PMEL (Premelanosome Protein)

Thus, knockout of the Pmel17 gene in melanoma cells alters pigmentation, vascularization, and oxygenation of tumors. These parameters are crucial for both tumor progression and therapeutic response.

Our results showed that Pmel and Pmel-Cd70-/- T cells exhibited significant yet equivalent efficacy in inhibiting tumor growth, indicating that potential CD27-CD70 interaction within adoptive T cells does not affect T-cell immunotherapy in this tumor model. This work is informative for designing adoptive T-cell therapy for cancer treatment.

Our comprehensive proteomic analysis highlights the potential role of neutrophils in LAM pathogenesis, with MMP8 and other proteases as potential drivers of lung destruction. PMEL and the 6-protein LAMScore are promising biomarkers for LAM, especially in patients with low VEGF-D levels. The high precision and reproducibility, the wide array of analytes measured, and the lowering costs of proteomics platforms indicate that in the future, LAM diagnosis could rely on clinically approved custom analyte panels without lung biopsy.

Nonetheless, we have observed a negative correlation between LDH levels and PFS, and a negative correlation between S100B levels and lymphocyte counts. The results of the study indicate that combinations of biomarkers, rather than any single biomarker alone, possess the highest clinical application potential, which urges further research on larger patient groups.

This study elucidates the mechanism linking polymyxin B-induced pigmentation and autophagy, demonstrating that polymyxin B causes the accumulation of PMEL17 within autophagosomes and inhibits its autophagic degradation, suggesting that autophagosomes may transform into melanosomes. These findings further contribute to the theoretical basis for autophagy regulating melanin synthesis, highlighting the multifaceted functions of autophagic proteins beyond degradation within autolysosomes.

Further analysis found that PMEL expression negatively correlated with the reduction rate of TSC-RAMLs after mTORC1 inhibitor treatment (r = -0.50, p = 0.0022), both after 3 months (r = -0.47, p = 0.048) and 6 months of treatment (r = -0.52, p = 0.028). PMEL expression positively correlated with the tumor size of TSC-RAMLs, and inversely with the reduction rate of TSC-RAMLs after mTORC1 inhibitor treatment, which may suggest that PMEL may serve as a predictive biomarker for the efficacy of mTORC1 inhibitor treatment.

As opposed to the normal dendritic localization of melanosomes, the disruption of melanosome matrix generation in NPC1 deficient cells causes an accumulation of immature melanosomes adjacent to the plasma membrane.. Together with the melanosomal localization of NPC1 in wild type cells, these findings suggest that NPC1 is directly involved in tyrosinase transport from the trans-Golgi network (TGN) to melanosomes and melanosome maturation, indicating a novel function for NPC1.

Further, western blot and immunofluorescence analysis suggested that the W104F mutation may cause mild ER retention, possibly associated with early misfolding, and lysosomal misaggregation, thus, reducing functional fibril formation. Our results demonstrate that C-mannosylation of PMEL is required for proper melanosome development by regulating PMEL-derived fibril formation.

To enable temporal gene manipulation in the melanocyte lineage, we established a novel inducible Cre-driver mouse line by targeting an all-in-one tetracycline/doxycycline (Dox)-inducible Cre expression cassette into the Pmel locus (Pmel ), a gene locus preferentially expressed in pigment cells. Therefore, the Pmel mouse line is suitable for assessing gene functions in melanocytes using an in vivo inducible reverse genetics approach. Furthermore, we unexpectedly identified previously unrecognized PMEL-expressing cells in non-pigmentary organs in the mice, suggesting unanticipated functions of PMEL other than melanosome formation.

Cytokines modified with our carbonic anhydrase 2 (CA2)-based cytoDRiVE® drug responsive domain (DRD) were evaluated for control of protein levels with the CA2 ligand, acetazolamide (ACZ). Conclusions While IL-15 drives expansion and persistence of cytoTIL15 TM cells without IL-2, adding pleotropic and highly immune-stimulatory members of the IFN, IL-1 or TNF families may provide enhanced efficacy for patients with solid tumors marked by an immunosuppressive TME. Ethics Approval All animal studies were IACUC approved