Rajesh G. Krishnan

Exploring the resilience potentials of a responsive team managing clinical deterioration: A systems analysis

Shalini Ganasan, Maneesh Kumar, David Slater, Rajesh G. Krishnan et autres

Clinically deteriorating patients require timely care to prevent harm. This study examines how a responsive team delivers resilient care via the Rapid Response System (RRS) by analysing the four resilience potentials (anticipating, monitoring, responding, and learning). Using an integrated Systems Thinking for …

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Phase I multi-center clinical and biomarker study of the dual-action androgen receptor inhibitor ONCT-534

Matthew R. Chrostek, James Robinson, Rajesh G. Krishnan, Evan Y. Yu et autres

ONCT-534 is a dual-action androgen receptor inhibitor (DAARI) that combines AR antagonism and degradation via N-terminal domain binding, additionally targeting AR splice variants. In this study patients received ONCT-534 daily ranging from 40 to 1200 mg. The primary objectives were safety and …

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Desymmetrization of meso -Anhydride Enabled Enantioselective Synthesis of (−)-7-(Bromomethylene)-3-amidobicyclo[2.2.1]heptane-2-carboxamide, a Scaffold for Divergent Drug Discovery Synthesis

Jianqing Li, Subramaniam Krishnananthan, Daniel Smith, Chetan Padmakar Darne et autres

An enantioselective synthesis (>99% ee) of (−)-(1 R, 2 S, 3 R, 4 R,Z )-7-(bromomethylene)- N -(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2,2,2-trifluoroacetamido)bicyclo[2.2.1]heptane-2-carboxamide ((−)- 1 ), a scaffold for divergent drug discovery synthesis, has been developed. The synthesis employed dimethyl(phenyl)silyl moiety as a “masked” hydroxy group and started …

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EXTH-103. A prototype mRNA LNP neoantigen vaccine remodels the tumour microenvironment of a syngeneic model of glioblastoma

Shannon Snelling, Joanna Pyczek, Xueqing Lun, Varsha Thoppey Manoharan et autres

Abstract Despite significant advances in understanding the biology of glioblastoma (GBM), the disease remains fatal within 15 months of diagnosis. Emerging immunotherapies including vaccines targeting somatic alterations hold promise but need to address challenges including the highly immunosuppressive GBM tumour microenvironment which …

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TMIC-120. Investigating EGFRvIII mRNA LNP vaccine-induced re-programming of the GBM TME using the 10x Genomics Visium HD platform

Varsha Thoppey Manoharan, Shannon Snelling, Gurveer Gill, Robert Nechanitzky et autres

Abstract Glioblastoma (GBM) is a lethal brain tumor refractory to standard therapies, highlighting the need for alternative treatments. Immunotherapies, particularly cancer vaccines targeting neoantigens, offer a compelling approach to enhance anti-tumor immunity. To this end, we developed a preclinical mRNA lipid nanoparticle …

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Type I interferon limits central nervous system autoimmunity by modulating the microRNA-21–FOXO1 axis in pathogenic T helper 17 cells

Johnna Francis Varghese, Mai Fujiwara, Amrendra K. Ajay, Lucien P. Garo et autres

IFN-β, a type I interferon, has been used as a first-line therapy for patients with multiple sclerosis (MS) for more than 30 years; however, the cellular and molecular basis of its therapeutic efficacy remains unclear. Here, we first used experimental autoimmune encephalomyelitis …

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Development of a Multigram Preparation of Optically Pure (−)-7-(Bromomethylene)-3-amidobicyclo[2.2.1]heptane-2-carboxamide BMT-395137, a Versatile Scaffold for Divergent Drug Discovery Synthesis

Jianqing Li, Daniel Smith, Lyndon A. M. Cornelius, Subramaniam Krishnananthan et autres

This paper describes the development of a synthetic route for the multigram synthesis of (−)-(1 R,2 S,3 R,4 R, Z )-7-(bromomethylene)- N -(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2,2,2-trifluoroacetamido)bicyclo[2.2.1]heptane-2-carboxamide ((−) -14, BMT-395173), a versatile scaffold for divergent drug discovery synthesis. This new process begins with readily available commercial …

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SARS-CoV-2 spike antibody and T cell response in MS patients on high efficacy therapies post vaccine

Shrishti Saxena, Alena Zhirova, Rajesh G. Krishnan, Brian C. Healy et autres

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Development of a scalable synthesis of RORγt inverse agonist, BMT-399150

Roshan Y. Nimje, Premsai Rai Neithnadka, Sivakumar Ganesan, Prakasam Kuppusamy et autres

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Nasal anti-CD3 monoclonal antibody ameliorates traumatic brain injury, enhances microglial phagocytosis and reduces neuroinflammation via IL-10-dependent Treg–microglia crosstalk

Saef Izzy, Taha Yahya, Omar Albastaki, Hadi Abou‐El‐Hassan et autres

Neuroinflammation plays a crucial role in traumatic brain injury (TBI), contributing to both damage and recovery, yet no effective therapy exists to mitigate central nervous system (CNS) injury and promote recovery after TBI. In the present study, we found that nasal administration …

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Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy

Wesley Nogueira Brandão, Nimansha Jain, Zhuoran Yin, Kilian L. Kleemann et autres

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role …

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Comparison of a SARS-CoV-2 mRNA booster immunization containing additional antigens to a spike-based mRNA vaccine against Omicron BA.5 infection in hACE2 mice

Jacklyn R. Hurst, Maedeh Naghibosadat, Patrick Budowski, Jun Li et autres

The emergence of SARS-CoV-2 variants presents challenges to vaccine effectiveness, underlining the necessity for next-generation vaccines with multiple antigens beyond the spike protein. Here, we investigated a multiantigenic booster containing spike and a chimeric construct composed of nucleoprotein (N) and membrane (M) …

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