Objective:
To report on safety and effectiveness of subcutaneous cladribine (Litak®) in multiple sclerosis (MS) patients.
Methods:
Litak® was offered to MS-patients irrespective of disease course. ...Litak® 10 mg was administered for 3–4 days during week 1. Based on lymphocyte count at week 4, patients received another 0–3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-hole-peg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidence-of-progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts.
Results:
In all, 208 patients received at least one course of treatment. Age at baseline was 44 (17–72) years and EDSS 0–8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data (n = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data (n = 13) had NEPAD. Of n = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months.
Conclusions:
Litak® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage.
An experimental investigation was conducted using reactive and nonreactive impinging liquids ejected from a single element doublet. The liquid combinations used were nitric acid and hydrazine, nitric ...acid and water, and water and water. Still photographs taken of the impingements were used to study the resulting sprays. A new method is presented for studying the impinging liquids based on the mean droplet diameter in certain regions of the spray. This method provides a way of determining whether or not the liquids are mixing. If the liquids are not mixing, the motion of a representative drop of each liquid is calculated to determine if penetration or separation is occurring. Each liquid combination resulted in mixing except, one nitric acid and hydrazine combination, which resulted in penetration. The nitric acid and hydrazine combination was of particular interest due to the possibility of reactive stream separation occurring. However, no evidence of stream separation was found. A light colored vapor, which is believed to be due to a nonignition reaction, was observed in a few of the nitric acid and hydrazine photographs.
The continuous remodeling of the tumor microenvironment (TME) during prostate tumorigenesis is emerging as a critical event that facilitates cancer growth, progression and drug-resistance. Recent ...advances have identified extensive communication networks that enable tumor-stroma cross-talk, and emphasized the functional importance of diverse, heterogeneous stromal fibroblast populations during malignant growth. Cancer-associated fibroblasts (CAFs) are a vital component of the TME, which mediate key oncogenic events including angiogenesis, immunosuppression, metastatic progression and therapeutic resistance, thus presenting an attractive therapeutic target. Nevertheless, how fibroblast heterogeneity, recruitment, cell-of-origin and differential functions contribute to prostate cancer remains to be fully delineated. Developing our molecular understanding of these processes is fundamental to developing new therapies and biomarkers that can ultimately improve clinical outcomes. In this review, we explore the current challenges surrounding fibroblast identification, discuss new mechanistic insights into fibroblast functions during normal prostate tissue homeostasis and tumorigenesis, and illustrate the diverse nature of fibroblast recruitment and CAF generation. We also highlight the promise of CAF-targeted therapies for the treatment of prostate cancer.
Stem cells reside in specialized microenvironments or niches that balance stem cell proliferation and differentiation.1,2 The extracellular matrix (ECM) is an essential component of most niches, ...because it controls niche homeostasis, provides physical support, and conveys extracellular signals.3–11 Basement membranes (BMs) are thin ECM sheets that are constituted mainly by Laminins, Perlecan, Collagen IV, and Entactin/Nidogen and surround epithelia and other tissues.12 Perlecans are secreted proteoglycans that interact with ECM proteins, ligands, receptors, and growth factors such as FGF, PDGF, VEGF, Hedgehog, and Wingless.13–18 Thus, Perlecans have structural and signaling functions through the binding, storage, or sequestering of specific ligands. We have used the Drosophila ovary to assess the importance of Perlecan in the functioning of a stem cell niche. Ovarioles in the adult ovary are enveloped by an ECM sheath and possess a tapered structure at their anterior apex termed the germarium. The anterior tip of the germarium hosts the germline niche, where two to four germline stem cells (GSCs) reside together with a few somatic cells: terminal filament cells (TFCs), cap cells (CpCs), and escort cells (ECs).19 We report that niche architecture in the developing gonad requires trol, that niche cells secrete an isoform-specific Perlecan-rich interstitial matrix, and that DE-cadherin-dependent stem cell-niche adhesion necessitates trol. Hence, we provide evidence to support a structural role for Perlecan in germline niche establishment during larval stages and in the maintenance of a normal pool of stem cells in the adult niche.
•The Drosophila ovarian niche contains a Perlecan-rich interstitial matrix•Niche cells express and secrete specific Perlecan isoforms•Absence of trol results in aberrant niches containing fewer niche and stem cells•trol regulates DE-cadherin levels in larval and adult niche cells
Tissues host stem cells in niches that normally contain extracellular matrix (ECM). Díaz-Torres et al. identify the ECM molecule Perlecan as an essential component of the ovarian niche in Drosophila. Results reveal the importance of Perlecan for proper niche morphogenesis during pre-adult development and for tissue homeostasis in the adult female.
Serial synchrotron crystallography (SSX) is an emerging technique for static and time‐resolved protein structure determination. Using specifically patterned silicon chips for sample delivery, the ...`hit‐and‐return' (HARE) protocol allows for efficient time‐resolved data collection. The specific pattern of the crystal wells in the HARE chip provides direct access to many discrete time points. HARE chips allow for optical excitation as well as on‐chip mixing for reaction initiation, making a large number of protein systems amenable to time‐resolved studies. Loading of protein microcrystals onto the HARE chip is streamlined by a novel vacuum loading platform that allows fine‐tuning of suction strength while maintaining a humid environment to prevent crystal dehydration. To enable the widespread use of time‐resolved serial synchrotron crystallography (TR‐SSX), detailed technical descriptions of a set of accessories that facilitate TR‐SSX workflows are provided.
The HARE chip and a toolbox of helpful instrumentation for time‐resolved serial synchrotron crystallography are presented.
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