Designing students\u27 first clinical day of orientation

This webinar is designed to help clinical faculty prepare for their first clinical day to prepare students to be safe and prepared for their clinical rotation

Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer

Many prostate cancers relapse after initial chemotherapy treatment. Combining molecular and chemotherapy together with encapsulation of drugs in nanocarriers provides effective drug delivery and toxicity reduction. We developed core shell lipid-polymer hybrid nanoparticles (CSLPHNPs) with poly (lactic-co-glycolic acid) (PLGA) core and lipid layer containing docetaxel and clinically used inhibitor of sphingosine kinase 1 (SK1) FTY720 (fingolimod). We show for the first time that FTY720 (both free and in CSLPHNPs) re-sensitizes castrate resistant prostate cancer cells and tumors to docetaxel, allowing a four-fold reduction in effective dose. Our CSLPHNPs showed high serum stability and a long shelf life. CSLPHNPs demonstrated a steady uptake by tumor cells, sustained intracellular drug release and in vitro efficacy superior to free therapies. In a mouse model of human prostate cancer, CSLPHNPs showed excellent tumor targeting and significantly lower side effects compared to free drugs, importantly, reversing lymphopenia induced by FTY720. Overall, we demonstrate that nanoparticle encapsulation can improve targeting, provide low off-target toxicity and most importantly reduce FTY720-induced lymphopenia, suggesting its potential use in clinical cancer treatment

Animal species identification in historical parchments by CWT-CNN classifier applied to UV-Visible-NIR spectroscopic data

Identification of animal species in medieval parchment manuscripts is highly relevant in cultural heritage studies. Usually, species identification is performed with slightly invasive methods. In this study, we propose a contactless methodology based on reflectance spectrophotometry (ultraviolet–visible–near-infrared) and a machine learning approach for data analysis. Spectra were recorded from both historical and modern parchments crafted from calf, goat, and sheep skins. First, a continuous wavelet transform was performed on the spectral data as a preprocessing step. Then, a semisupervised neural network with a 2-component architecture was applied to the preprocessed data. The network architecture chosen was CWT-CNN (continuous wavelet transform–convolutional neural network), which, in this case, is composed of a convolutional autoencoder and a single-layer dense network classifier. Species classification on holdout historical parchments was attained with a mean accuracy of 79%. The analysis of Shapley additive explanations values highlighted the main spectral ranges responsible for species discrimination. Our study shows that the animal species signature is encoded in a wide band-convoluted wavelength range rather than in specific narrow bands, implying a complex phenotype expression that influences the light scattering by the material. Indeed, the overall skin composition, in both micro- and macroscopic physicochemical properties, is relevant for animal identification in parchment manuscripts

MIASTENIJA GRAVIS

Naziv bolesti miastenija gravis dolazi od grčke i latinske riječi, a znači „teška mišićna slabost“. To je rijetka bolest. Spada u grupu neuromuskularnih bolesti i u grupu autimunih bolesti, gdje organizam stvara protutijela protiv receptora na mišićnim stanicama i tako priječi i remeti prijenos podražaja sa živaca na mišiće. Mišići se brzo umaraju i javlja se slabost mišića. Tipično za ovu bolest je da slabost oscilira u toku dana, pa je snaga ujutro bolja, a u večernjim satima manja, odnosno da su simptomi nakon odmora manji, a pojačavaju se kod napora. Bolest se javlja u svim životnim dobima, od djetinjstva, mladosti do visoke starosti, najčešće u 3. I 4. desetljeću, a u zadnje vrijeme je dijagnosticirana veća učestalost bolesnika starije životne dobi

Secondary ion mass spectrometry, a powerful tool for revealing ink formulations and animal skins in medieval manuscripts

XRD diffractograms, ToF-SIMS MS and ATR-FTIR spectrometry spectra, recorded on inks on historical parchments (pigments, inked areas). ToF-SIMS and ATR-FTIR spectra from non-inked areas of the parchments. See the read-me file for complete description of the files and structure, and the main manuscript for the methodology. The PCA algorithm code is also provided. Article abstract : Book production by medieval scriptoria have gained growing interest in recent studies. In this context, identifying ink compositions and parchment animal species from illuminated manuscripts is of great importance. Here, we introduce time-of-flight secondary ion mass spectrometry (ToF-SIMS) as a non-invasive tool to identify both inks and animal skins in manuscripts, at the same time. For this purpose, both positive and negative ion spectra in inked and non-inked areas were recorded. Chemical compositions of pigments (decoration) or black inks (text) were determined by searching for characteristic ion mass peaks. Animal skins were identified by data processing of raw ToF-SIMS spectra using Principal Component Analysis (PCA). In illuminated manuscripts from 15th c. to 16th c., malachite (green), azurite (blue), cinnabar (red) inorganic pigments, as well as iron-gall black ink, were identified. Carbon black and indigo (blue) organic pigments were also identified. Animal skins were identified in modern parchments of known animal species by a two-steps PCA procedure. We believe the proposed method will find extensive application in material studies of medieval manuscripts, as it is non-invasive, highly sensitive and able to identify both inks and animal skins at the same time, even from traces of pigments and tiny scanned areas.In-house PCA algorithm requires python. ToF-SIMS raw data require SurfaceLab software. ATR-FTIR raw data (.0) can be read with free-licence software (Fityk). XRD diffractograms are directly exported in .txt from .xyz files. Funding provided by: Namur Institute of Structured Matter, University of NamurCrossref Funder Registry ID: http://dx.doi.org/10.13039/501100023393Award Number:Analytical and data processing methods can be found in the manuscript

Pembrolizumab plus Olaparib in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort A Study

Metastatic castration-resistant prostate cancer; Olaparib; PembrolizumabCáncer de próstata metastásico resistente a la castración; Olaparib; PembrolizumabCàncer de pròstata metastàtic resistent a la castració; Olaparib; PembrolizumabBackground Pembrolizumab and olaparib have shown single-agent activity in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC). Objective To evaluate the efficacy and safety of pembrolizumab plus olaparib in mCRPC. Design, setting, and participants Cohort A of the phase 1b/2 KEYNOTE-365 study enrolled patients with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 mo of screening. Intervention Pembrolizumab 200 mg intravenously every 3 wk plus olaparib 400-mg capsule or 300-mg tablet orally twice daily. Outcome measurements and statistical analysis The primary endpoints were safety, confirmed prostate-specific antigen (PSA) response rate, and objective response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, by blinded independent central review. The secondary endpoints included radiographic progression-free survival (rPFS) and overall survival (OS). Results and limitations Of 104 enrolled patients, 102 were treated. The median age was 70 yr (interquartile range [IQR], 65–76), and 59 patients (58%) had measurable disease as per RECIST v1.1. The median time from the first dose to database cutoff was 24 mo (IQR, 22–47). The confirmed PSA response rate was 15%. The confirmed ORR was 8.5% (five partial responses) for patients with measurable disease. The median rPFS was 4.5 mo (95% confidence interval [CI], 4.0–6.5) and median OS was 14 mo (95% CI, 10.4–18.2). Clinical activity was consistent across the programmed death ligand 1 (PD-L1)-positive and homologous recombination repair mutation subgroups. Treatment-related adverse events (TRAEs) occurred in 93 patients (91%). Grade 3–5 TRAEs occurred in 49 patients (48%). Six deaths (5.9%) were due to adverse events; two (myocardial infarction and unknown cause) were attributed to treatment. Limitations of the study include the single-arm design. Conclusions Pembrolizumab plus olaparib had a safety profile consistent with the profiles of the individual agents and demonstrated antitumor activity in previously treated patients with molecularly unselected, docetaxel-pretreated mCRPC

Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis : a genome-wide association study

Myasthenia gravis is a chronic autoimmune disease characterized by autoantibody-mediated interference of signal transmission across the neuromuscular junction. We performed a genome-wide association study (GWAS) involving 1,873 patients diagnosed with acetylcholine receptor antibody-positive myasthenia gravis and 36,370 healthy individuals to identify disease-associated genetic risk loci. Replication of the discovered loci was attempted in an independent cohort from the UK Biobank. We also performed a transcriptome-wide association study (TWAS) using expression data from skeletal muscle, whole blood, and tibial nerve to test the effects of disease-associated polymorphisms on gene expression. We discovered two signals in the genes encoding acetylcholine receptor subunits that are the most common antigenic target of the autoantibodies: a GWAS signal within the cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit (CHRNB1) gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at PTPN22, HLA-DQA1/HLA-B, and TNFRSF11A were confirmed. Subgroup analyses demonstrate that early-and late-onset cases have different genetic risk factors. Genetic correlation analysis confirmed a genetic link between myasthenia gravis and other autoimmune diseases, such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Finally, we applied Priority Index analysis to identify potentially druggable genes/proteins and pathways. This study provides insight into the genetic architecture underlying myasthenia gravis and demonstrates that genetic factors within the loci encoding acetylcholine receptor subunits contribute to its pathogenesis.Peer reviewe

Geoheritage and Geodiversity Assessment Framework for Practical Application to Geoconservation of the Coromandel Peninsula, New Zealand

Life on Earth is influenced by abiotic nature, providing resources and shelter for living beings on the Earth. Hence, this part of nature should be well treated and protected. Study of geodiversity can facilitate education about abiotic nature and processes occurring around us. Geodiversity as a discipline is relatively young, but worthy of more attention and development. As well as a stand-alone scientific field, it may draw on other scientific disciplines in understanding the connection between natural materials and abiotic processes. Our research explores the paradigm of geodiversity and defines its meanings and elements. This will help us make the first steps in developing a methodology of assessment of geodiversity for any type of territory on our planet. This article provides a conceptual framework, which is based on detailed description of the methodology. Additionally, it will build a better understanding about the connections between abiotic and biotic factors in the environment, and human society within that environment. Here we provide a globally applicable method, using the Coromandel Peninsula as a case study. Coromandel Peninsula is in the north part of the North Island of New Zealand. This environmentally diverse and ecologically rich region is shaped by interactions between volcanic activities and terrestrial/shallow marine sedimentation, potentially providing a rich geodiversity. A systematic table defining the elements of geodiversity is the main product of our research, and we demonstrate how these elements can be assessed in a simple way to define values of facets of abiotic nature, ultimately resulting in a holistic, integrated, and complete view of our unliving environment. This study is an initial step in building a common system for assessment of geodiversity of any part of our world using the most available data and records as a foundational database.fals

FGFR1 and WT1 are markers of human prostate cancer progression

BACKGROUND: Androgen-independent prostate adenocarcinomas are responsible for about 6% of overall cancer deaths in men. METHODS: We used DNA microarrays to identify genes related to the transition between androgen-dependent and androgen-independent stages in the LuCaP 23.1 xenograft model of prostate adenocarcinoma. The expression of the proteins encoded by these genes was then assessed by immunohistochemistry on tissue microarrays (TMA) including human prostate carcinoma samples issued from 85 patients who had undergone radical prostatectomy. RESULTS: FGFR1, TACC1 and WT1 gene expression levels were associated with the androgen-independent stage in xenografts and human prostate carcinoma samples. MART1 protein expression was correlated with pT2 tumor stages. CONCLUSION: Our results suggest that each of these four genes may play a role, or at least reflect a stage of prostate carcinoma growth/development/progression