Preclinical development of a chimeric antigen receptor T cell therapy targeting FGFR4 in rhabdomyosarcoma.

Pediatric patients with relapsed or refractory rhabdomyosarcoma (RMS) have dismal cure rates, and effective therapy is urgently needed. The oncogenic receptor tyrosine kinase fibroblast growth factor receptor 4 (FGFR4) is highly expressed in RMS and lowly expressed in healthy tissues. Here, we describe a second-generation FGFR4-targeting chimeric antigen receptor (CAR), based on an anti-human FGFR4-specific murine monoclonal antibody 3A11, as an adoptive T cell treatment for RMS.

FGFR4-Targeted Chimeric Antigen Receptors Combined with Anti-Myeloid Polypharmacy Effectively Treat Orthotopic Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue cancer in children. Treatment outcomes, particularly for relapsed/refractory or metastatic disease, have not improved in decades. The current lack of novel therapies and low tumor mutational burden suggest that chimeric antigen receptor (CAR) T-cell therapy could be a promising approach to treating RMS.

Solid Tumor Microenvironment Can Harbor and Support Functional Properties of Memory T Cells.

Robust T cell responses are crucial for effective anti-tumor responses and often dictate patient survival. However, in the context of solid tumors, both endogenous T cell responses and current adoptive T cell therapies are impeded by the immunosuppressive tumor microenvironment (TME). A multitude of inhibitory signals, suppressive immune cells, metabolites, hypoxic conditions and limiting nutrients are believed to render the TME non-conducive to sustaining productive T cell responses.

A role of the frontotemporal lobar degeneration risk factor TMEM106B in myelination.

TMEM106B encodes a lysosomal membrane protein and was initially identified as a risk factor for frontotemporal lobar degeneration. Recently, a dominant D252N mutation in TMEM106B was shown to cause hypomyelinating leukodystrophy. However, how TMEM106B regulates myelination is still unclear.

SMCR8 negatively regulates AKT and MTORC1 signaling to modulate lysosome biogenesis and tissue homeostasis.

The intronic hexanucleotide expansion in the C9orf72 gene is one of the leading causes of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), two devastating neurodegenerative diseases. C9orf72 forms a heterodimer with SMCR8 (Smith-Magenis syndrome chromosome region, candidate 8) protein. However, the physiological function of SMCR8 remains to be characterized.

The Interaction Between Progranulin with Sortilin and the Lysosome.

Accumulating evidence suggests that progranulin is essential for proper lysosomal function. Progranulin is a lysosomal resident protein and sortilin has been demonstrated to be the lysosomal trafficking receptor for progranulin. Here we describe the methods used to study the interaction between progranulin and sortilin, as well as the critical role of sortilin in mediating the lysosomal delivery of progranulin.

The interaction between progranulin and prosaposin is mediated by granulins and the linker region between saposin B and C.

The frontotemporal lobar degeneration (FTLD) protein progranulin (PGRN) is essential for proper lysosomal function. PGRN localizes in the lysosomal compartment within the cell. Prosaposin (PSAP), the precursor of lysosomal saposin activators (saposin A, B, C, D), physically interacts with PGRN.

Analytic characterization of biosimilars.

Purpose: The biosimilar development process, comparability for biological agents, and analytic characterization of biosimilars are described.

Summary: Healthcare providers must understand the requirements for biosimilar approval, including the science behind biosimilar development and testing that contributes to the totality of evidence. The foundation of development is to demonstrate that a biosimilar is highly similar to the reference product through analytic characterization.

The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway.

Hexanucleotide repeat expansion in the C9orf72 gene is a leading cause of frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS). Reduced expression of C9orf72 has been proposed as a possible disease mechanism. However, the cellular function of C9orf72 remains to be characterized.

Hyperuricemia and gout in solid-organ transplant: update in pharmacological management.

Hyperuricemia is a common comorbid condition experienced by up to 28% of kidney transplant recipients. These patients are at elevated risk of acute flare-ups of gout because of transplant-specific risk factors such as impaired renal function, chronic contributing pharmacotherapy (eg, calcineurin inhibitors, diuretics), and associated comorbid conditions. After transplant, treatment is often complicated by drug-drug interactions, renal impairment, and toxic effects of drugs with the use of first-line recommended agents.