, a broad molecular weight distribution (BMWD) linear PP, and a newly developed BMWD LCB PP for use in MO-FIM. The effects of foaming temperature and molecular architecture on cell morphology, surface roughness, and mechanical properties were studied by utilizing two chemical blowing agents (CBAs) with different activation temperatures and varying packing times. At the highest foaming temperatures, BMWD LCB PP foams exhibited 887% higher cell density, 46% smaller cell sizes, and more uniform cell structures than BWMD linear PP. Linear PP was found to have a surface roughness 23% higher on average than other resins. The BMWD LCB PP was found to have increased flexural modulus (44%) at the cost of decreased toughness (-88%) compared to linear PP. The branched architecture and high molecular weight of the BMWD LCB PP contributed to improved foam morphologies and surface quality in high-temperature MO-FIM conditions.

Tuning High and Low Temperature Foaming Behavior of Linear and Long-Chain Branched Polypropylene via Partial and Complete Melting.

While existing foam studies have identified processing parameters, such as high-pressure drop rate, and engineering measures, such as high melt strength, as key factors for improving foamability, there is a conspicuous absence of studies that directly relate foamability to material properties obtained from fundamental characterization. To bridge this gap, this work presents batch foaming studies on one linear and two long-chain branched polypropylene (PP) resins to investigate how foamability is affected by partial melting (Method 1) and complete melting followed by undercooling (Method 2). At temperatures above the melting point, similar expansion was obtained using both foaming procedures within each resin, while the PP with the highest strain hardening ratio (13) exhibited the highest expansion ratio (45 ± 3). At low temperatures, the foamability of all resins was dramatically improved using Method 2 compared to Method 1, due to access to lower foaming temperatures (<150 °C) near the crystallization onset. Furthermore, Method 2 resulted in a more uniform cellular structure over a wider temperature range (120-170 °C compared to 155-175 °C). Overall, strong extensional hardening and low onset of crystallization were shown to give rise to foamability at high and low temperatures, respectively, suggesting that both characteristics can be appropriately used to tune the foamability of PP in industrial foaming applications.

Development of alginate and gelatin-based pleural and tracheal sealants.

Pleural and tracheal injuries remain significant problems, and an easy to use, effective pleural or tracheal sealant would be a significant advance. The major challenges are requirements for adherence, high strength and elasticity, dynamic durability, appropriate biodegradability, and lack of cell or systemic toxicity. We designed and evaluated two sealant materials comprised respectively of alginate methacrylate and of gelatin methacryloyl, each functionalized by conjugation with dopamine HCl. Both compounds are cross-linked into easily applied as pre-formed hydrogel patches or as in situ hydrogels formed at the wound site utilizing FDA-approved photo-initiators and oxidants. Material testing demonstrates appropriate adhesiveness, tensile strength, burst pressure, and elasticity with no significant cell toxicity in vitro assessments. Air-leak was absent after sealant application to experimentally-induced injuries in ex-vivo rat lung and tracheal models and in ex vivo pig lungs. Sustained repair of experimentally-induced pleural injury was observed for up to one month in vivo rat models and for up to 2 weeks in vivo rat tracheal injury models without obvious air leak or obvious toxicities. The alginate-based sealant worked best in a pre-formed hydrogel patch whereas the gelatin-based sealant worked best in an in situ formed hydrogel at the wound site thus providing two potential approaches. These studies provide a platform for further pre-clinical and potential clinical investigations. STATEMENT OF SIGNIFICANCE: Pneumothorax and pleural effusions resulting from trauma and a range of lung diseases and critical illnesses can result in lung collapse that can be immediately life-threatening or result in chronic leaking (bronchopleural fistula) that is currently difficult to manage. This leads to significantly increased morbidity, mortality, hospital stays, health care costs, and other complications. We have developed sealants originating from alginate and gelatin biomaterials, each functionalized by methacryloylation and by dopamine conjugation to have desired mechanical characteristics for use in pleural and tracheal injuries. The sealants are easily applied, non-cytotoxic, and perform well in vitro and in vivo model systems of lung and tracheal injuries. These initial proof of concept investigations provide a platform for further studies.

Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma.

Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almost 4 years after treatment with NeoVax, a long-peptide vaccine targeting up to 20 personal neoantigens per patient ( NCT01970358 ). All patients were alive and six were without evidence of active disease. We observed long-term persistence of neoantigen-specific T cell responses following vaccination, with ex vivo detection of neoantigen-specific T cells exhibiting a memory phenotype. We also found diversification of neoantigen-specific T cell clones over time, with emergence of multiple T cell receptor clonotypes exhibiting distinct functional avidities. Furthermore, we detected evidence of tumor infiltration by neoantigen-specific T cell clones after vaccination and epitope spreading, suggesting on-target vaccine-induced tumor cell killing. Personal neoantigen peptide vaccines thus induce T cell responses that persist over years and broaden the spectrum of tumor-specific cytotoxicity in patients with melanoma.

Tunable Tensile Properties of Polypropylene and Polyethylene Terephthalate Fibrillar Blends through Micro-/Nanolayered Extrusion Technology.

Fiber-reinforcement is a well-established technique to enhance the tensile properties of polymer composites, which is achieved via changing the reinforcing material concentration and orientation. However, the conventional method can be costly and may lead to poor compatibility issues. To overcome these challenges, we demonstrate the use of micro-/nanolayer (MNL) extrusion technology to tune the mechanical properties of polypropylene (PP)/polyethylene terephthalate (PET) fibrillar blends. PET nanofibers-in-PP microfiber composites, with 3, 7, and 15 wt.% PET, are first prepared using a spunbond system to induce high aspect-ratio PET nanofibers. The PP/PET fibers are then reprocessed in an MNL extrusion system and subjected to shear and extensional flow fields in the channels of the uniquely designed layer multipliers. Increasing the mass flow rate and number of multipliers is shown to orient the PET nanofibers along the machine direction (MD), as confirmed via scanning electron microscopy. Tensile tests reveal that up to a 45% and 46% enhancement in elastic modulus and yield strength are achieved owing to the highly aligned PET nanofibers along the MD under strongest processing conditions. Overall, the range of tensile properties obtained using MNL extrusion implies that the properties of fiber-reinforced composites can be further tuned by employing this processing technique.

Highly expanded fine-cell foam of polylactide/polyhydroxyalkanoate/nano-fibrillated polytetrafluoroethylene composites blown with mold-opening injection molding.

To manufacture entirely biodegradable polylactic acid (PLA) foam with a high expansion ratio and a fine-cell structure, we attempted to design economically viable material recipe as well as the injection foam molding (FIM) process. It is well-known that PLA foam featuring high expansion and fine cells is challenging to achieve on FIM technique due to its intrinsically low melt strength. To overcome the inferior foaming characteristics of PLA in this study, nano-fibrils of polytetrafluoroethylene (PTFE) were added expecting an increase of molecular chain entanglements. Another bio-based biodegradable polymer, polyhydroxyalkanoate (PHA) was also blended with PLA to improve the impact strength of the final foams. High-pressure FIM process combined with mold-opening technique was performed to make highly expanded PLA foams with varied material recipes. A constant amount (0.6 wt%) of supercritical nitrogen was injected into FIM system and uniformly mixed with various polymer compositions. The gas-laden melt was injected into the mold cavity to create the foamed PLA samples. Finally, we could demonstrate that it is clearly feasible to manufacture entirely biodegradable PLA foams having a high expansion ratio and a desirable cellular structure using an advanced FIM process.

Enhanced Foamability with Shrinking Microfibers in Linear Polymer.

Strain hardening has important roles in understanding material structures and polymer processing methods, such as foaming, film forming, and fiber extruding. A common method to improve strain hardening behavior is to chemically branch polymer structures, which is costly, thus preventing users from controlling the degree of behavior. A smart microfiber blending technology, however, would allow cost-efficient tuning of the degree of strain hardening. In this study, we investigated the effects of compounding polymers with microfibers for both shear and extensional rheological behaviors and characteristics and thus for the final foam morphologies formed by batch physical foaming with carbon dioxide. Extensional rheometry showed that compounding of in situ shrinking microfibers significantly enhanced strain hardening compared to compounding of nonshrinking microfibers. Shear rheometry with linear viscoelastic data showed a greater increase in both the loss and storage modulus in composites with shrinking microfibers than in those with nonshrinking microfibers at low frequencies. The batch physical foaming results demonstrated a greater increase in the cell population density and expansion ratio with in situ shrinking microfibers than with nonshrinking microfibers. The enhancement due to the shrinkage of compounded microfibers decreasing with temperature implies that the strain hardening can be tailored by changing processing conditions.