fenretinide (RT-101) / reVision Therap - LARVOL DELTA

A PV-Interneuron Selective AAV9 Vector Restores SCN1A Expression and Rescues Phenotypes in a Mouse Model of Dravet Syndrome (AES 2025) - "RT101, an AAV9 vector which expresses dCas9-VP64 selectively within PV interneurons, significantly upregulates SCN1A and significantly improves survival with a reversal of hyperthermia-induced seizure phenotypes in a mouse model of Dravet syndrome. These results provide strong proof-of-concept data supporting the use of PV interneuron-selective gene modulation therapy in Dravet syndrome."

Preclinical • CNS Disorders • Epilepsy • NAV1

Emergence of carbapenem resistant Escherichia coli, Morganella morganii, Providencia rettgeri harboring blaNDM genes in minks from China. (PubMed, Vet Microbiol) - "Among these isolates, only one carried the blaNDM-5 gene, while the remaining six harbored the blaNDM-1 gene and exhibited high levels of meropenem resistance (32-128 µg/mL)...So, the emergence of these antimicrobial resistance genes in minks and their close association with humans and animals is alarming. Our findings highlight the urgent need for further surveillance of bacterial resistance to last-resort antibiotics in the animal settings One Health approach."

Journal

Occurrence and characteristics of extended-spectrum ß-lactamase-producing Escherichia coli in Swiss and imported retail chicken meat. (PubMed, J Glob Antimicrob Resist) - "The contamination with ESBL-EC in retail chicken meat in Switzerland is moderate; nevertheless, domestic and imported chicken meat is a potential vehicle for MDR ESBL-EC and for genes conferring resistance to clinically important antimicrobials including 3rd-generation cephalosporins and fluoroquinolones."

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Antimicrobial Resistance and Molecular Characterization of Escherichia coli from Healthy Chickens in Shandong, China from 2009 to 2014. (PubMed, Foodborne Pathog Dis) - "The isolates exhibited high resistant rates (>95%) to ampicillin, cefotaxime, ciprofloxacin, ceftiofur, and enrofloxacin...This study implied that E. coli isolated from healthy chickens could potentially serve as a reservoir of AMR and ARGs, and significant associations exist among AMR, ARGs, phylogenetic groups, and STs. Our study highlighted the need for routine surveillance of AMR in healthy chickens, and promoting appropriate antibiotic use and implementing regular monitoring of resistance in broilers are crucial for fostering the development of the poultry industry and safeguarding public health."

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CTX-M-55-type ESBL-producing fluoroquinolone-resistant Escherichia coli sequence type 23 repeatedly caused avian colibacillosis in Kagoshima Prefecture, Japan. (PubMed, J Glob Antimicrob Resist) - "APEC is often transferred from hatcheries to farms via healthy chicks, and the prudent use of antimicrobials and careful monitoring of resistant strains on poultry farms and hatcheries are important in preventing the selection and spread of high-risk APEC strains such as CTX-M-55-type ESBL-producing Og78-ST23."

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CTX-M-producing Escherichia coli ST602 carrying a wide resistome in South American wild birds: Another pandemic clone of One Health concern. (PubMed, One Health) - "SNP-based phylogenomic analysis, using an international genome database, revealed genomic relatedness (19-363 SNP differences) of GP188 with livestock and poultry strains, and genomic relatedness (61-318 differences) of UNB7 with environmental, human and livestock strains (Table S1), whereas phylogeographical analysis confirmed successful expansion of ST602 as a global clone of One Health concern. In summary, our results support that ESBL-producing E. coli ST602 harboring a wide resistome and virulome have begun colonizing wild birds in South America, highlighting a potential new reservoir of critical priority pathogens."

Journal

Vorinostat and fenretinide synergize in preclinical models of T-cell lymphoid malignancies via reactive oxygen species (AACR 2018) - P2; "Pan-histone deacetylase (HDAC) inhibitors vorinostat and belinostat, and class I specific HDAC inhibitor romidepsin have achieved FDA registration as 2nd line therapies for peripheral and/or cutaneous T-cell lymphomas. Like romidepsin, vorinostat combined with fenretinide achieved synergistic activity in preclinical models of TCLMs, but not in non-malignant cells, via a novel molecular mechanism. As vorinostat is an oral agent and not a PGP substrate it may have advantages in such combination therapy. These data support conducting a clinical trial of vorinostat combined with fenretinide in relapsed and refractory TCLMs."

Preclinical • Cutaneous T-cell Lymphoma • Indolent Lymphoma • Peripheral T-cell Lymphoma

Spread and Molecular Characteristics of Enterobacteriaceae Carrying fosA-Like Genes from Farms in China. (PubMed, Microbiol Spectr) - "In this study, we aimed to investigate the occurrence and molecular characteristics of fosfomycin-resistant Enterobacteriaceae isolates from pig, chicken and pigeon farms in Guangxi Province of China...Importantly, E. coli ST602 and ST2599 carrying fosA3 or fosA7.5 from food animals had high similarity to E. coli isolates from humans, suggesting that fosA-like genes can be transmitted to humans through the food chain, thus posing a serious threat to public health. Therefore, the prevalence of fosA-like genes isolated from animals should be further monitored."

Journal

Genomic Analysis of Acinetobacter baumannii Isolates Carrying OXA-23 and OXA-58 Genes from Animals Reveals ST1 and ST25 as Major Clonal Lineages. (PubMed, Antibiotics (Basel)) - "In conclusion, OXA-23 and OXA-58 were linked with ST1 and ST25, two globally distributed lineages in humans. The suggested transmission of certain lineages within and among VCs together with the acquisition of AbaR islands hints at a successful dissemination of multidrug-resistant strains in the VC environment."

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Co-occurrence of mcr-2 and mcr-3 genes on chromosome of multidrug-resistant Escherichia coli isolated from healthy individuals in Thailand. (PubMed, Int J Antimicrob Agents) - "The aim of this study was to characterize three strains of colistin-resistant E. coli isolated from feces samples of healthy individuals in Thailand...Since all these bacteria were isolated from healthy individuals and the identified STs have been found in a variety of origins, all these clones may serve as reservoir for horizontal and vertical transmission of mcr genes. Strategic action plans to control and prevent the spread of mcr genes are urgently needed."

Journal

Pembrolizumab for Early Triple-Negative Breast Cancer. (PubMed, N Engl J Med) - P3; "Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. (Funded by Merck Sharp & Dohme [a subsidiary of Merck]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.)."

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From farm to fork: colistin voluntary withdrawal in Portuguese farms reflected in decreasing occurrence of mcr-1-carrying Enterobacteriaceae from chicken meat. (PubMed, Environ Microbiol) - "This study supports colistin withdrawal potential efficacy in poultry production and highlights both poultry-production chain as a source of mcr-1 and the risk of foodborne transmission to poultry-meat consumers. Finally, in the antibiotic reduction/replacement context, other potential co-selective pressures (e.g., metals-Cu as feed additives) need to be further understood to guide concerted, effective and durable actions under "One Health" perspective."

Journal • Infectious Disease • Pneumonia

[VIRTUAL] Diversity of Sequence Types & Impact of Fitness Cost Among Carbapenem-resistant Acinetobacter baumannii Isolates (WMF 2021) - "All carbapenem-resistant isolates have either blaOXA-23 (n=14) of which six are also in possession of blaGES-11, or blaNDM-1 (n=2). Further research is necessary to understand the underlying dynamics affecting the spread of polyclonal carbapenem-resistant A. baumannii isolates in Libya."

Complement-mediated Rare Disorders • Infectious Disease

Molecular mechanistic and in vivo efficacy studies of Fn14-targeted fusion constructs containing human granzyme B (AACR 2018) - "These results, in combination with previous in vitro and in vivo studies, demonstrate that the completely human MRT-101 construct is a selective, highly potent, non-toxic and effective antigen-driven drug with significant potential for the treatment of Fn-14 positive tumors that acts through a new and unique mechanism of action. Research supported by Mirata Biopharma LLC and conducted, in part, by the Clayton Foundation for Research."

Preclinical • Triple Negative Breast Cancer

Dihydroceramide increase precedes golgi dispersal, pro-survival autophagy, ER stress, and UPR in fenretinide + safingol treated neuroblastoma cells (AACR 2018) - "Delineation of response pathways allowed the identification of mefloquine and ixazomib as new potential co-drugs to synergize 4-HPRS. Confirmatory studies in NB xenografts are in progress. Intravenous fenretinide is currently in a Phase 2 trial in adult refractory/relapsed Peripheral T-Cell Lymphoma."

IO Biomarker • PARP Biomarker • Neuroendocrine Tumor • Peripheral T-cell Lymphoma

Phase 2 Study to Determine if RTB101 Reduces the Severity of COVID-19 in Older Adults Residing in Nursing Homes (clinicaltrials.gov) - P2; N=550; Recruiting; Sponsor: Restorbio Inc.; Phase classification: P3 ➔ P2

Clinical • Phase classification • Infectious Disease • Novel Coronavirus Disease

CAF-1 and Rtt101p function within the replication-coupled chromatin assembly network to promote H4 K16ac, preventing ectopic silencing. (PubMed, PLoS Genet) - "This CAF-1-dependent pathway required the cullin Rtt101p, but was functionally distinct from an alternate pathway involving Rtt101p-dependent ubiquitination of histone H3 and the chromatin assembly factor Rtt106p. A major implication from this work is that cells have the inherent ability to create different chromatin modification patterns during DNA replication via differential processing and deposition of histones by distinct chromatin assembly pathways within the network."

Journal • Targeted Protein Degradation

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"Best of de AHA avec deux experts @PresidentCNCH @FranckAlbert101 @Dr_Walid_AMARA https://t.co/XKk9CWbwXM" (@CNCHcollege)

[VIRTUAL] FENRETINIDE (4-HPR), AN ORPHAN NUCLEAR RECEPTOR NR4A1 MODULATOR AMELIORATES PORTAL PRESSURE AND REDUCES LIVER FIBROSIS PRE CLINICALLY: A NOVEL KEY REGULATOR OF HEPATIC STELLATE CELL ACTIVATION (AASLD 2020) - "This novel study demonstrates that Fenretinide ameliorates rise in portal pressure and significantly reduces hepatic fibrosis. NR4A1 is a novel modulator of HSC activation and inactive form of this transcription factor is highly expressed in cirrhotic livers. Modulation of NR4A1 activity may be a promising avenue to treat cirrhosis with PHT."

Fibrosis • Gastroenterology • Hepatology • Hypertension • Immunology • Liver Cirrhosis • Portal Hypertension • CCL4 • COL1A1 • NR4A1 • PDGFRB

The role of essential fatty acids in cystic fibrosis and normalizing effect of fenretinide. (PubMed, Cell Mol Life Sci) - "Finally, a synthetic retinoid called fenretinide (N-(4-hydroxy-phenyl) retinamide) was shown to be able to correct the pro-inflammatory imbalance of PUFAs in CF. Therefore, its pharmacological actions and clinical potential are briefly discussed as well."

Journal • Review • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Inflammation • Respiratory Diseases

Vorinostat and fenretinide synergize in preclinical models of T-cell lymphoid malignancies. (PubMed, Anticancer Drugs) - "We have previously shown fenretinide synergized with the class I HDAC inhibitor romidepsin in preclinical models of TCLMs. As vorinostat is an oral agent and not a P-glycoprotein substrate it may have advantages in such combination therapy. These data support conducting a clinical trial of vorinostat combined with fenretinide in relapsed and refractory TCLMs."

Journal • Preclinical • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma

Phase 3 Study to Determine if RTB101 Reduces the Severity of COVID-19 in Older Adults Residing in Nursing Homes (clinicaltrials.gov) - P3; N=550; Recruiting; Sponsor: Restorbio Inc.; Trial completion date: Oct 2020 ➔ Jan 2021; Trial primary completion date: Sep 2020 ➔ Dec 2020

Clinical • Trial completion date • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease

"@ILFORDPhoto pan 400 #blackandwhitephotography with a 1966 Minolta SRT 101 #film @konicaminolta" (@IChalhoub)

Fenretinide reduces angiogenesis by downregulating CDH5, FOXM1 and eNOS genes and suppressing microRNA-10b. (PubMed, Mol Biol Rep) - "Besides, a significant decrease was observed in the levels of some angiogenesis-inducing genes, CDH5 (P < 0.001), FOXM1 (P < 0.001) and eNOS (P < 0.01 and P < 0.001) in endothelial cells treated with fenretinide. Our results have shown that fenretinide exhibited anti-angiogenic activity through the down-regulation of CDH5, FOXM1 and eNOS genes, and suppression of miR-10b."

Journal • Oncology • Solid Tumor