Mediator kinase inhibitors suppress triple-negative breast cancer growth and extend tumor suppression by mTOR and AKT inhibitors.

Triple-negative breast cancers (TNBC) are treated primarily by chemotherapy and lack clinically validated therapeutic targets. In particular, inhibitors of the PI3K/AKT/mTOR pathway, abnormally activated in many breast cancers, failed to achieve clinical efficacy in TNBC due to the development of adaptive drug resistance, which is largely driven by the transcriptomic plasticity of TNBC. Expression of CDK8/19 Mediator kinases that control transcriptional reprogramming correlates with relapse-free survival and treatment failure in breast cancer patients, including TNBC.

Characterization of the Lithium/Solid Electrolyte Interface in the Presence of Nanometer-thin TiO Layers for All-Solid-State Batteries.

It is still unclear which role space charge layers (SCLs) play within an all-solid-state battery during operation with high current densities, as well as to which extent they form. Herein, we use a solid electrolyte with a known SCL formation and investigate it in a symmetric cell under non-blocking conditions with Li metal electrodes. Since the used LICGC™ electrolyte is known for its instability against lithium, it is protected from rapid degradation by nanometer-thin layers of TiO deployed by atomic layer deposition.

BORIS/CTCFL epigenetically reprograms clustered CTCF binding sites into alternative transcriptional start sites.

Background: Pervasive usage of alternative promoters leads to the deregulation of gene expression in carcinogenesis and may drive the emergence of new genes in spermatogenesis. However, little is known regarding the mechanisms underpinning the activation of alternative promoters.

Results: Here we describe how alternative cancer-testis-specific transcription is activated.

Expression-Based Diagnosis, Treatment Selection, and Drug Development for Breast Cancer.

There is currently no gene expression assay that can assess if premalignant lesions will develop into invasive breast cancer. This study sought to identify biomarkers for selecting patients with a high potential for developing invasive carcinoma in the breast with normal histology, benign lesions, or premalignant lesions. A set of 26-gene mRNA expression profiles were used to identify invasive ductal carcinomas from histologically normal tissue and benign lesions and to select those with a higher potential for future cancer development (ADHC) in the breast associated with atypical ductal hyperplasia (ADH).

COVID-19 inflation weights in the UK and Germany.

The COVID-19 pandemic altered consumption patterns significantly in a short period of time. However, official inflation statistics take time to reflect changes in the weights of the CPI consumption basket. Using credit card data for the UK and Germany, we document how consumption patterns changed and quantify the resulting inflation bias.

An updated catalog of variants associated with neurodevelopmental disorder phenotypes.

Introduction: -related disorder (CRD) is a neurodevelopmental disorder (NDD) caused by monoallelic pathogenic variants in . The first variants in CRD cases were documented in 2013. To date, 76 variants have been further described in the literature.

NEDD9 Overexpression Causes Hyperproliferation of Luminal Cells and Cooperates with HER2 Oncogene in Tumor Initiation: A Novel Prognostic Marker in Breast Cancer.

HER2 overexpression occurs in 10-20% of breast cancer patients. HER2+ tumors are characterized by an increase in Ki67, early relapse, and increased metastasis. Little is known about the factors influencing early stages of HER2- tumorigenesis and diagnostic markers.

Long COVID? Prospects for economic scarring from the pandemic.

This paper examines the potential persistent effects (scarring) of the COVID-19 pandemic on the economy and the channels through which they may occur. Our findings from a broad set of historical recessions confirm that recessions are associated with persistent output losses and that the greatest scarring has occurred following financial crises. The amount of scarring following pandemic and epidemic recessions in the sample is in between that of typical recessions and financial crises.

Ectopic expression of meiotic cohesin generates chromosome instability in cancer cell line.

Many tumors express meiotic genes that could potentially drive somatic chromosome instability. While germline cohesin subunits SMC1B, STAG3, and REC8 are widely expressed in many cancers, messenger RNA and protein for RAD21L subunit are expressed at very low levels. To elucidate the potential of meiotic cohesins to contribute to genome instability, their expression was investigated in human cell lines, predominately in DLD-1.

[Clinical efficacy and safety of Ethoxidol in cerebrovascular diseases].

Objective: Evaluation of efficacy and clinical safety of ethylmethylhydroxypyridine malate (Ethoxidol) in cerebrovascular disease in out-patient, and in-patient setting.

Material And Methods: In the observational study was included of the 70 patients (aged 62.84±6.

[Efficacy of Mexidol in patients with type 2 diabetes mellitus with neurological complications].

Objective: Complications of Diabetes mellitus (DM), depends on the severity of hypoxic tissue damage. Amelioration of hypoxic injury may improve current therapy approaches and enhance the quality of life in patient's cohort suffered from DM.

Material And Methods: 30 pts which DM were enrolled into the study.

Nuclear Aurora-A kinase-induced hypoxia signaling drives early dissemination and metastasis in breast cancer: implications for detection of metastatic tumors.

Metastatic breast cancer causes most breast cancer-associated deaths, especially in triple negative breast cancers (TNBC). The metastatic drivers of TNBCs are still poorly understood, and effective treatment non-existent. Here we reveal that the presence of Aurora-A Kinase (AURKA) in the nucleus and metastatic dissemination are molecularly connected through HIF1 (Hypoxia-Inducible Factor-1) signaling.

Primary Cilium Is Involved in Stem Cell Differentiation and Renewal through the Regulation of Multiple Signaling Pathways.

Signaling networks guide stem cells during their lineage specification and terminal differentiation. Primary cilium, an antenna-like protrusion, directly or indirectly plays a significant role in this guidance. All stem cells characterized so far have primary cilia.

The combined action of CTCF and its testis-specific paralog BORIS is essential for spermatogenesis.

CTCF is a key organizer of the 3D genome. Its specialized paralog, BORIS, heterodimerizes with CTCF but is expressed only in male germ cells and in cancer states. Unexpectedly, BORIS-null mice have only minimal germ cell defects.

Functional Hierarchy and Cooperation of EMT Master Transcription Factors in Breast Cancer Metastasis.

Several master transcription factors (TF) can activate the epithelial-to-mesenchymal transition (EMT). However, their individual and combinatorial contributions to EMT in breast cancer are not defined. We show that overexpression of EMT-TFs individually in epithelial cells upregulated endogenous SNAI2, ZEB1/2, TCF4, and TWIST1/2 as a result of positive feedback mediated in part by suppression of their negative regulator miRNAs miR200s/203/205.

Opening large-conductance potassium channels selectively induced cell death of triple-negative breast cancer.

Background: Unlike other breast cancer subtypes that may be treated with a variety of hormonal or targeted therapies, there is a need to identify new, effective targets for triple-negative breast cancer (TNBC). It has recently been recognized that membrane potential is depolarized in breast cancer cells. The primary objective of the study is to explore whether hyperpolarization induced by opening potassium channels may provide a new strategy for treatment of TNBC.

Skeletal muscle reprogramming by breast cancer regardless of treatment history or tumor molecular subtype.

Increased susceptibility to fatigue is a negative predictor of survival commonly experienced by women with breast cancer (BC). Here, we sought to identify molecular changes induced in human skeletal muscle by BC regardless of treatment history or tumor molecular subtype using RNA-sequencing (RNA-seq) and proteomic analyses. Mitochondrial dysfunction was apparent across all molecular subtypes, with the greatest degree of transcriptomic changes occurring in women with HER2/neu-overexpressing tumors, though muscle from patients of all subtypes exhibited similar pathway-level dysregulation.

CTCF mediates chromatin looping via N-terminal domain-dependent cohesin retention.

The DNA-binding protein CCCTC-binding factor (CTCF) and the cohesin complex function together to shape chromatin architecture in mammalian cells, but the molecular details of this process remain unclear. Here, we demonstrate that a 79-aa region within the CTCF N terminus is essential for cohesin positioning at CTCF binding sites and chromatin loop formation. However, the N terminus of CTCF fused to artificial zinc fingers was not sufficient to redirect cohesin to non-CTCF binding sites, indicating a lack of an autonomously functioning domain in CTCF responsible for cohesin positioning.

Mutations in ARL2BP, a protein required for ciliary microtubule structure, cause syndromic male infertility in humans and mice.

Cilia are evolutionarily conserved hair-like structures with a wide spectrum of key biological roles, and their dysfunction has been linked to a growing class of genetic disorders, known collectively as ciliopathies. Many strides have been made towards deciphering the molecular causes for these diseases, which have in turn expanded the understanding of cilia and their functional roles. One recently-identified ciliary gene is ARL2BP, encoding the ADP-Ribosylation Factor Like 2 Binding Protein.

Expression in Ovarian Cancer Precursor Cells Alters the CTCF Cistrome and Enhances Invasiveness through .

High-grade serous carcinoma (HGSC) is the most aggressive and predominant form of epithelial ovarian cancer and the leading cause of gynecologic cancer-related death. We have previously shown that (also known as , rother f the egulator of mprinted ites) is expressed in most ovarian cancers, and is associated with global and promoter-specific DNA hypomethylation, advanced tumor stage, and poor prognosis. To explore its role in HGSC, we expressed in human fallopian tube secretory epithelial cells (FTSEC), the presumptive cells of origin for HGSC.

Human Breast Cancer Xenograft Model Implicates Peroxisome Proliferator-activated Receptor Signaling as Driver of Cancer-induced Muscle Fatigue.

Purpose: This study tested the hypothesis that a patient-derived orthotopic xenograft (PDOX) model would recapitulate the common clinical phenomenon of breast cancer-induced skeletal muscle (SkM) fatigue in the absence of muscle wasting. This study additionally sought to identify drivers of this condition to facilitate the development of therapeutic agents for patients with breast cancer experiencing muscle fatigue.

Experimental Design: Eight female BC-PDOX-bearing mice were produced via transplantation of tumor tissue from 8 female patients with breast cancer.

ADP-Ribosylation Factor-Like 2 (ARL2) regulates cilia stability and development of outer segments in rod photoreceptor neurons.

Photoreceptor cells are specialized neurons with a sensory cilium carrying an elaborate membrane structure, the outer segment (OS). Inherited mutations in genes involved in ciliogenesis frequently result in OS malformation and blindness. ADP-ribosylation factor-like 2 (ARL2) has recently been implicated in OS formation through its association with Binder of ARL2 (BART or ARL2BP), a protein linked to inherited blinding disease.