Plasma DNA as a "liquid biopsy" incompletely complements tumor biopsy for identification of mutations in a case series of four patients with oligometastatic breast cancer.

Purpose: Circulating tumor DNA in plasma may present a minimally invasive opportunity to identify tumor-derived mutations to inform selection of targeted therapies for individual patients, particularly in cases of oligometastatic disease where biopsy of multiple tumors is impractical. To assess the utility of plasma DNA as a "liquid biopsy" for precision oncology, we tested whether sequencing of plasma DNA is a reliable surrogate for sequencing of tumor DNA to identify targetable genetic alterations.

Methods: Blood and biopsies of 1-3 tumors were obtained from 4 evaluable patients with advanced breast cancer.

Description of a pharmacist-led clinical video telehealth group clinic for opioid overdose prevention and naloxone education.

To achieve the nationwide goal of reducing opioid-related deaths, a clinical pharmacy specialist-led clinical video telehealth (CVT) clinic was created at a Veterans Affairs medical center (VAMC) to deliver opioid overdose prevention and naloxone education to at-risk patients. The purpose of this innovative practice was to improve access to this potentially life-saving intervention to patients across urban and rural areas. This study is a single-center, descriptive analysis of adult patients across 2 VAMC campuses and 4 community-based outpatient clinics from July 11, 2016, through December 31, 2016.

Antimicrobial-induced cognitive side effects.

Introduction: Antimicrobial-induced cognitive side effects are often overlooked or underreported. Literature often reports symptoms of antimicrobial-induced cognitive impairment under more general blanket terms, such as neuropsychiatric side effects, neurotoxicity, or drug-induced delirium or encephalopathy.

Methods: A PubMed search using terms including antibiotics, antifungals, antivirals, antimalarials, side effects, cognitive, neurotoxicity, encephalopathy, and delirium was conducted.

Strategically Timing Inhibition of Phosphatidylinositol 3-Kinase to Maximize Therapeutic Index in Estrogen Receptor Alpha-Positive, PIK3CA-Mutant Breast Cancer.

Purpose: Phosphatidylinositol 3-kinase (PI3K) inhibitors are being developed for the treatment of estrogen receptor α (ER)-positive breast cancer in combination with antiestrogens. Understanding the temporal response and pharmacodynamic effects of PI3K inhibition in ER(+) breast cancer will provide a rationale for treatment scheduling to maximize therapeutic index.

Experimental Design: Antiestrogen-sensitive and antiestrogen-resistant ER(+) human breast cancer cell lines and mice bearing PIK3CA-mutant xenografts were treated with the antiestrogen fulvestrant, the PI3K inhibitor GDC-0941 (pictilisib; varied doses/schedules that provided similar amounts of drug each week), or combinations.

The PI3K/mTOR dual inhibitor P7170 demonstrates potent activity against endocrine-sensitive and endocrine-resistant ER+ breast cancer.

Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway has been implicated in anti-estrogen resistance in breast cancer. We tested the therapeutic potential of the novel PI3K/mTOR dual inhibitor P7170 in a panel of anti-estrogen-sensitive and anti-estrogen-resistant models of ER+ breast cancer. Estrogen receptor-positive (ER+) breast cancer cells were treated ±P7170.

Designing a resident research program.

Purpose: The development of a resident research program and the role of the residency research advisory board (RRAB) in the program are described.

Summary: Over the past decade, there have been numerous barriers to successfully implementing a residency research program. An RRAB was subsequently developed to assist with research mentoring to help prepare residents to incorporate research into future positions.

Effects of gangliosides on the activity of the plasma membrane Ca2+-ATPase.

Control of intracellular calcium concentrations ([Ca(2+)]i) is essential for neuronal function, and the plasma membrane Ca(2+)-ATPase (PMCA) is crucial for the maintenance of low [Ca(2+)]i. We previously reported on loss of PMCA activity in brain synaptic membranes during aging. Gangliosides are known to modulate Ca(2+) homeostasis and signal transduction in neurons.

Comparison of hemoglobin A1c goal achievement with the addition of pioglitazone to maximal/highest tolerated doses of sulfonylurea and metformin combination therapy.

Objectives: It has been proposed that the combination of thiazolidinedione (TZD) therapy to metformin and sulfonylurea is beneficial due to each medication having a unique mechanism of action. Within the Veterans Affairs Hospital, specific criteria of use define when TZD therapy can be initiated. Most patients who receive TZD therapy have failed other medications prior to use.

Effects of paraquat-induced oxidative stress on the neuronal plasma membrane Ca(2+)-ATPase.

Oxidative stress leads to the disruption of calcium homeostasis in brain neurons; however, the direct effects of oxidants on proteins that regulate intracellular calcium ([Ca(2+)](i)) are not known. The calmodulin (CaM)-stimulated plasma membrane Ca(2+)-ATPase (PMCA) plays a critical role in regulating [Ca(2+)](i). Our previous in vitro studies showed that PMCA present in brain synaptic membranes is readily inactivated by a variety of reactive oxygen species (ROS).

Partitioning of the plasma membrane Ca2+-ATPase into lipid rafts in primary neurons: effects of cholesterol depletion.

Spatial and temporal alterations in intracellular calcium [Ca(2+)](i) play a pivotal role in a wide array of neuronal functions. Disruption in Ca(2+) homeostasis has been implicated in the decline in neuronal function in brain aging and in neurodegenerative disorders. The plasma membrane Ca(2+)-ATPase (PMCA) is a high affinity Ca(2+) transporter that plays a crucial role in the termination of [Ca(2+)](i) signals and in the maintenance of low [Ca(2+)](i) essential for signaling.

RNA--induced silencing of the plasma membrane Ca2+-ATPase 2 in neuronal cells: effects on Ca2+ homeostasis and cell viability.

Intraneuronal calcium ([Ca(2+)](i)) regulation is altered in aging brain, possibly because of the changes in critical Ca(2+) transporters. We previously reported that the levels of the plasma membrane Ca(2+)-ATPase (PMCA) and the V(max) for enzyme activity are significantly reduced in synaptic membranes in aging rat brain. The goal of these studies was to use RNA(i) techniques to suppress expression of a major neuronal isoform, PMCA2, in neurons in culture to determine the potential functional consequences of a decrease in PMCA activity.

p35/Cyclin-dependent kinase 5 is required for protection against beta-amyloid-induced cell death but not tau phosphorylation by ceramide.

Ceramide is a bioactive sphingolipid that can prevent calpain activation and beta-amyloid (A beta) neurotoxicity in cortical neurons. Recent evidence supports A beta induction of a calpain-dependent cleavage of the cyclin-dependent kinase 5 (cdk5) regulatory protein p35 that contributes to tau hyperphosphorylation and neuronal death. Using cortical neurons isolated from wild-type and p35 knockout mice, we investigated whether ceramide required p35/cdk5 to protect against A beta-induced cell death and tau phosphorylation.

A non-toxic Hsp90 inhibitor protects neurons from Abeta-induced toxicity.

The molecular chaperones have been implicated in numerous neurodegenerative disorders in which the defining pathology is misfolded proteins and the accumulation of protein aggregates. In Alzheimer's disease, hyperphosphorylation of tau protein results in its dissociation from microtubules and the formation of pathogenic aggregates. An inverse relationship was demonstrated between Hsp90/Hsp70 levels and aggregated tau, suggesting that Hsp90 inhibitors that upregulate these chaperones could provide neuroprotection.

beta-Amyloid and endoplasmic reticulum stress responses in primary neurons: effects of drugs that interact with the cytoskeleton.

In vitro studies designed to probe the cellular mechanisms underlying beta-amyloid (Abeta) toxicity in neurons have implicated several processes, including hyperphosphorylation of the microtubule (MT)-associated protein tau, loss of MT stability, and increased cytosolic calcium levels. Given that Alzheimer's disease involves accumulation of aggregates of two different proteins, the potential involvement of the unfolded protein response (UPR) and endoplasmic reticulum (ER) dysfunction has been suggested to lead to cell death. The relationship between these apparently divergent factors and pathways in Abeta toxicity is still unclear.