This study provides important insights into how the use of active drug PK assays, coupled with mechanistic follow-up, can inform and enable ongoing benefit/risk assessment for individuals participating in FIH dose-escalation trials. Translational studies that lead to a better understanding of the underlying biology of cognate T- and B-cell interactions, ultimately resulting in ADA development to novel biotherapeutics, are needed.

Our study found that VSV-IFNβ -TYRP1 can be safely administered via intratumoral (IT) and IV routes in a previously treated population of patients with MUM. Although there were no clear objective radiographic responses to VSV-IFNβ-TYRP1, dose-dependent immunogenicity to TYRP1 and other melanoma antigens was seen.

P1, N=12, Active, not recruiting, Mayo Clinic | Trial completion date: Apr 2024 --> Jan 2027 | Trial primary completion date: Apr 2024 --> Jan 2027

P1, N=12, Active, not recruiting, Mayo Clinic | Trial completion date: Apr 2023 --> Apr 2024 | Trial primary completion date: Apr 2023 --> Apr 2024

While OV response alone is not sufficient for clinical benefit, the evidence of epitope spreading is encouraging. Future studies of VSV-IFNb-TYRP1 will evaluate combinations with other therapies.

P1, N=20, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed | Trial completion date: Jan 2023 --> Jul 2022 | Trial primary completion date: Jan 2023 --> Jul 2022

P1, N=72, Suspended, Mayo Clinic | Trial completion date: Mar 2022 --> Apr 2023 | Recruiting --> Suspended | Trial primary completion date: Mar 2022 --> Apr 2023

P1, N=20, Active, not recruiting, Hoffmann-La Roche | N=310 --> 20

P1, N=310, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P1, N=310, Recruiting, Hoffmann-La Roche | Trial completion date: Sep 2023 --> Jan 2023 | Trial primary completion date: Sep 2023 --> Jan 2023

The expression of genes related to melanin synthesis, such as tyrosinase, tyrosinase-related protein-1, tyrosinase-related protein-2, and microphthalmia-associated transcription factor, also supports these phenomena, which means that even in the presence of resveratrol, grape extract will strengthen the function of α-MSH in promoting melanin synthesis. Therefore, these results also provide a point of view for research on cosmetics.

Thus, miR155HG silencing inhibited the malignant biological behavior of OC cells by targeting the miR-155-5p/TYRP1 axis. The present study provides novel insights into the underlying mechanism of OC progression.

Furthermore, salicylic acid treatment suppressed expression of transport complex-associated proteins melanophilin and myosin Va in two UVB-treated melanocytic cell lines, suppressed phagocytosis of fluorescent microspheres by UVB-stimulated human keratinocytes (HaCaT), inhibited protease-activated receptor 2 activation by reducing both Ca release and activation of phosphoinositide 3 kinase/AKT and mitogen-activated protein kinases and induced anti-melanogenic effects in zebrafish. Collectively, these results indicate that salicylic acid within ginseng root can inhibit melanocyte melanogenesis and melanin transport, while also suppressing keratinocyte phagocytic function.

These results indicate that neoantigen-based vaccines are optimized by potentiating IL-2R signaling in CD4 and CD8 neoantigen-reactive T cells by using high-dose mIL-2/CD25, leading to more effective tumor clearance.

Last, THC was formulated into a lecithin based nanoemulsion, and an in vitro Franz diffusion cell study using Strat-M membrane concluded that the nanoemulsion could significantly enhance the membrane permeation compared to the unformatted THC suspension. This research demonstrated the anti-melanogenic benefits of THC on the melanoma and keratinocyte cell models and the topical delivery efficacy could be significantly enhanced using a lecithin based nanoemulsion.

Finally, L-cysteinamide was shown to increase pheomelanin content while decreasing eumelanin and total melanin contents in MNT-1 cells. This study suggests that L-cysteinamide has an optimal structure that can effectively and safely inhibit eumelanin synthesis in MNT-1 cells and HEMs, and will be useful in controlling skin hyperpigmentation.

Treatment of subjects with skin pigmentation with AYC-P-E-containing cream formulations resulted in 3.33%, 7.06%, and 8.68% improvement in the melanin levels at 2, 4, and 8 weeks, respectively. Our findings suggest that AYC-P-E inhibits excessive melanogenesis by activating MEK/ERK and AKT signaling, potentiating its cosmetic applications in hyperpigmentation treatment.

The auraptene has also displayed the anti-melanogenic activity through direct tyrosinase enzyme inhibition (IC of 29.7 µg/ml) and could modulate the expression of major melanogenesis-related genes including tyrosinase, tyrosinase-related protein 1, and dopachrome tautomerase in the murine melanoma cell line. The auraptene from Ferula szowitsiana root exhibited antibacterial, antioxidant, and melanogenesis inhibitory activities.

This compound is also manufactured with epigallocatechin gallate (EGCG) as a substrate and is refined after the enzyme reaction...We also confirmed α-MSH-mediated CREB activities through a luciferase reporter assay, and that the quantities of cAMP were reduced by TSA in the enzyme linked immunosorbent assay (ELISA) results. Based on these findings, TSA should be considered an effective inhibitor of hyperpigmentation.

Collectively, our study demonstrated that PAs are potential tyrosinase inhibitors and have good antimelanoma effects. These findings provide a theoretical support for the application of tyrosinase inhibitors and for further drug development.

Conclusion Our findings indicate that genetic testing should be restricted to Czech patients with melanoma under 50 and with recurrent disease, positive family melanoma or cancer history. Supported by grants: AZV NV18-03-00024, NV19-03-00279, NV16-30954A, SVV2019/260367, PROGRES Q28/LF1No conflict of interest.

Conclusion Our findings indicate that genetic testing should be restricted to Czech patients with melanoma under 50 and with recurrent disease, positive family melanoma or cancer history. Supported by grants: AZV NV18-03-00024, NV19-03-00279, NV16-30954A, SVV2019/260367, PROGRES Q28/LF1No conflict of interest.

Conclusion Our findings indicate that genetic testing should be restricted to Czech patients with melanoma under 50 and with recurrent disease, positive family melanoma or cancer history. Supported by grants: AZV NV18-03-00024, NV19-03-00279, NV16-30954A, SVV2019/260367, PROGRES Q28/LF1No conflict of interest.

Conclusion Our findings indicate that genetic testing should be restricted to Czech patients with melanoma under 50 and with recurrent disease, positive family melanoma or cancer history. Supported by grants: AZV NV18-03-00024, NV19-03-00279, NV16-30954A, SVV2019/260367, PROGRES Q28/LF1No conflict of interest.

More potent ligands were obtained by multimerizing Thiamidol™ moieties, leading to homotetrameric structures that avidly bound to melanoma cells, as revealed by flow cytometry. These findings suggest that melanoma lesions may, in the future, be targeted not only by monoclonal antibody reagents but also by small organic ligands.

These results demonstrate that PA can effectively suppress melanin synthesis in melanoma cells. Taken together, our results show that PA could serve as a potential inhibitor of melanogenesis, and hence could be explored as a possible skin-lightening agent.

Melanin formation was confirmed in the zebrafish model using quercetin derivatives. Therefore, OQ might be a valuable asset for the development of novel skin-whitening agents.

Patients with high free UPK2 mRNA expression had unfavorable survival outcomes compared with those with low UPK2 expression. Therefore, free UPK2 mRNA expression in the plasma may have the potential to act as an indicator of postoperative recurrence in patients with early stage LUAD.

The macrophage checkpoint CD47-SIRPα has been targeted in over a dozen early phase clinical cancer trials, but efficacy is clear in only one trial to date with a fraction of lymphoma patients responding when anti-CD47 is infused only in combination with tumor-opsonizing rituximab (anti-CD20)...We conclude from these data that complete disruption of CD47 is important for efficacy, as even low amounts of CD47 can inhibit phagocytosis. Secondly, humoral immunity can also be generated and can durably protect from tumor engraftment and growth, provided B cells are not also ablated.

These results indicated that DBL promotes anti-melanogenesis by inhibiting the transportation of melanosomes. Therefore, DBL is a potent antioxidant and depigmenting agent that may be used in whitening cosmetics.

P1, N=72, Recruiting, Mayo Clinic | Trial completion date: Mar 2021 --> Mar 2022 | Trial primary completion date: Mar 2021 --> Mar 2022

Notably, this model also performed effectively in predicting the survival of patients under immunotherapy. In summary, this work provides a deeper understanding of the state of immune infiltration in melanoma and a prediction model that might guide the clinical treatment of patients with melanoma.

We detected common genetic variants involved in melanocyte biology or other biological pathways, such as hormonal signalling pathways or proinflammatory pathways, that contribute to the melanoma risk or nevi count in wild-type MC1R Spanish individuals.

Our findings indicate that TYRP1 can be used as a potential biomarker in the development of targeted therapy in UM. Further studies on melanogenesis markers associated with TYRP1 could provide us a better understanding in this field.

Here, using mouse preclinical models of melanoma (both solid tumor and lung metastasis), we found that the therapeutic efficacy of the specific antitumor antibody TA99 (anti-TYRP1) is significantly enhanced by immune checkpoint blockade...Our findings suggest that MEKi induced an increased expression of tumor-associated antigens, which, in combination with antitumor antibodies, generated a robust adaptive antitumor response that was sustained by immune checkpoint inhibition therapy. These improved therapeutic effects of specific antitumor antibodies by current standard-of-care therapeutics have potential near-term translation to the clinic, in light of fully humanized anti-TYRP1 antibodies currently in clinical development.

From these analyses, we have identified recurrently amplified and deleted genomic regions, potential causal agents, and the involvement of specific interleukins and cell-adhesion proteins in ulcerated and metastatic tumors.This study is one of the first to profile the molecular landscape of ALM in a Latin American population. We hope that it will contribute to increasing the diversity of cancer genomics datasets, help highlight differences in disease biology, and provide insights that may inform therapeutic strategies for all patients with this lethal malignancy.

A similar trend of elevated levels of expression was observed for Gαq/11, AKT, and mTOR. These observations indicate that the ectopic expression of Grm1 in melanocytes drive the formation of leptomeningeal melanocytic lesions and that the Tg(Grm1) mouse can be used for further studies aimed at understanding the mechanistic basis of leptomeningeal melanocytoma and other leptomeningeal diseases.

Tebentafusp caused transient increases in inflammatory cytokines and chemokines in serum and modified the micro-environment of metastatic uveal melanoma tumors to sensitize to cytotoxic CD8+ cells.[1] NCT01211262; ASCO 2019 [2] Clinical Cancer Research; 2020.[3] #195; ESMO IO; 2020

In addition, autophagosome formation and the expression levels of the autophagy-related proteins mTOR, p-mTOR, Beclin-1, Atg12, and LC3 were higher in 7-MSI-treated B16-F1 cells than in non-treated cells. These results indicate that 7-MSI can inhibit melanin synthesis in B16-F1 cells by suppressing melanogenesis and autophagy activation and thus can potentially be used as a novel multifunctional cosmetic agent.

Importantly, they showed the highest expression in melanoma samples compared to other tumors. In general, we characterized the CD8 T cell subpopulations in melanoma and identified that not only genes of immunosuppressive checkpoints but also PMEL, TYRP1, and EDNRB could serve as potential targets for melanoma therapy.

We confirmed that stimulation or repression of melanogenesis with L-Tyr or 5-Brd-2'-dU, respectively, generated changes in melanin concentration, reduction in proliferation, and changes in expression of microRNAs 470-3p, 470-5p, 30d-5p, 129-5p, 148b-3p, 27b-3p, and 211-5p, which presented patterns of coordinated and reciprocal co-expression, related to changes in melanogenesis through their putative targets Mitf, Tyr and Tyrp1, and control of cell cycle and senescence: Cyclin D1, Cdk2, Cdk4, p21, and p27. These findings provide insights into the molecular biology of melanoma of the way miRNAs are coordinated and reciprocal expression that may operate in a network as molecular bases for understanding changes in pigmentation and decreased proliferation induced in B16F1 melanoma cells exposed to L-Tyr and 5-Brd-2'-dU.

To characterize B6-Dct-H2BGFP mice, we confirmed not only the expression of GFP in all melanocyte lineage cells, but also doxycycline regulation of GFP expression...In contrast, CD34-/secondary hair germ (SHG) McSCs differentiated into pigmented melanocytes, with higher expression of melanogenic markers Tyr (71±1%), Tyrp1 (68±4%), and Mitf (75±7%). These results establish the utility of B6-Dct-H2BGFP bitransgenic mice for future in vivo studies of melanocytes requiring a defined genetic background.