S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models.

Background: Understanding why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well remains a challenge. This study aims to understand the potential underlying mechanisms distinguishing early-stage TNBC tumors that respond to clinical intervention from non-responders, as well as to identify clinically viable therapeutic strategies, specifically for TNBC patients who may not benefit from existing therapies.

Methods: We conducted retrospective bioinformatics analysis of historical gene expression datasets to identify a group of genes whose expression levels in early-stage tumors predict poor clinical outcomes in TNBC.

S100A8/A9 predicts triple-negative breast cancer response to PIM kinase and PD-1/PD-L1 inhibition.

It remains elusive why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well. Our retrospective analysis of historical gene expression datasets reveals that increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors is robustly associated with subsequent disease progression in TNBC. Although it has recently gained recognition as a potential anticancer target, S100A8/A9 has not been integrated into clinical study designs evaluating molecularly targeted therapies.

Oncogene-regulated release of extracellular vesicles.

Oncogenes can alter metabolism by changing the balance between anabolic and catabolic processes. However, how oncogenes regulate tumor cell biomass remains poorly understood. Using isogenic MCF10A cells transformed with nine different oncogenes, we show that specific oncogenes reduce the biomass of cancer cells by promoting extracellular vesicle (EV) release.

Activation-Induced Rigidity in Neurologically and Cognitively Healthy Individuals Aged 18-90 Years: A Cross-Sectional Study.

Background: Rigidity is a key clinical feature of Parkinson's disease (PD), but in a very early phase of the disease it may be absent and can be enhanced through active movements of the arm contralateral to the one being tested.

Objective: To evaluate in a large cohort of neurologically and cognitively healthy (NCH) subjects aged 18-90 years if activation-induced rigidity (AR) is present in all age classes, and if there are biological differences between subjects showing AR (AR+) and not showing AR (AR-).

Methods: 2,228 NCH subjects categorized as young adult (18-44 years), adult (45-64 years), elderly (65-74 years), and old/oldest-old (75-90 years) were included in the analysis, and underwent brain MRI.

APOE Genotypes and Brain Imaging Classes in Normal Cognition, Mild Cognitive Impairment, and Alzheimer's Disease: A Longitudinal Study.

Objective: To evaluate in 419 stroke-free cognitively normal subjects (CN) aged 45-82 years covering during a long prospective study (11.54 ± 1.47 years) the preclinical to dementia spectrum: 1) the distribution of small vessel disease (V) and brain atrophy (A) aggregated as following: V-/A-, V-/A+, V+/A-, V+/A+; 2) the relationship of these imaging classes with individual apolipoprotein E (APOE) genotypes; 3) the risk of progression to Alzheimer Disease (AD) of the individual APOE genotypes.

A risk-associated Active transcriptome phenotype expressed by histologically normal human breast tissue and linked to a pro-tumorigenic adipocyte population.

Background: Previous studies have identified and validated a risk-associated Active transcriptome phenotype commonly expressed in the cancer-adjacent and histologically normal epithelium, stroma, and adipose containing peritumor microenvironment of clinically established invasive breast cancers, conferring a 2.5- to 3-fold later risk of dying from recurrent breast cancer. Expression of this Active transcriptome phenotype has not yet been evaluated in normal breast tissue samples unassociated with any benign or malignant lesions; however, it has been associated with increased peritumor adipocyte composition.

Exfoliation of α-Zirconium Phosphate Using Tetraalkylammonium Hydroxides.

α-Zirconium phosphate (α-ZrP), a classical layered compound, has found widespread application. Exfoliation of α-ZrP has been mainly achieved by propylamine (PA) or tetrabutylammonium hydroxide (TBAOH), but the exact mechanism of exfoliation has not been completely elucidated. We examined the feasibility of exfoliation utilizing tetraalkylammonium hydroxide (TXAOH) and investigated the stepwise intercalation/exfoliation mechanism of α-ZrP.

MYC Dysregulates Mitosis, Revealing Cancer Vulnerabilities.

Tumors that overexpress the MYC oncogene are frequently aneuploid, a state associated with highly aggressive cancers and tumor evolution. However, how MYC causes aneuploidy is not well understood. Here, we show that MYC overexpression induces mitotic spindle assembly defects and chromosomal instability (CIN) through effects on microtubule nucleation and organization.

Isolated, Subtle Neurological Abnormalities in Mild Cognitive Impairment Types.

Background: Isolated, subtle neurological abnormalities (ISNA) are commonly seen in aging and have been related to cerebral small vessel disease (SVD) and subcortical atrophy in neurologically and cognitively healthy aging subjects.

Objective: To investigate the frequency of ISNA in different mild cognitive impairment (MCI) types and to evaluate for each MCI type, the cross-sectional relation between ISNA and white matter hyperintensities (WMH), lacunes, caudate atrophy, and ventricular enlargement.

Methods: One thousand two hundred fifty subjects with different MCI types were included in the analysis and underwent brain magnetic resonance imaging.

Mild Parkinsonian Signs in a Hospital-based Cohort of Mild Cognitive Impairment Types: A Cross-sectional Study.

Background: Mild Parkinsonian Signs (MPS) have been associated with Mild Cognitive Impairment (MCI) types with conflicting results.

Objective: To investigate the association of individual MPS with different MCI types using logistic ridge regression analysis, and to evaluate for each MCI type, the association of MPS with caudate atrophy, global cerebral atrophy, and the topographical location of White Matter Hyperintensities (WMH), and lacunes.

Methods: A cross-sectional study was performed among 1,168 subjects with different types of MCI aged 45-97 (70,52 ± 9,41) years, who underwent brain MRI.

Nociceptive Primitive Reflexes in Neurologically and Cognitively Healthy Aging Subjects.

Background: To assess the prevalence of three nociceptive primitive reflexes (nPR), i.e., glabellar tap, snout reflex, and palmomental reflex, in neurologically and cognitively healthy (NCH) aging subjects.

Association Between Atrophy of the Caudate Nuclei, Global Brain Atrophy, Cerebral Small Vessel Disease and Mild Parkinsonian Signs in Neurologically and Cognitively Healthy Subjects Aged 45-84 Years: A Crosssectional Study.

Background: Mild Parkinsonian signs (MPS) are commonly seen in aging, and have been related to cerebral Small Vessel Diseases (SVD) with no univocal results.

Objective: The aim of this study was to investigate the cross-sectional relation between MPS and White Matter Hyperintensities (WMH), lacunes, caudate atrophy, and global cerebral atrophy in a large cohort of Neurologically and Cognitively Healthy (NCH) aging individuals.

Method: 1,219 NCH individuals were included in the analysis, and underwent standard brain MRI.

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity.

Vascular Risk Factors, Vascular Diseases, and Imaging Findings in a Hospital-based Cohort of Mild Cognitive Impairment Types.

Background: Mild Cognitive Impairment (MCI) is a transitional state between normal cognition and dementia.

Objective: The aim of this study is to investigate the role of vascular risk factors, vascular diseases, cerebrovascular disease and brain atrophy in a large hospital-based cohort of MCI types including 471 amnestic MCI (a-MCI), 693 amnestic MCI multiple domain (a-MCImd), 322 single non-memory MCI (snm-MCI), and 202 non amnestic MCI multiple domain (na-MCImd). For comparison, 1,005 neurologically and cognitively healthy subjects were also evaluated.

Comprehensive analysis of normal adjacent to tumor transcriptomes.

Histologically normal tissue adjacent to the tumor (NAT) is commonly used as a control in cancer studies. However, little is known about the transcriptomic profile of NAT, how it is influenced by the tumor, and how the profile compares with non-tumor-bearing tissues. Here, we integrate data from the Genotype-Tissue Expression project and The Cancer Genome Atlas to comprehensively analyze the transcriptomes of healthy, NAT, and tumor tissues in 6506 samples across eight tissues and corresponding tumor types.

Cancer recurrence monitoring using hyperpolarized [1-C]pyruvate metabolic imaging in murine breast cancer model.

The purpose of this work was to study the anatomic and metabolic changes that occur with tumor progression, regression and recurrence in a switchable MYC-driven murine breast cancer model. Serial H MRI and hyperpolarized [1-C]pyruvate metabolic imaging were used to investigate the changes in tumor volume and glycolytic metabolism over time during the multistage tumorigenesis. We show that acute de-induction of MYC expression in established tumors results in rapid tumor regression and significantly reduced glycolytic metabolism as measured by pyruvate-to-lactate conversion.

Reprogramming of Cancer Metabolism by MYC.

The past few decades have welcomed tremendous advancements toward understanding the functional significance of altered metabolism during tumorigenesis. However, many conclusions drawn from studies of cancer cells in a dish (i.e.

MYC-driven inhibition of the glutamate-cysteine ligase promotes glutathione depletion in liver cancer.

How MYC reprograms metabolism in primary tumors remains poorly understood. Using integrated gene expression and metabolite profiling, we identify six pathways that are coordinately deregulated in primary MYC-driven liver tumors: glutathione metabolism; glycine, serine, and threonine metabolism; aminoacyl-tRNA biosynthesis; cysteine and methionine metabolism; ABC transporters; and mineral absorption. We then focus our attention on glutathione (GSH) and glutathione disulfide (GSSG), as they are markedly decreased in MYC-driven tumors.

PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression.

Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC-an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors.

GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity.

Breast cancers possess fundamentally altered metabolism that fuels their pathogenicity. While many metabolic drivers of breast cancers have been identified, the metabolic pathways that mediate breast cancer malignancy and poor prognosis are less well understood. Here, we used a reactivity-based chemoproteomic platform to profile metabolic enzymes that are enriched in breast cancer cell types linked to poor prognosis, including triple-negative breast cancer (TNBC) cells and breast cancer cells that have undergone an epithelial-mesenchymal transition-like state of heightened malignancy.

Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer.

Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-negative breast cancer (TNBC), as compared to estrogen receptor-, progesterone receptor- or human epidermal growth factor 2 receptor-positive (RP) breast cancer. We and others have shown that MYC alters metabolism during tumorigenesis. However, the role of MYC in TNBC metabolism remains mostly unexplored.

Multiple breast cancer risk variants are associated with differential transcript isoform expression in tumors.

Genome-wide association studies have identified over 70 single-nucleotide polymorphisms (SNPs) associated with breast cancer. A subset of these SNPs are associated with quantitative expression of nearby genes, but the functional effects of the majority remain unknown. We hypothesized that some risk SNPs may regulate alternative splicing.

Isolated, subtle, neurological abnormalities in neurologically and cognitively healthy aging subjects.

The aim of this study is to describe the frequency of isolated, subtle, neurological abnormalities (ISNAs) in a large population of neurologically and cognitively healthy subjects and to compare ISNAs to various types of MRI-detected cerebrovascular lesions and subcortical brain atrophy in different age classes. 907 subjects were selected from a large, prospective hospital-based study. At baseline neurological examination, 17 ISNAs were selected.

Dengue virus induces and requires glycolysis for optimal replication.

Unlabelled: Viruses rely on host cellular metabolism to provide the energy and biosynthetic building blocks required for their replication. Dengue virus (DENV), a member of the Flaviviridae family, is one of the most important arthropod-borne human pathogens worldwide. We analyzed global intracellular metabolic changes associated with DENV infection of primary human cells.

Vaccinia virus requires glutamine but not glucose for efficient replication.

Unlabelled: Viruses require host cell metabolism to provide the necessary energy and biosynthetic precursors for successful viral replication. Vaccinia virus (VACV) is a member of the Poxviridae family, and its use as a vaccine enabled the eradication of variola virus, the etiologic agent of smallpox. A global metabolic screen of VACV-infected primary human foreskin fibroblasts suggested that glutamine metabolism is altered during infection.