The Characterization of the Th1/Th2 Ratio in Multiple Sclerosis Patients and its Response to a Dietary Supplement Regimen.

INTRODUCTION: Multiple sclerosis (MS) is a debilitating neurodegenerative disease affecting the central nervous system, causing disability and life-threatening complications. The interplay between immune cells and signaling pathways is a topic for investigating novel therapies. Past research has shown how the Th1/Th2 ratio plays a key role in the pathogenesis of MS lesions. Modulating the Th1/Th2 ratios with an efficacious dietary supplement may improve some of the consequences of MS. METHODS: Participants (n = 15) diagnosed with MS for an average of 12.4 years (standard deviation = 7.4; range = 2, 25) were enrolled in a clinical trial in which they consumed a dietary supplement regimen daily for 12 months. Venous blood was drawn at baseline and 12-month follow-up and peripheral blood mononuclear cells, cytokines, and growth factors were quantified. Infections, physical functioning, and quality of life were also assessed at baseline and 12 months. RESULTS: The IL-2/IL-10 and IFN-γ/IL-10 ratios were significantly higher than those of the healthy adults, and while only IFN-γ/IL-10 increased significantly at 12 months, all ratios other than IFN-γ/TNF-α increased over the course of the intervention. The decrease in yeast infections was inversely correlated with IL-2/TNF-α and IFN-γ/TNF-α. Significant improvements in physical functioning and quality of life correlated with changes in the Th1/Th2 ratios in response to the dietary supplement regimen. CONCLUSIONS: The results show that dietary supplementation somewhat impacted the Th1/Th2 ratios over the course of the intervention (toward more Th1 dominance), and those changes were related to various clinical improvements of the participants' symptoms in cognitive, motor, and psychosocial dimensions.

Pan-cancer Genomic Analysis of AXL Mutations Reveals a Novel, Recurrent, Functionally Activating AXL W451C Alteration Specific to Myxofibrosarcoma.

Myxofibrosarcoma (MFS) is a common soft tissue sarcoma of the elderly that typically shows low tumor mutational burden, with mutations in TP53 and in genes associated with cell cycle checkpoints ( RB1 , CDKN2A ). Unfortunately, no alterations or markers specific to MFS have been identified and, as a consequence, there are no effective targeted therapies. The receptor tyrosine kinase AXL, which drives cellular proliferation, is targetable by new antibody-based therapeutics. Expression of AXL messenger RNA is elevated in a variety of sarcoma types, with the highest levels reported in MFS, but the pathogenic significance of this finding remains unknown. To assess a role for AXL abnormalities in MFS, we undertook a search for AXL genomic alterations in a comprehensive genomic profiling database of 463,546 unique tumors (including 19,879 sarcomas, of which 315 were MFS) interrogated by targeted next-generation DNA and/or RNA sequencing. Notably, the only genomic alterations recurrent in a specific sarcoma subtype were AXL W451C (n = 8) and AXL W450C (n = 2) mutations. The tumors involved predominantly older adults (age: 44 to 81 [median: 72] y) and histologically showed epithelioid and spindle-shaped cells in a variably myxoid stroma, with 6 cases diagnosed as MFS, 3 as undifferentiated pleomorphic sarcoma (UPS), and 1 as low-grade sarcoma. The AXL W451C mutation was not identified in any non-sarcoma malignancy. A review of publicly available data sets revealed a single AXL W451C-mutant case of UPS that clustered with MFS/UPS by methylation profiling. Functional studies revealed a novel activation mechanism: the W451C mutation causes abnormal unregulated dimerization of the AXL receptor tyrosine kinase through disulfide bond formation between pairs of mutant proteins expressing ectopic cysteine residues. This dimerization triggers AXL autophosphorylation and activation of downstream ERK signaling. We further report sarcomas of diverse histologic subtypes with AXL gene amplifications, with the highest frequency of amplification identified in MFS cases without the W451C mutation. In summary, the activating AXL W451C mutation appears highly specific to MFS, with a novel mechanism to drive unregulated signaling. Moreover, AXL gene amplifications and messenger RNA overexpression are far more frequent in MFS than in other sarcoma subtypes. We conclude that these aberrations in AXL are distinct features of MFS and may aid diagnosis, as well as the selection of available targeted therapies.

Microfluidic Sensor Based on Cell-Imprinted Polymer-Coated Microwires for Conductometric Detection of Bacteria in Water.

The rapid, inexpensive, and on-site detection of bacterial contaminants using highly sensitive and specific microfluidic sensors is attracting substantial attention in water quality monitoring applications. Cell-imprinted polymers (CIPs) have emerged as robust, cost-effective, and versatile recognition materials with selective binding sites for capturing whole bacteria. However, electrochemical transduction of the binding event to a measurable signal within a microfluidic device to develop easy-to-use, compact, portable, durable, and affordable sensors remains a challenge. For this paper, we employed CIP-functionalized microwires (CIP-MWs) with an affinity towards E. coli and integrated them into a low-cost microfluidic sensor to measure the conductometric transduction of CIP-bacteria binding events. The sensor comprised two CIP-MWs suspended perpendicularly to a PDMS microchannel. The inter-wire electrical resistance of the microchannel was measured before, during, and after exposure of CIP-MWs to bacteria. A decline in the inter-wire resistance of the sensor after 30 min of incubation with bacteria was detected. Resistance change normalization and the subsequent analysis of the sensor's dose-response curve between 0 to 109 CFU/mL bacteria revealed the limits of detection and quantification of 2.1 × 105 CFU/mL and 7.3 × 105 CFU/mL, respectively. The dynamic range of the sensor was 104 to 107 CFU/mL where the bacteria counts were statistically distinguishable from each other. A linear fit in this range resulted in a sensitivity of 7.35 µS per CFU/mL. Experiments using competing Sarcina or Listeria cells showed specificity of the sensor towards the imprinted E. coli cells. The reported CIP-MW-based conductometric microfluidic sensor can provide a cost-effective, durable, portable, and real-time solution for the detection of pathogens in water.