Converging and evolving immuno-genomic routes toward immune escape in breast cancer.

The interactions between tumor and immune cells along the course of breast cancer progression remain largely unknown. Here, we extensively characterize multiple sequential and parallel multiregion tumor and blood specimens of an index patient and a cohort of metastatic triple-negative breast cancers. We demonstrate that a continuous increase in tumor genomic heterogeneity and distinct molecular clocks correlated with resistance to treatment, eventually allowing tumors to escape from immune control.

Integrated Analysis of Ovarian Juvenile Granulosa Cell Tumors Reveals Distinct Epigenetic Signatures and Recurrent TERT Rearrangements.

Purpose: Adult granulosa cell tumor (AGCT) is characterized by the somatic FOXL2 p.C134W mutation, and recurrences have been associated with TERT promoter and KMT2D-truncating mutations. Conversely, the molecular underpinnings of the rare juvenile granulosa cell tumor (JGCT) have not been well elucidated.

Expression of orexin-A (hypocretin-A) in the hypothalamus after traumatic brain injury: A postmortem evaluation.

Traumatic brain injury (TBI) is one of the leading causes of mortality and morbidity. The key component of TBI pathophysiology is traumatic axonal injury (TAI), commonly referred to as diffuse axonal injury (DAI). Coma is a serious complication which can occur following traumatic brain injury (TBI).

Sequencing identifies multiple early introductions of SARS-CoV-2 to the New York City region.

Effective public response to a pandemic relies upon accurate measurement of the extent and dynamics of an outbreak. Viral genome sequencing has emerged as a powerful approach to link seemingly unrelated cases, and large-scale sequencing surveillance can inform on critical epidemiological parameters. Here, we report the analysis of 864 SARS-CoV-2 sequences from cases in the New York City metropolitan area during the COVID-19 outbreak in spring 2020.

Clinicopathologic significance of protein lysine methyltransferases in cancer.

Protein lysine methyltransferases (PKMTs) constitute a large family of approximately 50 chromatin modifiers that mono-, di- and/or tri-methylate lysine residues on histone and non-histone substrates. With the advent of The Cancer Genome Atlas, it became apparent that this family of chromatin modifiers harbors frequent genetic and expression alterations in multiple types of cancer. In this regard, past and ongoing preclinical studies have provided insight into the mechanisms of action of some of these enzymes, laying the ground for the ongoing development of PKMT inhibitors as novel anticancer therapeutics.

The diagnostic utility of EZH2 H-score and Ki-67 index in non-invasive breast apocrine lesions.

In diagnostic breast pathology, there is no reliable applicable immunostain to help discern atypical and in situ apocrine lesions from benign apocrine tissue. At present, the diagnosis of non-invasive apocrine lesions remains challenging with current diagnoses rendered based on discrete morphologic characteristics on conventional hematoxylin and eosin staining. Interobserver variability is significant even among subspecialists partly due to lack of adjuvant diagnostic immunohistochemical stains.

Correlative study of epigenetic regulation of tumor microenvironment in spindle cell melanomas and cutaneous malignant peripheral nerve sheath tumors.

The tumor microenvironment (TME) plays critical roles in tumor growth and progression, however key regulators of gene expression in the TME of cutaneous malignant peripheral nerve sheath tumor (C-MPNST) and spindle cell melanoma (SCM) have not been well elucidated. Herein, we investigate the epigenetic regulation of promoters and gene bodies and their effect on the TME composition of C-MPNSTs and SCMs. A cohort of 30 patients was analyzed using differential gene expression (DGE) and gene set enrichment analysis (GSEA) using the Nanostring platform.

WITHDRAWN: ASSOCIATION OF INITIAL VIRAL LOAD IN SARS-CoV-2 PATIENTS WITH OUTCOME AND SYMPTOMS.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.

Association of Initial Viral Load in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Patients with Outcome and Symptoms.

The dynamics of viral load (VL) of the severe acute respiratory syndrome coronavirus 2 and its association with different clinical parameters remain poorly characterized in the US patient population. Herein, we investigate associations between VL and parameters, such as severity of symptoms, disposition (admission versus direct discharge), length of hospitalization, admission to the intensive care unit, length of oxygen support, and overall survival in 205 patients from a tertiary care center in New York City. VL was determined using quantitative PCR and log10 transformed for normalization.

Sequencing identifies multiple early introductions of SARS-CoV-2 to the New York City Region.

Effective public response to a pandemic relies upon accurate measurement of the extent and dynamics of an outbreak. Viral genome sequencing has emerged as a powerful approach to link seemingly unrelated cases, and large-scale sequencing surveillance can inform on critical epidemiological parameters. Here, we report the analysis of 864 SARS-CoV-2 sequences from cases in the New York City metropolitan area during the COVID-19 outbreak in Spring 2020.

WHSC1 monomethylates histone H1 and induces stem-cell like features in squamous cell carcinoma of the head and neck.

Squamous cell carcinoma of the head and neck (SCCHN) is a malignancy with poor outcomes, thus novel therapies are urgently needed. We recently showed that WHSC1 is necessary for the viability of SCCHN cells through H3K36 di-methylation. Here, we report the identification of its novel substrate, histone H1, and that WHSC1-mediated H1.

Molecular Profiling of Atypical Tenosynovial Giant Cell Tumors Reveals Novel Non- Fusions.

Tenosynovial giant cell tumor (TGCT) is a benign neoplasm characterized by recurrent fusions involving the colony-stimulating factor 1 () gene and translocation partners including collagen type VI alpha 3 chain () or S100 calcium-binding protein A10 (). Herein, we report three atypical TGCT cases with very unusual morphology comprising areas with increased cellular atypia, mitotic activity, and worrisome features that harbor unique non- gene fusions. Anchored multiplex PCR (AMP) for next-generation sequencing utilizing a customized panel targeting 86 cancer-related genes was performed, and it identified novel non--driven gene fusions: , , and .

Fibrolipoma of the left ventricle: an uncommon incidental autopsy finding.

Fibrolipoma of the heart is an unusual benign tumorous entity encountered, if present, during an ordinary imaging workout or at autopsy. It is often clinically silent but it can also be symptomatic depending on the size and location of the tumor. We report a case of an 82-year-old man with a medical history of malignant pleural mesothelioma.

Immune profiles in primary squamous cell carcinoma of the head and neck.

Objectives: In this study we describe the tumor microenvironment, the signaling pathways and genetic alterations associated with the presence or absence of CD8+ T-cell infiltration in primary squamous cell carcinoma of the head and neck (SCCHN) tumors.

Materials And Methods: Two SCCHN multi-analyte cohorts were utilized, the Cancer Genome Atlas (TCGA) and the Chicago Head and Neck Genomics (CHGC) cohort. A well-established chemokine signature classified SCCHN tumors into high and low CD8+ T-cell inflamed phenotypes (TCIP-H, TCIP-L respectively).

Thyroid Gland as a Target of Secondary Malignancies - an Autopsy Study and Review Data.

Aim: Secondary malignancies of the thyroid gland are rarely diagnosed but their incidence at autopsy is not uncommon.

Materials And Methods: To investigate the clinicopathological features of patients with metastatic tumours of the thyroid gland, we reviewed autopsy records and pathological features of 36 cases with thyroidal secondary tumours from 266 cases of malignant neoplasias (excluding cases of primary thyroid cancer), over a 16-year period.

Results: There were 19 men and 17 women in the study, ranging in age from 37 to 95 years (mean 70.

Development of novel SUV39H2 inhibitors that exhibit growth suppressive effects in mouse xenograft models and regulate the phosphorylation of H2AX.

Protein methyltransferase SUV39H2 was reported to methylate histone H2AX at lysine 134 and enhance the formation of phosphorylated H2AX (γ-H2AX), which causes chemoresistance of cancer cells. We found that a series of imidazo[1,2-]pyridine compounds that we synthesized could inhibit SUV39H2 methyltransferase activity. One of the potent compounds, OTS193320, was further analyzed in studies.

The role of protein methyltransferases as potential novel therapeutic targets in squamous cell carcinoma of the head and neck.

Squamous cell carcinoma of the head and neck is a lethal disease with suboptimal survival outcomes and standard therapies with significant comorbidities. Whole exome sequencing data recently revealed an abundance of genetic and expression alterations in a family of enzymes known as protein methyltransferases in a variety of cancer types, including squamous cell carcinoma of the head and neck. These enzymes are mostly known for their chromatin-modifying functions through methylation of various histone substrates, though evidence supports their function also through methylation of non-histone substrates.

Protein methyltransferases and demethylases dictate CD8+ T-cell exclusion in squamous cell carcinoma of the head and neck.

A subset of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) benefit from pembrolizumab and nivolumab, but the majority of patients do not probably due to lack of activated cytotoxic CD8+ T-cells in their tumor tissues. Herein, we aim to investigate whether specific protein methyltransferases (PMTs) and demethylases (PDMTs) could play any roles in the CD8+ T-cell exclusion process in HPV-negative SCCHN. RNA sequencing data from the TCGA database were interrogated for HPV-negative SCCHN patients using a 10-gene chemokine signature that classifies SCCHN tissues into CD8+ T-cell inflamed and non-CD8+ T-cell inflamed phenotypes.

Critical roles of protein methyltransferases and demethylases in the regulation of embryonic stem cell fate.

Accumulating evidence has recently shown that protein methyltransferases and demethylases are crucial regulators in either maintaining pluripotent states or inducing differentiation of embryonic stem cells. These enzymes control pluripotent signatures by mediating activation or repression of histone marks, or through direct methylation of non-histone proteins. Importantly, chromatin modifiers can influence the fate of many differentiation-related genes by loosening chromatin and allowing for transcriptional activation of lineage-specific genes.

Critical roles of SMYD2-mediated β-catenin methylation for nuclear translocation and activation of Wnt signaling.

Accumulation of β-catenin in the nucleus is a hallmark of activation of the Wnt/β-catenin signaling pathway, which drives development of a large proportion of human cancers. However, the mechanism of β-catenin nuclear translocation has not been well investigated. Here we report biological significance of SMYD2-mediated lysine 133 (K133) methylation of β-catenin on its nuclear translocation.

Characterization of the T-Cell Receptor Repertoire and Immune Microenvironment in Patients with Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck.

Squamous cell carcinoma of the head and neck (SCCHN) is a lethal cancer with a suboptimal 5-year overall survival of approximately 50% with surgery and/or definitive chemoradiotherapy. Novel treatments are thus urgently awaited. Immunotherapy with checkpoint blockade has emerged as a promising option for patients with recurrent/metastatic SCCHN; however, it has not been investigated in the curative-intent setting yet.

Effects of SMYD2-mediated EML4-ALK methylation on the signaling pathway and growth in non-small-cell lung cancer cells.

A specific subtype of non-small-cell lung cancer (NSCLC) characterized with an EML4-ALK fusion gene, which drives constitutive oncogenic activation of anaplastic lymphoma kinase (ALK), shows a good clinical response to ALK inhibitors. We have reported multiple examples implying the biological significance of methylation on non-histone proteins including oncogenic kinases in human carcinogenesis. Through the process to search substrates for various methyltransferases using an in vitro methyltransferase assay, we found that a lysine methyltransferase, SET and MYND domain-containing 2 (SMYD2), could methylate lysine residues 1451, 1455, and 1610 in ALK protein.

WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck cancer.

While multiple post-translational modifications have been reported to regulate the function of epidermal growth factor receptor (EGFR), the effect of protein methylation on its function has not been well characterized. In this study, we show that WHSC1L1 mono-methylates lysine 721 in the tyrosine kinase domain of EGFR, and that this methylation leads to enhanced activation of its downstream ERK cascade without EGF stimulation. We also show that EGFR K721 mono-methylation not only affects the function of cytoplasmic EGFR, but also that of nuclear EGFR.