Measurement precision and evaluation of the diameter profiles of single wool fibers

A recent model of the Single Fiber Analyzer 3001 (SIFAN3001) was firstly employed to obtain the single wool fiber diameter profiles (SfFDPs) at multiple orientations. The results showed that using SIFAN3001 to measure fiber diameter at four orientations for 50 single fibers randomly sub-sampled from each mid-side sample can produce average fiber diameter profiles (AS fFDPs) of fibers within staples. Within the testing regime used, the precision estimates for the total samples were &plusmn;1.3 &micro;m for the mean fiber diameter of staples and 1.4 &micro;m for the average fiber diameter of the AS fFDPs at each scanned step in the diameter profile. The mean diameter ratio (ellipticity) obtained from the four orientations was 1.08&plusmn;0.01, confirming that the Merino wool fibers under review were elliptical rather than circular. The elliptical morphology of wool fibers and the precision of the fiber diameter measurement at each point along a fiber will be considered in the development of a mechanical model of Staple Strength testing.<br /

HER2 chimeric antigen receptor T cell immunotherapy is an effective treatment for diffuse intrinsic pontine glioma

Advance Access date 4 May 2023Background: Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMG) of the thalamus and spinal cord are rare but devastating high-grade glial tumors of childhood with no curative treatment. Despite aggressive treatment attempts the prognosis has remained poor. Chimeric antigen receptor (CAR) T cell therapy has been identified as a promising new approach in the treatment of DMG tumors; however, additional targets are urgently required given known tumor heterogeneity and the prospect of antigen escape of this cancer. Methods: Using cell surface mass spectrometry, we detected high HER2 cell surface protein across a panel of patient-derived DIPG cells, thereby identifying an existing CAR T cell therapy for use in DIPG. Primary human T cells were transduced to express a second-generation HER2 CAR and interrogated for efficacy against patient-derived DIPG cells. Results: HER2 CAR T cells demonstrated potent and antigen-specific cytotoxicity and cytokine secretion when co-cultured with patient-derived DIPG cells. Furthermore, HER2 CAR T cells provided a significant regression in intracranial DIPG xenograft tumors. Conclusions: HER2 CAR T cells are already in clinic development and are well tolerated in pediatric patients. Here we provide strong preclinical evidence for the inclusion of DIPG patients in future pediatric CNS tumor HER2 CAR T cell clinical trials.Stacie S. Wang, Alexander J. Davenport, Melinda Iliopoulos, Hannah E. Hughes-Parry, Katherine A. Watson, Valeria Arcucci, Matthias Mulazzani, David D. Eisenstat, Jordan R. Hansford, Ryan S. Cross, and Misty R. Jenkin

A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections

Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤0.06 g/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibioticinduced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.Mark A. T. Blaskovich ... Abiodun D. Ogunniy ... Darren J. Trott ... et al

Repurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis

The emergence of polymyxin resistance in carbapenem-resistant and extended-spectrum β-lactamase (ESBL)-producing bacteria is a critical threat to human health, and alternative treatment strategies are urgently required. We investigated the ability of the hydroxyquinoline analog ionophore PBT2 to restore antibiotic sensitivity in polymyxin-resistant, ESBL-producing, carbapenem-resistant Gram-negative human pathogens. PBT2 resensitized Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa to last-resort polymyxin class antibiotics, including the less toxic next-generation polymyxin derivative FADDI-287, in vitro. We were unable to select for mutants resistant to PBT2 + FADDI-287 in polymyxin-resistant E. coli containing a plasmid-borne mcr-1 gene or K. pneumoniae carrying a chromosomal mgrB mutation. Using a highly invasive K. pneumoniae strain engineered for polymyxin resistance through mgrB mutation, we successfully demonstrated the efficacy of PBT2 + polymyxin (colistin or FADDI-287) for the treatment of Gram-negative sepsis in immunocompetent mice. In comparison to polymyxin alone, the combination of PBT2 + polymyxin improved survival and reduced bacterial dissemination to the lungs and spleen of infected mice. These data present a treatment modality to break antibiotic resistance in high-priority polymyxin-resistant Gram-negative pathogens.David M.P. De Oliveira, Lisa Bohlmann, Trent Conroy, Freda E.-C. Jen, Arun Everest-Dass, Karl A. Hansford, Raghu Bolisetti, Ibrahim M. El-Deeb, Brian M. Forde, Minh-Duy Phan, Jake A. Lacey, Aimee Tan, Tania Rivera-Hernandez, Stephan Brouwer, Nadia Keller, Timothy J. Kidd, Amanda J. Cork, Michelle J. Bauer, Gregory M. Cook, Mark R. Davies, Scott A. Beatson, David L. Paterson, Alastair G. McEwan, Jian Li, Mark A. Schembri, Mark A. T. Blaskovich, Michael P. Jennings, Christopher A. McDevitt, Mark von Itzstein, Mark J. Walke