Self-assembling nanoparticles for delivery of miR-603 and miR-221 in glioblastoma as a new strategy to overcome resistance to temozolomide.

Glioblastoma (GBM) is a highly aggressive brain cancer with poor clinical outcome. Unfortunately, chemotherapy with temozolomide (TMZ) has a limited efficacy due to resistance mainly attributed to O6-methylguanine methyl transferase (MGMT) activity. Recently, miR-603 and miR-221 have been identified to target MGMT, thus improving the efficacy of temozolomide (TMZ) in the treatment of GBM.

Opposite sides of the same coin: syndrome evidence, child abuse and the wrongful conviction of Peter Hugh McGregor Ellis.

Introduction of evidence relating to the now-discredited behavioural-science syndrome known as 'child sexual abuse accommodation syndrome' in demonstrates the danger of syndrome reasoning in judicial fact finding. Comparable syndrome evidence is still used in the Family Court in the form of 'parental alienation syndrome'. should sound the death knell for all forensic applications of unreliable syndrome reasoning in the courts.

The Total Mass of Per- and Polyfluoroalkyl Substances (PFASs) in California Cosmetics.

Cosmetics make up one of the consumer product categories most widely known to contain perfluoroalkyl and polyfluoroalkyl substances (PFASs), including precursors to perfluorooctanoic acid (PFOA) and other perfluoroalkyl acids (PFAAs). Because of the way cosmetics are used, most of the PFASs present in these products are likely to reach wastewater treatment plants (WWTPs), which suggests that cosmetics may contribute significantly to the load of PFOA and other PFASs at WWTPs. However, the majority of PFASs present as intentional ingredients in cosmetics cannot be quantified with the available analytical methods.

Mesenchymal Stromal Cell Delivery Via Cardiopulmonary Bypass Provides Neuroprotection in a Juvenile Porcine Model.

Oxidative/inflammatory stresses due to cardiopulmonary bypass (CPB) cause prolonged microglia activation and cortical dysmaturation, thereby contributing to neurodevelopmental impairments in children with congenital heart disease (CHD). This study found that delivery of mesenchymal stromal cells (MSCs) via CPB minimizes microglial activation and neuronal apoptosis, with subsequent improvement of cortical dysmaturation and behavioral alteration after neonatal cardiac surgery. Furthermore, transcriptomic analyses suggest that exosome-derived miRNAs may be the key drivers of suppressed apoptosis and STAT3-mediated microglial activation.

Impact of C- and N-terminal protection on the stability, metal chelation and antimicrobial properties of calcitermin.

The main limitation to the use of antimicrobial peptides (AMPs) as regular drugs, against antibiotic and antifungal resistance, mainly relates to their rapid degradation by proteolytic enzymes. The introduction of suitable structural changes in the peptide chain can make the peptide less susceptible to the action of proteases, thus overcoming this problem. To improve the plasma stability of calcitermin, a metal-chelating AMP present in the human respiratory tract and investigated in the present study, C- and/or N- terminal modifications have been introduced in the native sequence.

Fluorescent nanodiamonds as innovative delivery systems for MiR-34a replacement in breast cancer.

Nanodiamonds are innovative nanocrystalline carbon particles able to deliver chemically conjugated miRNAs. In oncology, the use of miRNA-based therapies may represent an advantage, based on their ability to simultaneously target multiple intracellular oncogenic targets. Here, nanodiamonds were tested and optimized to deliver miR-34a, a miRNA playing a key role in inhibiting tumor development and progression in many cancers.

A Call to Assess the Impacts of Course-Based Undergraduate Research Experiences for Career and Technical Education, Allied Health, and Underrepresented Students at Community Colleges.

Course-based undergraduate research experiences (CUREs) have the potential to impact student success and reduce barriers for students to participate in undergraduate research. Literature review has revealed that, while CUREs are being implemented at both community colleges (CCs) and bachelor's degree-granting institutions, there are limited published studies on the differential impacts CUREs may have on CC students in allied health programs, career and technical education, and nursing pathways (termed "workforce" in this essay). This essay summarizes proposed outcomes of CURE instruction and explores possible reasons for limited reporting on outcomes for CC and workforce students.

MiR-182-3p targets TRF2 and impairs tumor growth of triple-negative breast cancer.

The telomeric repeat-binding factor 2 (TRF2) is a telomere-capping protein that plays a key role in the maintenance of telomere structure and function. It is highly expressed in different cancer types, and it contributes to cancer progression. To date, anti-cancer strategies to target TRF2 remain a challenge.

CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder.

Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS.

Hybrid Self-Assembling Nanoparticles Encapsulating Zoledronic Acid: A Strategy for Fostering Their Clinical Use.

Self-assembling nanoparticles (SANPs) promise an effective delivery of bisphosphonates or microRNAs in the treatment of glioblastoma (GBM) and are obtained through the sequential mixing of four components immediately before use. The self-assembling approach facilitates technology transfer, but the complexity of the SANP preparation protocol raises significant concerns in the clinical setting due to the high risk of human errors during the procedure. In this work, it was hypothesized that the SANP preparation protocol could be simplified by using freeze-dried formulations.

Host diversification is concurrent with linear motif evolution in a Mastadenovirus hub protein.

Over one hundred Mastadenovirus types infect seven orders of mammals. Virus-host coevolution may involve cospeciation, duplication, host switch and partial extinction events. We reconstruct Mastadenovirus diversification, finding that while cospeciation is dominant, the other three events are also common in Mastadenovirus evolution.

Anti-tumoural activity of the G-quadruplex ligand pyridostatin against BRCA1/2-deficient tumours.

The cells with compromised BRCA1 or BRCA2 (BRCA1/2) function accumulate stalled replication forks, which leads to replication-associated DNA damage and genomic instability, a signature of BRCA1/2-mutated tumours. Targeted therapies against BRCA1/2-mutated tumours exploit this vulnerability by introducing additional DNA lesions. Because homologous recombination (HR) repair is abrogated in the absence of BRCA1 or BRCA2, these lesions are specifically lethal to tumour cells, but not to the healthy tissue.

Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects.

Background: Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) is one of the most effective single-drug systemic therapy against advanced HCC, but the identification of novel combination regimens for a continued improvement in overall survival is a big challenge. Recent studies highlighted the crucial role of focal adhesion kinase (FAK) in HCC growth.

Impact of Cardiopulmonary Bypass on Neurogenesis and Cortical Maturation.

Objective: Neurodevelopmental delays and frontal lobe cortical dysmaturation are widespread among children with congenital heart disease (CHD). The subventricular zone (SVZ) is the largest pool of neural stem/progenitor cells in the postnatal brain. Our aim is to determine the effects of cardiopulmonary bypass (CPB) on neurogenesis and cortical maturation in piglets whose SVZ development is similar to human infants.

FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids towards cholangiocarcinoma.

Background & Aims: About 15% of intrahepatic cholangiocarcinomas (iCCAs) express fibroblast growth factor receptor 2 (FGFR2) fusion proteins (FFs), usually alongside mutational inactivation of TP53, CDKN2A or BAP1. In FFs, FGFR2 residues 1-768 fuse to sequences encoded by a diverse array of partner genes (>60) causing oncogenic FF activation. While FGFR-specific tyrosine kinase inhibitors (F-TKI) provide clinical benefit in FF iCCA, responses are partial and/or limited by resistance mechanisms, such as the V565F substitution in the FGFR2 gatekeeper residue.

FrustratometeR: an R-package to compute local frustration in protein structures, point mutants and MD simulations.

Summary: Once folded, natural protein molecules have few energetic conflicts within their polypeptide chains. Many protein structures do however contain regions where energetic conflicts remain after folding, i.e.

Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study.

Background: HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity.

NGOME-Lite: Proteome-wide prediction of spontaneous protein deamidation highlights differences between taxa.

Asparagines in proteins deamidate spontaneously, which changes the chemical structure of a protein and often affects its function. Current prediction algorithms for asparagine deamidation require a structure as an input or are too slow to be applied at a proteomic scale. We present NGOME-Lite, a new version of our sequence-based predictor for spontaneous asparagine deamidation that is faster by over two orders of magnitude at a similar degree of accuracy.

Hybrid lipid self-assembling nanoparticles for brain delivery of microRNA.

Hybrid self-assembling nanoparticles (SANPs) have been previously designed as novel drug delivery system that overcomes stability issues following long-term storage and with an easy scale-up. This system has been successfully used to deliver anionic-charged agents, e.g.

Harnessing Omics Approaches on Advanced Preclinical Models to Discovery Novel Therapeutic Targets for the Treatment of Metastatic Colorectal Cancer.

Metastatic colorectal cancer (mCRC) remains challenging because of the emergence of resistance mechanisms to anti-epidermal growth factor receptor (EGFR) therapeutics, so more effective strategies to improve the patients' outcome are needed. During the last decade, the application of a multi-omics approach has contributed to a deeper understanding of the complex molecular landscape of human CRC, identifying a plethora of drug targets for precision medicine. Target validation relies on the use of experimental models that would retain the molecular and clinical features of human colorectal cancer, thus mirroring the clinical characteristics of patients.

Circulating miRNAs in Small Extracellular Vesicles Secreted by a Human Melanoma Xenograft in Mouse Brains.

The identification of liquid biomarkers remains a major challenge to improve the diagnosis of melanoma patients with brain metastases. Circulating miRNAs packaged into tumor-secreted small extracellular vesicles (sEVs) contribute to tumor progression. To investigate the release of tumor-secreted miRNAs by brain metastasis, we developed a xenograft model where human metastatic melanoma cells were injected intracranially in nude mice.

TRF2 and VEGF-A: an unknown relationship with prognostic impact on survival of colorectal cancer patients.

Background: Colorectal cancer is one of most common tumors in developed countries and, despite improvements in treatment and diagnosis, mortality rate of patients remains high, evidencing the urgent need of novel biomarkers to properly identify colorectal cancer high-risk patients that would benefit of specific treatments. Recent works have demonstrated that the telomeric protein TRF2 is over-expressed in colorectal cancer and it promotes tumor formation and progression through extra-telomeric functions. Moreover, we and other groups evidenced, both in vitro on established cell lines and in vivo on tumor bearing mice, that TRF2 regulates the vascularization mediated by VEGF-A.

From single gene analysis to single cell profiling: a new era for precision medicine.

Molecular profiling of DNA and RNA has provided valuable new insights into the genetic basis of non-malignant and malignant disorders, as well as an increased understanding of basic mechanisms that regulate human disease. Recent technological advances have enabled the analyses of alterations in gene-based structure or function in a comprehensive, high-throughput fashion showing that each tumor type typically exhibits distinct constellations of genetic alterations targeting one or more key cellular pathways that regulate cell growth and proliferation, evasion of the immune system, and other aspects of cancer behavior. These advances have important implications for future research and clinical practice in areas as molecular diagnostics, the implementation of gene or pathway-directed targeted therapy, and the use of such information to drive drug discovery.