A systematic comparison of PCA‐based Statistical Process Monitoring methods for high‐dimensional,time‐dependent Processes

High‐dimensional and time‐dependent data pose significant challenges to Statistical Process Monitoring. Most of the high‐dimensional methodologies to cope with these challenges rely on some form of Principal Component Analysis (PCA) model, usually classified as nonadaptive and adaptive. Nonadaptive methods include the static PCA approach and Dynamic Principal Component Analysis (DPCA) for data with autocorrelation. Methods, such as DPCA with Decorrelated Residuals, extend DPCA to further reduce the effects of autocorrelation and cross‐correlation on the monitoring statistics. Recursive Principal Component Analysis and Moving Window Principal Component Analysis, developed for nonstationary data, are adaptive. These fundamental methods will be systematically compared on high‐dimensional, time‐dependent processes (including the Tennessee Eastman benchmark process) to provide practitioners with guidelines for appropriate monitoring strategies and a sense of how they can be expected to perform. The selection of parameter values for the different methods is also discussed. Finally, the relevant challenges of modeling time‐dependent data are discussed, and areas of possible further research are highlighted. © 2016 American Institute of Chemical Engineers AIChE J, 62: 1478–1493, 2016     

Improving dissolution kinetics of pharmaceuticals by fluidized bed impregnation of active pharmaceutical ingredients

Investigational drugs are increasingly becoming less soluble in aqueous media, thus, presenting real challenges during development. Previous work has successfully demonstrated the manufacturing of pharmaceuticals using fluidized bed (FB) impregnation of APIs onto porous carriers. This study demonstrates the usefulness of FB impregnation in formulating poorly soluble drugs. We show that dissolution of Fenofibrate is greatly improved by FB impregnation onto Neusilin^® (Fuji Health Science Inc, Burlington, NJ USA), a synthetic amorphous form of magnesium alumino‐metasilicate. We impregnate Neusilin^® for range of loadings and examine Fenofibrate's physical state. Dissolution of impregnated formulations is drug loading dependent and loadings below 40% show great improvement (decrease) in release time compared to physical blend. Release times are further improved by milling. We also examine feasibility of coimpregnating Fenofibrate with additives and observe stability (1.5 years) of the amorphous form of Fenofibrate inside Neusilin^®. This stabilization significantly improves Fenofibrate's dissolution kinetics, making our formulation comparable to one of the current market formulations, TriCor^® tablets (AbbVie Inc, North Chicago, IL USA). © 2016 American Institute of Chemical Engineers AIChE J, 62: 4201–4214, 2016     

Au/TS‐1 catalyst for propene epoxidation with H2/O2: A novel strategy to enhance stability by tuning charging sequence

For propene epoxidation with H₂ and O₂, the catalytic performance of Au/TS‐1 catalyst is extremely sensitive to preparation parameters of deposition‐precipitation (DP) method. In this work, effect of charging sequence in DP process on catalyst structure and catalytic performance of Au/TS‐1 catalyst is first investigated. For different charging sequences, the compositions of Au complexes (e.g., [AuCl(OH)₃]^?) and pore property of TS‐1 (i.e., with or without H₂O prefilling micropores) could affect the transfer of Au complexes into the micropores, resulting in different Au locations and thus significantly different catalytic performance. Notably, when TS‐1 is first filled with H₂O and then mixed with Au complexes, the reduced Au/TS‐1 catalyst could expose Au nanoparticles on the external surface of TS‐1 and show high stability. The results provide direct evidence showing that micropore blocking is the deactivation mechanism. Based on the results, a simple strategy to design highly stable Au/Ti‐based catalysts is developed. © 2016 American Institute of Chemical Engineers AIChE J, 62: 3963–3972, 2016     

ForceSpinning of polyacrylonitrile for mass production of lithium‐ion battery separators

We present results on the Forcespinning^® (FS) of Polyacrylonitrile (PAN) for mass production of polymer nanofiber membranes as separators for Lithium‐ion batteries (LIBs). Our results presented here show that uniform, highly fibrous mats from PAN produced using Forcespinning^®, exhibit improved electrochemical properties such as electrolyte uptake, low interfacial resistance, high oxidation limit, high ionic conductivity, and good cycling performance when used in lithium ion batteries compared to commercial PP separator materials. This article introduces ForceSpinning^®, a cost effective technique capable of mass producing high quality fibrous mats, which is completely different technology than the commonly used in‐house centrifugal method. This Forcespinning^® technology is thus the beginning of the nano/micro fiber revolution in large scale production for battery separator application. This is the first time to report results on the cycle performance of LIB‐based polymer nanofiber separators made by Forcespinning^® technology. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 132, 42847.     

Platelet lysate and adipose mesenchymal stromal cells on silk fibroin nonwoven mats for wound healing

In this work platelet lysate (PL) and adipose‐derived mesenchymal stromal cells (ASCs) seeded on nonwoven fibroin mats were in vitro and in vivo evaluated for tissue regenerative applications. Nonwoven mats obtained by a large scale water entanglement technique were characterized for their physico‐chemical properties. Results indicated a high purity of fibroin fibers, their stability after sterilization process and appropriate technological properties suitable for tissue engineering. Moreover, the scaffolds in vitro supported adhesion and migration of ASCs and the presence of PL improved the cell proliferation. The products were then applied on epithelial/dermal wounds carried out on the dorsal surface of rabbit: the skin reparative process was solved in 9 days, with a completely restitutio ad integrum of the epithelium in animals treated with PL alone; ASCs did not further improve the wound healing. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 42942.     

Primary Founder Mutations in the PRKDC Gene Increase Tumor Mutation Load in Colorectal Cancer

The clonal composition of a malignant tumor strongly depends on cellular dynamics influenced by the asynchronized loss of DNA repair mechanisms. Here, our aim was to identify founder mutations leading to subsequent boosts in mutation load. The overall mutation burden in 591 colorectal cancer tumors was analyzed, including the mutation status of DNA-repair genes. The number of mutations was first determined across all patients and the proportion of genes having mutation in each percentile was ranked. Early mutations in DNA repair genes preceding a mutational expansion were designated as founder mutations. Survival analysis for gene expression was performed using microarray data with available relapse-free survival. Of the 180 genes involved in DNA repair, the top five founder mutations were in PRKDC (n = 31), ATM (n = 26), POLE (n = 18), SRCAP (n = 18), and BRCA2 (n = 15). PRKDC expression was 6.4-fold higher in tumors compared to normal samples, and higher expression led to longer relapse-free survival in 1211 patients (HR = 0.72, p = 4.4 × 10⁻³). In an experimental setting, the mutational load resulting from UV radiation combined with inhibition of PRKDC was analyzed. Upon treatments, the mutational load exposed a significant two-fold increase. Our results suggest PRKDC as a new key gene driving tumor heterogeneity.     

Novel Therapeutic Opportunities in Neoadjuvant Setting in Urothelial Cancers: A New Horizon Opened by Molecular Classification and Immune Checkpoint Inhibitors

Muscle invasive bladder cancer (MIBC) is a widespread malignancy with a worse prognosis often related to a late diagnosis. For early-stage MIBC pts, a multidisciplinary approach is mandatory to evaluate the timing of neoadjuvant chemotherapy (NAC) and surgery. The current standard therapy is platinum-based NAC (MVAC-methotrexate, vinblastine, doxorubicin, and cisplatin or Platinum–Gemcitabine regimens) followed by radical cystectomy (RC) with lymphadenectomy. However, preliminary data from Vesper trial highlighted that dose-dense NAC MVAC is endowed with a good pathological response but shows low tolerability. In the last few years, translational-based research approaches have identified several candidate biomarkers of NAC esponsiveness, such as ERCC2, ERBB2, or DNA damage response (DDR) gene alterations. Moreover, the recent consensus MIBC molecular classification identified six molecular subtypes, characterized by different sensitivity to chemo- or targeted or immunotherapy, that could open a novel procedure for patient selection and also for neoadjuvant therapies. The Italian PURE-01 phase II Trial extended data on efficacy and resistance to Immune Checkpoint Inhibitors (ICIs) in this setting. In this review, we summarize the most relevant literature data supporting NAC use in MIBC, focusing on novel therapeutic strategies such as immunotherapy, considering the better patient stratification and selection emerging from novel molecular classification.     

Gut Microbiota and Short Chain Fatty Acids: Implications in Glucose Homeostasis

Gut microbiota encompasses a wide variety of commensal microorganisms consisting of trillions of bacteria, fungi, and viruses. This microbial population coexists in symbiosis with the host, and related metabolites have profound effects on human health. In this respect, gut microbiota plays a pivotal role in the regulation of metabolic, endocrine, and immune functions. Bacterial metabolites include the short chain fatty acids (SCFAs) acetate (C2), propionate (C3), and butyrate (C4), which are the most abundant SCFAs in the human body and the most abundant anions in the colon. SCFAs are made from fermentation of dietary fiber and resistant starch in the gut. They modulate several metabolic pathways and are involved in obesity, insulin resistance, and type 2 diabetes. Thus, diet might influence gut microbiota composition and activity, SCFAs production, and metabolic effects. In this narrative review, we discuss the relevant research focusing on the relationship between gut microbiota, SCFAs, and glucose metabolism.     

Total Electron Detachment and Induced Cationic Fragmentation Cross Sections for Superoxide Anion (O2−) Collisions with Benzene (C6H6) Molecules

In this study, novel experimental total electron detachment cross sections for O₂⁻ collisions with benzene molecules are reported for the impact energy range (10–1000 eV), as measured with a transmission beam apparatus. By analysing the positively charged species produced during the collision events, relative total ionisation cross sections were derived in the incident energy range of 160–900 eV. Relative partial ionisation cross sections for fragments with m/z ≤ 78 u were also given in this energy range. We also confirmed that heavier compounds (m/z > 78 u) formed for impact energies between 550 and 800 eV. In order to further our knowledge about the collision dynamics governing the fragmentation of such heavier molecular compounds, we performed molecular dynamics calculations within the framework of the Density Functional Theory (DFT). These results demonstrated that the fragmentation of these heavier compounds strongly supports the experimental evidence of m/z = 39–42, 50, 60 (u) cations formation, which contributed to the broad local maximum in the total ionisation observed from 550 to 800 eV. This work reveals the reactivity induced by molecular anions colliding with hydrocarbons at high energies, processes that can take place in the interstellar medium under various local conditions.     

Design and Characterization of Myristoylated and Non-Myristoylated Peptides Effective against Candida spp. Clinical Isolates

The increasing resistance of fungi to antibiotics is a severe challenge in public health, and newly effective drugs are required. Promising potential medications are lipopeptides, linear antimicrobial peptides (AMPs) conjugated to a lipid tail, usually at the N-terminus. In this paper, we investigated the in vitro and in vivo antifungal activity of three short myristoylated and non-myristoylated peptides derived from a mutant of the AMP Chionodracine. We determined their interaction with anionic and zwitterionic membrane-mimicking vesicles and their structure during this interaction. We then investigated their cytotoxic and hemolytic activity against mammalian cells. Lipidated peptides showed a broad spectrum of activity against a relevant panel of pathogen fungi belonging to Candida spp., including the multidrug-resistant C. auris. The antifungal activity was also observed vs. biofilms of C. albicans, C. tropicalis, and C. auris. Finally, a pilot efficacy study was conducted on the in vivo model consisting of Galleria mellonella larvae. Treatment with the most-promising myristoylated peptide was effective in counteracting the infection from C. auris and C. albicans and the death of the larvae. Therefore, this myristoylated peptide is a potential candidate to develop antifungal agents against human fungal pathogens.