Glutamate Transport Proteins and Metabolic Enzymes are Poor Prognostic Factors in Invasive Lobular Carcinoma.

Invasive Lobular Carcinoma (ILC) is a subtype of breast cancer characterized by distinct biological features, and limited glucose uptake coupled with increased reliance on amino acid and lipid metabolism. Our prior studies highlight the importance of glutamate as a key regulator of ILC tumor growth and therapeutic response. Here we examine the expression of four key proteins involved in glutamate transport and metabolism - SLC3A2, SLC7A11, GPX4, and GLUD1/2 - in a racially diverse cohort of 72 estrogen receptor-positive (ER+) ILC and 50 ER+ invasive ductal carcinoma, no special type (IDC/NST) patients with primary disease.

Manipulating mitochondrial reactive oxygen species alters survival in unexpected ways in a Drosophila Cdk5 model of neurodegeneration.

Reactive oxygen species (ROS) are associated with aging and neurodegeneration, but the significance of this association remains obscure. Here, using a Drosophila Cdk5 model of age-related neurodegeneration, we probe this relationship in the pathologically relevant tissue, the brain, by quantifying three specific mitochondrial ROS and manipulating these redox species pharmacologically. Our goal is to ask whether pathology-associated changes in redox state are detrimental for survival, whether they may be beneficial responses to pathology, or whether they are covariates of pathology that do not alter viability.

Senescent cell clearance ameliorates temporal lobe epilepsy and associated spatial memory deficits in mice.

Current therapies for the epilepsies only treat the symptoms, but do not prevent epileptogenesis (the process in which epilepsy develops). Many cellular responses during epileptogenesis are also common hallmarks of , which halts proliferation of damaged cells. Clearing senescent cells (SCs) restores function in several age-associated and neurodegenerative disease models.

Changes in mitochondrial distribution occur at the axon initial segment in association with neurodegeneration in Drosophila.

Changes in mitochondrial distribution are a feature of numerous age-related neurodegenerative diseases. In Drosophila, reducing the activity of Cdk5 causes a neurodegenerative phenotype and is known to affect several mitochondrial properties. Therefore, we investigated whether alterations of mitochondrial distribution are involved in Cdk5-associated neurodegeneration.

Triptolide and its prodrug Minnelide target high-risk MYC-amplified medulloblastoma in preclinical models.

Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings.

STAG2 mutations regulate 3D genome organization, chromatin loops, and Polycomb signaling in glioblastoma multiforme.

Inactivating mutations of genes encoding the cohesin complex are common in a wide range of human cancers. STAG2 is the most commonly mutated subunit. Here we report the impact of stable correction of endogenous, naturally occurring STAG2 mutations on gene expression, 3D genome organization, chromatin loops, and Polycomb signaling in glioblastoma multiforme (GBM).

MANIPULATING MITOCHONDRIAL REACTIVE OXYGEN SPECIES ALTERS SURVIVAL IN UNEXPECTED WAYS IN A MODEL OF NEURODEGENERATION.

Reactive oxygen species (ROS) are associated with aging and neurodegeneration, but the significance of this association remains obscure. Here, using a model of age-related neurodegeneration, we probe this relationship in the pathologically relevant tissue, the brain, by quantifying three specific mitochondrial ROS and manipulating these redox species pharmacologically. Our goal is to ask whether pathology-associated changes in redox state are detrimental for survival, whether they may be beneficial responses, or whether they are simply covariates of pathology that do not alter viability.

Changes in mitochondrial distribution occur at the axon initial segment in association with neurodegeneration in .

Changes in mitochondrial distribution are a feature of numerous age-related neurodegenerative diseases. In , reducing the activity of Cdk5 causes a neurodegenerative phenotype and is known to affect several mitochondrial properties. Therefore, we investigated whether alterations of mitochondrial distribution are involved in Cdk5-associated neurodegeneration.

The Journey to Improve the College of American Pathologists Cancer Biomarker Reporting Protocols.

Context.—: Biomarker reporting has increasingly become a key component of pathology reporting, providing diagnostic, prognostic, and actionable therapeutic data for patient care.

Objective.

Clinicopathologic Characteristics of PANDAS in a Young Adult: A Case Report.

Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) is an acute onset or exacerbation of neuropsychiatric symptoms following a group A streptococcus infection. It is believed to be a result of autoimmune response to streptococcal infection, but there is insufficient evidence to fully support this theory. Although this disease is primarily thought to be a disease of childhood, it is reported to occur also in adults.

Mass spectrometry imaging discriminates glioblastoma tumor cell subpopulations and different microvascular formations based on their lipid profiles.

Glioblastoma is a prevalent malignant brain tumor and despite clinical intervention, tumor recurrence is frequent and usually fatal. Genomic investigations have provided a greater understanding of molecular heterogeneity in glioblastoma, yet there are still no curative treatments, and the prognosis has remained unchanged. The aggressive nature of glioblastoma is attributed to the heterogeneity in tumor cell subpopulations and aberrant microvascular proliferation.

The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations.

Aging and age-related neurodegeneration are both associated with the accumulation of unfolded and abnormally folded proteins, highlighting the importance of protein homeostasis (termed proteostasis) in maintaining organismal health. To this end, two cellular compartments with essential protein folding functions, the endoplasmic reticulum (ER) and the mitochondria, are equipped with unique protein stress responses, known as the ER unfolded protein response (UPR ) and the mitochondrial UPR (UPR ), respectively. These organellar UPRs play roles in shaping the cellular responses to proteostatic stress that occurs in aging and age-related neurodegeneration.

The tumor immune microenvironment of primary and metastatic HER2- positive breast cancers utilizing gene expression and spatial proteomic profiling.

Background: The characterization of the immune component of the tumor microenvironment (TME) of human epidermal growth factor receptor 2 positive (HER2+) breast cancer has been limited. Molecular and spatial characterization of HER2+ TME of primary, recurrent, and metastatic breast tumors has the potential to identify immune mediated mechanisms and biomarker targets that could be used to guide selection of therapies.

Methods: We examined 15 specimens from eight patients with HER2+ breast cancer: 10 primary breast tumors (PBT), two soft tissue, one lung, and two brain metastases (BM).

Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion.

Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC). The extracellular matrix (ECM) contributes to immune exclusion. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes.

Astrocyte senescence and SASP in neurodegeneration: tau joins the loop.

Tau accumulation is a core component of Alzheimer's disease and other neurodegenerative tauopathies. While tau's impact on neurons is a major area of research, the effect of extracellular tau on astrocytes is largely unknown. This article summarizes our recent studies showing that astrocyte senescence plays a critical role in neurodegenerative diseases and integrates extracellular tau into the regulatory loop of senescent astrocyte-mediated neurotoxicity.

STAG2 as a prognostic biomarker in low-grade non-muscle invasive bladder cancer.

Objective: Improvements to bladder cancer risk stratification guidelines are needed to better tailor post-operative surveillance and adjuvant therapy to individual patients. We previously identified STAG2 as a commonly mutated tumor suppressor gene in bladder cancer and an independent predictor of progression in NMIBC. Here we test the value of combining STAG2 immunostaining with other risk stratification biomarkers in NMIBC, and as an individual biomarker in MIBC.

Protein Expression of Angiotensin-Converting Enzyme 2 (ACE2) is Upregulated in Brains with Alzheimer's Disease.

Alzheimer's disease is a chronic neurodegenerative disorder and represents the main cause of dementia globally. Currently, the world is suffering from the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur.

Angiotensin-converting enzyme 2 (ACE2) is upregulated in Alzheimer's disease brain.

Alzheimer's disease is a chronic neurodegenerative disorder and represents the main cause of dementia. Currently, the world is suffering from the pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur.

Cytokine Storms in Cancer and COVID-19.

During the COVID-19 pandemic, research on "cytokine storms" has been reinvigorated in the field of infectious disease, but it also has particular relevance to cancer research. Interleukin-6 (IL-6) has emerged as a key component of the immune response to SARS-CoV-2, such that the repurposing of anti-IL-6 therapeutics for COVID-19 is now a major line of investigation, with several ongoing clinical trials. We lay a framework for understanding the role of IL-6 in the context of cancer research and COVID-19 and suggest how lessons learned from cancer research may impact SARS-CoV-2 research and vice versa.

Isolation and characterization of antibody fragments selective for human FTD brain derived TDP-43 variants.

Background: Frontotemporal dementia (FTD) is the second leading cause of early onset dementia following Alzheimer's disease. It involves atrophy of the frontal and temporal regions of the brain affecting language, memory, and behavior. Transactive response DNA-binding protein 43 (TDP-43) pathology is found in most FTD and ALS cases.