EGCG suppresses PD-1 expression of T cells via inhibiting NF-κB phosphorylation and nuclear translocation.

Epigallocatechin-3-gallate (EGCG) is an important tea polyphenol with anti-tumor potential. Our previous studies revealed that EGCG was a promising immune checkpoint inhibitor (ICI) as it could downregulate expression of programmed cell death 1 ligand 1 (PD-L1) in tumor cells, thereby resulting tumor killing effect. In particular, EGCG can effectively avoid the inflammatory storm caused by anti-tumor therapy, which is a healthy green capacity absent from many ICIs.

Granzyme F: Exhaustion Marker and Modulator of Chimeric Antigen Receptor T Cell-Mediated Cytotoxicity.

Granzymes are a family of proteases used by CD8 T cells to mediate cytotoxicity and other less-defined activities. The substrate and mechanism of action of many granzymes are unknown, although they diverge among the family members. In this study, we show that mouse CD8+ tumor-infiltrating lymphocytes (TILs) express a unique array of granzymes relative to CD8 T cells outside the tumor microenvironment in multiple tumor models.

H3K4me3 remodeling induced acquired resistance through O-GlcNAc transferase.

Aims: Drivers of the drug tolerant proliferative persister (DTPP) state have not been well investigated. Histone H3 lysine-4 trimethylation (H3K4me3), an active histone mark, might enable slow cycling drug tolerant persisters (DTP) to regain proliferative capacity. This study aimed to determine H3K4me3 transcriptionally active sites identifying a key regulator of DTPPs.

Allergenicity of partially hydrolyzed whey and casein formulas evaluated by ImmunoCAP inhibition assay and basophil activation test.

Background: When exclusive breastfeeding is not possible, partially hydrolyzed formula (PHF) is often used as a starter formula for infants. Some children develop allergic symptoms, including anaphylaxis, after the first intake of cow protein. Therefore, the tolerability of PHF in infants with cow's milk allergy (CMA) is important information.

mRNA is downregulated by miR-155 in regulatory T cells, and reduced blood levels are associated with poor prognosis in metastatic melanoma patients.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an immune checkpoint expressed in regulatory T (Treg) cells and activated T lymphocytes. Despite its potential as a treatment strategy for melanoma, CTLA-4 inhibition has limited efficacy. Using data from The Cancer Genome Atlas (TCGA) melanoma database and another dataset, we found that decreased mRNA was associated with a poorer prognosis in metastatic melanoma.

Ethanol Metabolism and Melanoma.

Malignant melanoma is the deadliest form of skin cancer. Despite significant efforts in sun protection education, melanoma incidence is still rising globally, drawing attention to other socioenvironmental risk factors for melanoma. Ethanol and acetaldehyde (AcAH) are ubiquitous in our diets, medicines, alcoholic beverages, and the environment.

Identification of Factors Necessary for Enabling Technology-Based Dietary Record Surveys: A Qualitative Focus Group Interview with Japanese Dietitians.

Weighed food records together with an in-person interview approach constitute the most basic methods used to estimate energy and nutrient intakes in dietary surveys. In the background of the coronavirus disease-2019 pandemic, the need for non-face-to-face dietary surveys using information and communication technology (ICT) is increasing. We aimed to evaluate ICT-based dietary record surveys and identify factors that may enable this survey method to become more widely used in the future.

Alcohol as a Non-UV Social-Environmental Risk Factor for Melanoma.

Although cancer mortality has declined among the general population, the incidence of melanoma continues to rise. While identifying high-risk cohorts with genetic risk factors improves public health initiatives and clinical care management, recognizing modifiable risk factors such as social-environmental risk factors would also affect the methods of patient outreach and education. One major modifiable social-environmental risk factor associated with melanoma is ultraviolet (UV) radiation.

Expression of IL-37 Induces a Regulatory T-Cell-like Phenotype and Function in Jurkat Cells.

The anti-inflammatory cytokine interleukin-37 (IL-37) plays a key role in inhibiting innate and adaptive immunity. Past results have shown that IL-37 is elevated in human Treg cells compared to other T cell subsets and contributes to enhancing the Treg transcription factor, forkhead box protein P3 (FOXP3). However, it is unknown if ectopic expression of IL-37 in non-Treg CD4+ T cells can lead to the development of Treg phenotype and function.

EphB4 and ephrinB2 act in opposition in the head and neck tumor microenvironment.

Differential outcomes of EphB4-ephrinB2 signaling offers formidable challenge for the development of cancer therapeutics. Here, we interrogate the effects of targeting EphB4 and ephrinB2 in head and neck squamous cell carcinoma (HNSCC) and within its microenvironment using genetically engineered mice, recombinant constructs, pharmacologic agonists and antagonists. We observe that manipulating the EphB4 intracellular domain on cancer cells accelerates tumor growth and angiogenesis.

PEGylated Liposomes Accumulate in the Areas Relevant to Skin Toxicities Passive Extravasation across "Leaky" Endothelium.

PEGylated liposome is the cornerstone platform for modern drug delivery. Unfortunately, as exemplified by PEGylated liposomal doxorubicin (aka Doxil), altered doxorubicin pharmacokinetics causes off-target accumulation in the skin, including the palms and feet, leading to severe dose-limiting toxicity. In addition to Doxil, other nanoparticles and PEGylated liposomes exhibit significant deposition in the skin, but mechanisms of accumulation are poorly understood.

Combining Carbon-Ion Irradiation and PARP Inhibitor, Olaparib Efficiently Kills BRCA1-Mutated Triple-Negative Breast Cancer Cells.

Background: Triple-negative breast cancer (TNBC) exhibits poor prognosis due to the lack of targets for hormonal or antibody-based therapies, thereby leading to limited success in the treatment of this cancer subtype. Poly (ADP-ribose) polymerase 1 (PARP1) is a critical factor for DNA repair, and using PARP inhibitor (PARPi) is one of the promising treatments for BRCA-mutated (BRCA mut) tumors where homologous recombination repair is impaired due to BRCA1 mutation. Carbon ion (C-ion) radiotherapy effectively induces DNA damages in cancer cells.

Circulating CD8 mucosal-associated invariant T cells correlate with improved treatment responses and overall survival in anti-PD-1-treated melanoma patients.

Objectives: While much of the research concerning factors associated with responses to immune checkpoint inhibitors (ICIs) has focussed on the contributions of conventional peptide-specific T cells, the role of unconventional T cells, such as mucosal-associated invariant T (MAIT) cells, in human melanoma remains largely unknown. MAIT cells are an abundant population of innate-like T cells expressing a semi-invariant T-cell receptor restricted to the MHC class I-like molecule, MR1, presenting vitamin B metabolites derived from bacteria. We sought to characterise MAIT cells in melanoma patients and determined their association with treatment responses and clinical outcomes.

Expression Differences in BCL2 Family Members between Uveal and Cutaneous Melanomas Account for Varying Sensitivity to BH3 Mimetics.

Uveal melanoma (UM) is a subtype of melanoma. Although they share a melanocytic origin with cutaneous melanoma (CM), patients with UM have few treatment options. BCL2 homologous 3 mimetics are small-molecule drugs that mimic proapoptotic BCL2 family members.

EGCG Inhibits Tumor Growth in Melanoma by Targeting JAK-STAT Signaling and Its Downstream PD-L1/PD-L2-PD1 Axis in Tumors and Enhancing Cytotoxic T-Cell Responses.

Over the last decade, therapies targeting immune checkpoints, such as programmed death-1 (PD-1), have revolutionized the field of cancer immunotherapy. However, low response rates and immune-related adverse events remain a major concern. Here, we report that epigallocatechin gallate (EGCG), the most abundant catechin in green tea, inhibits melanoma growth by modulating an immune response against tumors.

Insertion/deletion and microsatellite alteration profiles in induced pluripotent stem cells.

We here demonstrate that microsatellite (MS) alterations are elevated in both mouse and human induced pluripotent stem cells (iPSCs), but importantly we have now identified a type of human iPSC in which these alterations are considerably reduced. We aimed in our present analyses to profile the InDels in iPSC/ntESC genomes, especially in MS regions. To detect somatic de novo mutations in particular, we generated 13 independent reprogramed stem cell lines (11 iPSC and 2 ntESC lines) from an identical parent somatic cell fraction of a C57BL/6 mouse.

Targeting CDK4/6 Represents a Therapeutic Vulnerability in Acquired BRAF/MEK Inhibitor-Resistant Melanoma.

There is a clear need to identify targetable drivers of resistance and potential biomarkers for salvage therapy for patients with melanoma refractory to the combination of BRAF and MEK inhibition. In this study, we performed whole-exome sequencing on -V600E-mutant melanoma patient tumors refractory to the combination of BRAF/MEK inhibition and identified acquired oncogenic mutations in and loss of the tumor suppressor gene We hypothesized the acquired resistance mechanisms to BRAF/MEK inhibition were reactivation of the MAPK pathway and activation of the cell-cycle pathway, which can both be targeted pharmacologically with the combination of a MEK inhibitor (trametinib) and a CDK4/6 inhibitor (palbociclib). , we found that combination of CDK4/6 and MEK inhibition significantly decreased tumor growth in two BRAF/MEK inhibitor-resistant patient-derived xenograft models.

Inhibition of CtBP-Regulated Proinflammatory Gene Transcription Attenuates Psoriatic Skin Inflammation.

Psoriasis is a chronic immune-mediated disease characterized by excessive proliferation of epidermal keratinocytes and increased immune cell infiltration to the skin. Although it is well-known that psoriasis pathogenesis is driven by aberrant production of proinflammatory cytokines, the mechanisms underlying the imbalance between proinflammatory and anti-inflammatory cytokine expression are incompletely understood. In this study, we report that the transcriptional coregulators CtBP1 and 2 can transactivate a common set of proinflammatory genes both in the skin of imiquimod-induced mouse psoriasis model and in human keratinocytes and macrophages stimulated by imiquimod.

Anti-inflammatory Effect of Cannabidiol and Palmitoylethanolamide Containing Topical Formulation on Skin in a 12- O -Tetradecanoylphorbol-13-Acetate-Induced Dermatitis Model in Mice.

Background: Chronic inflammatory skin disorders, such as atopic dermatitis, have significant disease burden worldwide. Although efficacious, the adverse effect profile of topical corticosteroids limits long-term use. As an alternative, cannabinoids have been shown to have anti-inflammatory therapeutic effects.

Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion.

Interleukin-1β (IL-1β)-mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1β expression in cutaneous melanoma samples ( = 469) compared to normal skin ( = 324), with a highly significant correlation between NLRP3 and IL-1β ( < 0.

NLRP1 Functions Downstream of the MAPK/ERK Signaling via ATF4 and Contributes to Acquired Targeted Therapy Resistance in Human Metastatic Melanoma.

The V600E mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and its downstream effector responses. Uncovering the hidden downstream effectors can aid in understanding melanoma biology and improve targeted therapy efficacy. The inflammasome sensor, NACHT, LRR, and PYD domains-containing protein 1 (NLRP1), is responsible for IL-1β maturation and itself is a melanoma tumor promoter.

An Observational Study of the Application of a Topical Cannabinoid Gel on Sensitive Dry Skin.

Atopic dermatitis (AD) is a chronic skin disorder characterized by pruritus, erythema and excoriation. While AD has a multifactorial etiology, neuro-signaling pathways are now recognized to play an essential role in the pathogenesis of AD, particularly pruritus. Neuromodulators, such as topical naltrexone, are being utilized in AD treatment.