A New Horizon on Knee Osteoarthritis: A Review of Alternative Treatment Modalities

Purpose: The purpose of this review is to determine the effectiveness and utility of alternative knee osteoarthritis treatments in order to assess their clinical applications compared to traditional NSAID and corticosteroid injection therapy. Methods: We analyzed 23 randomized control trials, systematic reviews, and meta analyses to compare the effectiveness of hyaluronic acid (HA), plasma rich protein (PRP) injections, and mesenchymal stem (MSC) cell injections. The individuals used in this study were over 18 years old, had moderate to severe knee osteoarthritis, and had failed at least 1 form of conservative treatment. Quantitative (imaging studies and ROM testing) and qualitative results (pain and quality of life surveys) were analyzed in order to determine the effectiveness of treatment in these individuals. Results: PRP and MSC injections displayed minor improvement in knee cartilage and patient pain questionnaires, while HA was found to only provide benefit when combined with other therapies. Conclusion: Although each method is safe and has been shown to provide benefits in certain circumstances, it is still unclear how much of a benefit these alternative treatments can provide due to the inconsistencies in formulation and timelines between treatments in the studies. More research is needed to understand the efficacy of these alternative treatments. Keywords: plasma rich protein, PRP, hyaluronic acid, HA, mesenchymal stem cell, MSC, knee osteoarthritis treatmen

Enhanced CO2 capture by cupuassu shell-derived activated carbon with high microporous volume

Here, we report the preparation of microporous-activated carbons from a Brazilian natural lignocellulosic agricultural waste, cupuassu shell, by pyrolysis at 500 ºC and KOH activation under different experimental conditions and their subsequent application as adsorbent for CO2 capture. The effect of the KOH:precursor ratio (wt/wt%) and the activation temperature on the porous texture of activated carbons have been studied. The values of specific surface area ranged from 1132 to 2486 m2/g, and the overall micropore volume ranged from 0.73 to 1.02 cm3/g. Carbons activated with 2:1 ratio of KOH and activation temperature of 700 ºC presented a CO2 adsorption at 1 bar of 7.8 and 4.4 mmol/g at 0 °C and 25 ºC, respectively. The isosteric heat of adsorption, Qst, was calculated for all samples by applying the Clausius–Clapeyron approach to CO2 adsorption isotherms at both temperatures. The values of CO2 adsorption capacities are among the highest reported in the literature, especially for activated carbons produced from biomass.The Brazilian agencies Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) are gratefully acknowledged for financial support. JSA acknowledge financial support from MINECO: Projects MAT2016-80285-P, Generalitat Valenciana (PROMETEOII /2014/004) and EU Funding H2020-MSCA-RISE-NanoMed Project

New Chondrosarcoma Cell Lines with Preserved Stem Cell Properties to Study the Genomic Drift During In Vitro/In Vivo Growth

For the cancer genomics era, there is a need for clinically annotated close-to-patient cell lines suitable to investigate altered pathways and serve as high-throughput drug-screening platforms. This is particularly important for drug-resistant tumors like chondrosarcoma which has few models available. Here we established and characterized new cell lines derived from two secondary (CDS06 and CDS11) and one dedifferentiated (CDS-17) chondrosarcomas as well as another line derived from a CDS-17-generated xenograft (T-CDS17). These lines displayed cancer stem cell-related and invasive features and were able to initiate subcutaneous and/or orthotopic animal models. Different mutations in Isocitrate Dehydrogenase-1 (IDH1), Isocitrate Dehydrogenase-2 (IDH2), and Tumor Supressor P53 (TP53) and deletion of Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) were detected both in cell lines and tumor samples. In addition, other mutations in TP53 and the amplification of Mouse Double Minute 2 homolog (MDM2) arose during cell culture in CDS17 cells. Whole exome sequencing analysis of CDS17, T-CDS17, and matched patient samples confirmed that cell lines kept the most relevant mutations of the tumor, uncovered new mutations and revealed structural variants that emerged during in vitro/in vivo growth. Altogether, this work expanded the panel of clinically and genetically-annotated chondrosarcoma lines amenable for in vivo studies and cancer stem cell (CSC) characterization. Moreover, it provided clues of the genetic drift of chondrosarcoma cells during the adaptation to grow conditions

Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial.

The ExteNET trial demonstrated improved invasive disease-free survival (iDFS) with neratinib, an irreversible pan-HER tyrosine kinase inhibitor, versus placebo in patients with human epidermal growth factor receptor 2-positive (HER2+)/hormone receptor-positive (HR+) early-stage breast cancer (eBC). ExteNET was a multicenter, randomized, double-blind, phase III trial of 2840 patients with HER2+ eBC after neoadjuvant/adjuvant trastuzumab-based therapy. Patients were stratified by HR status and randomly assigned 1-year oral neratinib 240 mg/day or placebo. The primary endpoint was iDFS. Descriptive analyses were performed in patients with HR+ eBC who initiated treatment ≤ 1 year (HR+/≤ 1-year) and > 1 year (HR+/> 1-year) post-trastuzumab. HR+/≤ 1-year and HR+/> 1-year populations comprised 1334 (neratinib, n = 670; placebo, n = 664) and 297 (neratinib, n = 146; placebo, n = 151) patients, respectively. Absolute iDFS benefits at 5 years were 5.1% in HR+/≤ 1-year (hazard ratio, 0.58; 95% confidence interval [CI], 0.41-0.82) and 1.3% in HR+/>1-year (hazard ratio, 0.74; 95% CI, 0.29-1.84). In HR+/≤ 1-year, neratinib was associated with a numerical improvement in overall survival (OS) at 8 years (absolute benefit, 2.1%; hazard ratio, 0.79; 95% CI, 0.55-1.13). Of 354 patients in the HR+/≤ 1-year group who received neoadjuvant therapy, 295 had residual disease, and results showed absolute benefits of 7.4% at 5-year iDFS (hazard ratio, 0.60; 95% CI, 0.33-1.07) and 9.1% at 8-year OS (hazard ratio, 0.47; 95% CI, 0.23-0.92). There were fewer central nervous system events with neratinib. Adverse events were similar to those previously reported. Neratinib significantly improved iDFS in the HER2+/HR+/≤ 1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment. Numerical improvements in central nervous system events and OS were consistent with iDFS benefits and suggest long-term benefit for neratinib in this population

USP7 cooperates with NOTCH1 to drive the oncogenic transcriptional program in T-cell leukemia

Purpose: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes. Experimental Design: To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples, and xenograft models. Results: We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. USP7 is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo. Conclusions: These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia