Keratin–cinnamon essential oil biocomposite fibrous patches for skin burn care

Keratin based electrospun fibres containing cinnamon essential oil are highly antioxidant and antibacterial, and promote reduced tissue inflammation after skin burns

Binding and Internalization in Receptor‐Targeted Carriers: The Complex Role of CD44 in the Uptake of Hyaluronic Acid‐Based Nanoparticles (siRNA Delivery)

This paper is about the actual role of CD44 in the perspective of a hyaluronic acid (HA)-based, targeted therapy. CD44 is the main HA receptor: it is present both in healthy and cancerous cells, but is overexpressed in many carcinomas, with important roles in their initiation and malignancy. This, and its endocytic capacities, have encouraged the use of HA to design CD44-targeting carriers. Here, we have used HA-decorated nanoparticles to deliver a siRNA payload to a panel of human cells comprising both tumoral (AsPC-1, PANC-1, HT-29, HCT-116) and non-tumoral (fibroblasts, differently polarized THP-1 macrophages, HUVEC) lines; we have evaluated in a comparative and quantitative fashion the initial binding of the nanoparticles, their internalization rate and the eventual silencing efficiency (cyclophilin B (PPIB) gene).A first result of our study is that, in general, tumoral cells internalized faster and experienced higher silencing than non-tumoral cells. This result is promising as it suggests that, when in a tumor environment, HA nanocarriers may have limited off-target effects.A more far-reaching result comes from the quantitative analysis of the inter-relation between the four parameters of our study (i.e. total CD44 expression, extent of HA cell surface binding, internalization rate and silencing efficiency). Our experiments showed no correlation between extent of binding (an early event) and any of the other parameters. On the contrary, silencing correlated well both with the speed of the internalization process and also with CD44 expression. This study, therefore, confirms on one hand that HA-based carriers can perform a targeted therapeutic action, but on the other it suggests that this may not be due to the selective binding of a cell surface marker, but possibly to a later recognition event leading to selective internalization

Conjugates of Cryptophycin and RGD or isoDGR Peptidomimetics for Targeted Drug Delivery

Borbély AN, Figueras Agustí E, Martins A, et al. Conjugates of Cryptophycin and RGD or isoDGR Peptidomimetics for Targeted Drug Delivery. ChemistryOpen. 2019;8(6):737-742.RGD-cryptophycin and isoDGR-cryptophycin conjugates were synthetized by combining peptidomimetic integrin ligands and cryptophycin, a highly potent tubulin-binding antimitotic agent across lysosomally cleavable Val-Ala or uncleavable linkers. The conjugates were able to effectively inhibit binding of biotinylated vitronectin to integrin alphavbeta3, showing a binding affinity in the same range as that of the free ligands. The antiproliferative activity of the novel conjugates was evaluated on human melanoma cells M21 and M21-L with different expression levels of integrin alphavbeta3, showing nanomolar potency of all four compounds against both cell lines. Conjugates containing uncleavable linker show reduced activity compared to the corresponding cleavable conjugates, indicating efficient intracellular drug release in the case of cryptophycin-based SMDCs. However, no significant correlation between the in vitro biological activity of the conjugates and the integrin alphavbeta3 expression level was observed, which is presumably due to a non-integrin-mediated uptake. This reveals the complexity of effective and selective alphavbeta3 integrin-mediated drug delivery

Truncating Variants in RFC1 in Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome

INTRODUCTION: Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome (CANVAS) is an autosomal recessive neurodegenerative disease characterized by adult onset and slowly progressive sensory neuropathy, cerebellar dysfunction, and vestibular impairment. In most cases, the disease is caused by biallelic (AAGGG)n repeat expansions in the second intron of the Replication Factor Complex subunit 1 (RFC1). However, a small number of cases with typical CANVAS do not carry the common biallelic repeat expansion. The objective of this study was to expands the genotypic spectrum of CANVAS by identifying point mutations in RFC1 coding region associated with this condition. METHODS: Fifteen individuals diagnosed with CANVAS and carrying only one heterozygous (AAGGG)n expansion in RFC1 underwent WGS or WES to test for the presence of a second variant in RFC1 or other unrelated gene. To assess the impact of truncating variants on RFC1 expression we tested the level of RFC1 transcript and protein on patients' derived cell lines. RESULTS: We identified seven patients from five unrelated families with clinically defined CANVAS carrying a heterozygous (AAGGG)n expansion together with a second truncating variant in trans in RFC1, which included: c.1267C>T (p.Arg423Ter), c.1739_1740del (p.Lys580SerfsTer9), c.2191del (p.Gly731GlufsTer6) and c.2876del (p.Pro959GlnfsTer24). Patient fibroblasts containing the c.1267C>T (p.Arg423Ter) or c.2876del (p.Pro959GlnfsTer24) variants demonstrated nonsense-mediated mRNA decay and reduced RFC1 transcript and protein. DISCUSSION: Our report expands the genotype spectrum of RFC1 disease. Full RFC1 sequencing is recommended in cases affected by typical CANVAS and carrying monoallelic (AAGGG)n expansions. Also, it sheds further light on the pathogenesis of RFC1 CANVAS as it supports the existence of a loss of function mechanism underlying this complex neurodegenerative condition

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients