Multi-omic characterization of consensus molecular subtype 1 (CMS1) colorectal cancer with dampened immune response improves precision medicine.

Colorectal cancer (CRC) is a heterogenous disease with distinct biological and clinical subgroups, each with different prognoses and responses to therapy. In this case report, taking inspiration from a case of locally advanced CRC with serine/threonine-protein kinase B-raf (BRAF) V600E mutation, we highlight an atypical consensus molecular subtype 1 (CMS1). Deep multi-omic analyses showed a limited expression of programmed cell death protein 1 (PD-1) and reduced T-cell infiltration, including CD8 and natural killer (NK) cells, in the analyzed CMS1 tumor.

Lead bioaccumulation in human breast cancer tissue is associated with DNA instability and cell death resistance.

Lead (Pb) is increasingly recognized for its potential to alter cellular processes and contribute to cancer development. Although Pb is classified as a probable carcinogen by the IARC, the clinical evidence for its role in breast cancer is inconsistent and limited to epidemiological studies yet. The aim of this study was to investigate the Pb bioaccumulation in human breast cancer tissues by correlating its concentration with specific cancer factors related to carcinogenesis.

Aging and Gender Modify the Risk of Carotid Plaque Thrombosis Related to Dyslipidemic Profile.

Background: Dyslipidemia plays a critical role in carotid plaque instability and related cerebrovascular events. Reduction of low-density lipoprotein cholesterol (LDL-C) levels decreases ischemic stroke risk; however, a residual cardiovascular risk persists. Starting from this evidence, this study evaluated the impact of dyslipidemia on carotid plaque instability while also considering age and gender.

Deletion of p63 exon 13 in mice reveals C-terminal isoform-specific functions in epithelial development.

The transcription factor p63 is an essential regulator of epithelial development. Yet, the complexity at the 3'UTR, which gives rise to the three distinct C-terminal protein isoforms (α, β, and γ), remains unresolved and opens an investigation on the in vivo role of the C-terminus. This region, codified by exon 13, harbors genetic mutations leading to AEC syndrome.

Mesenchymal stromal cells highly expressing Sca-1 promote breast cancer lung metastasis through recruiting myeloid cells.

Mesenchymal stem/stromal cells (MSCs) are integral components of the tumor microenvironment and critical for the colonization of disseminated cancer cells; specifically, stem cell antigen (Sca-1) is recognized as a surface marker of MSCs. In this study, we found that MSCs highly expressing Sca-1 are positively associated with lung metastasis. MSCs derived from the lungs of mice bearing metastasized breast tumors (LMSCs) exhibited higher level of Sca-1 compared to those with adenoma.

The WWP1-JARID1B axis sustains acute myeloid leukemia chemoresistance.

To uncover substrates mediating the oncogenic activity of WWP1 in acute myeloid leukemia (AML), we performed a proteomic analysis that identified the histone demethylase /JARID1B as a candidate target. Of note, JARID1B is indispensable for efficient recruitment of several DNA damage repair factors and for damage resolution, thus negatively influencing the sensitivity of cancer cells to chemo- and radiation therapies. Validation of JARID1B as a substrate of WWP1 revealed a positive regulation of JARID1B half-life by WWP1 through the establishment of K63-linked polyubiquitin chains.

p63 and ZNF148 cooperate to regulate head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a common and aggressive malignancy. While significant advances have been made in the management of low-grade cancer, treatment of advanced HNSCC remains challenging. Here, we used a proteomic approach to find binding partners of the oncogene p63, the most frequently amplified transcription factor in HNSCC.

LEADR, a p63 target, dampens interferon signalling in bladder cancer.

Bladder cancer affects over half a million people worldwide each year. Recent advances in early detection allowed a successful management of non-aggressive cancers, yet the recurrence rate remains high. Aggressive muscle-invasive bladder tumours are life-threatening and challenging to cure.

B cell-derived acetylcholine mitigates skin inflammation in mice through α9 nicotinic acetylcholine receptor-mediated signaling.

Chronic inflammatory skin disorders are characterized by keratinocyte hyperproliferation and hyperactivation as well as immune cell infiltration. We investigated whether immune cell-derived acetylcholine (ACh) is a modulator of skin inflammation in mice. Here, we identify skin epithelial B cells as a key source of ACh that damps down inflammation.

High baseline levels of PD-L1 reduce the heterogeneity of immune checkpoint signature and sensitize anti-PD1 therapy in lung and colorectal cancers.

Immune checkpoint blockade (ICB) therapy only induces durable responses in a subset of cancer patients. The underlying mechanisms of such selective efficacy remain largely unknown. By analyzing the expression profiles of immune checkpoint molecules in different statuses of murine tumors, we found that tumor progression generally randomly upregulated multiple immune checkpoints, thus increased the Heterogeneity of Immune checkpoint Signature (HIS) and resulted in immunotherapeutic resistance.

Ultrastructural studies distinguish skin diversities among Galápagos iguanas.

Iguanas exhibit diverse colors and behaviors reflecting evolutionarily adaptation to various habitats; in particular, the Galápagos iguanas represent unique color morphologies with distinct ecological niches. While external coloration in iguanas has ecological implications, comprehensive studies on the histological and ultrastructural aspects of their skin can provide insight into their adaptation to extreme environments, such as high UV exposure. Starting from these considerations the present study investigates the histological, ultrastructural and immunohistochemical features to comprehensively characterize the skin in adults of three species of Galápagos iguanas (A.

Implications of Mineralization Biomarkers in Breast Cancer Outcomes Beyond Calcifications.

The aim of this work was to explore the biomarkers associated with epithelial to mesenchymal transition (EMT) and mineralization processes as new prognostic factors across different breast cancer phenotypes. To this end, 133 breast biopsies, including benign and malignant lesions, with or without microcalcifications, were retrospectively collected. Immunohistochemical analysis was performed to evaluate the expression of vimentin, BMP-2, BMP-4, RANKL, Runx2, OPN, PTX3, and SDF-1, while Kaplan-Meier plots were used to assess their prognostic impact on overall survival in a dataset of 2976 breast cancer patients.

Aluminum Concentration Is Associated with Tumor Mutational Burden and the Expression of Immune Response Biomarkers in Colorectal Cancers.

Environmental pollution poses a significant risk to public health, as demonstrated by the bioaccumulation of aluminum (Al) in colorectal cancer (CRC). This study aimed to investigate the potential mutagenic effect of Al bioaccumulation in CRC samples, linking it to the alteration of key mediators of cancer progression, including immune response biomarkers. Aluminum levels in 20 CRC biopsy samples were analyzed using inductively coupled plasma mass spectrometry (ICP-MS).

Unveiling the molecular profile of a prostate carcinoma: implications for personalized medicine.

Background: Prostate cancer is the most common diagnosed tumor and the fifth cancer related death among men in Europe. Although several genetic alterations such as ERG-TMPRSS2 fusion, MYC amplification, PTEN deletion and mutations in p53 and BRCA2 genes play a key role in the pathogenesis of prostate cancer, specific gene alteration signature that could distinguish indolent from aggressive prostate cancer or may aid in patient stratification for prognosis and/or clinical management of patients with prostate cancer is still missing. Therefore, here, by a multi-omics approach we describe a prostate cancer carrying the fusion of TMPRSS2 with ERG gene and deletion of 16q chromosome arm.

When do the pathological signs become evident? Study of human mesenchymal stem cells in MDPL syndrome.

Aging syndromes are rare genetic disorders sharing the features of accelerated senescence. Among these, Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy (MDPL; OMIM #615381) is a rare autosomal dominant disease due to a in-frame deletion in gene, encoding the catalytic subunit of DNA polymerase delta. Here, we investigated how MSCs may contribute to the phenotypes and progression of premature aging syndromes such as MDPL.

Thioredoxin-interacting protein (TXNIP) is a substrate of the NEDD4-like E3 ubiquitin-protein ligase WWP1 in cellular redox state regulation of acute myeloid leukemia cells.

The HECT-type E3 ubiquitin WWP1 (also known as NEDD4-like E3 ubiquitin-protein ligase WWP1) acts as an oncogenic factor in acute myeloid leukemia (AML) cells. WWP1 overexpression in AML confers a proliferative advantage to leukemic blasts (abnormal immature white blood cells) and counteracts apoptotic cell death and differentiation. In an effort to elucidate the molecular basis of WWP1 oncogenic activities, we identified WWP1 as a previously unknown negative regulator of thioredoxin-interacting protein (TXNIP)-mediated reactive oxygen species (ROS) production in AML cells.

ABCC1 Is a ΔNp63 Target Gene Overexpressed in Squamous Cell Carcinoma.

The transcription factor ΔNp63 plays a pivotal role in maintaining the integrity of stratified epithelial tissues by regulating the expression of distinct target genes involved in lineage specification, cell stemness, cell proliferation and differentiation. Here, we identified the ABC transporter subfamily member as a novel ΔNp63 target gene. We found that in immortalized human keratinocytes and in squamous cell carcinoma (SCC) cells, ∆Np63 induces the expression of ABCC1 by physically occupying a p63-binding site (p63 BS) located in the first intron of the gene locus.

Molecular profiling of a bladder cancer with very high tumour mutational burden.

The increasing incidence of urothelial bladder cancer is a notable global concern, as evidenced by the epidemiological data in terms of frequency, distribution, as well as mortality rates. Although numerous molecular alterations have been linked to the occurrence and progression of bladder cancer, currently there is a limited knowledge on the molecular signature able of accurately predicting clinical outcomes. In this report, we present a case of a pT3b high-grade infiltrating urothelial carcinoma with areas of squamous differentiation characterized by very high tumor mutational burden (TMB), with up-regulations of immune checkpoints.

SOD2 promotes the immunosuppressive function of mesenchymal stem cells at the expense of adipocyte differentiation.

The potent immunomodulatory function of mesenchymal stem/stromal cells (MSCs) elicited by proinflammatory cytokines IFN-γ and TNF-α (IT) is critical to resolve inflammation and promote tissue repair. However, little is known about how the immunomodulatory capability of MSCs is related to their differentiation competency in the inflammatory microenvironment. In this study, we demonstrate that the adipocyte differentiation and immunomodulatory function of human adipose tissue-derived MSCs (MSC(AD)s) are mutually exclusive.