Phosphatidylinositol 3-kinase (PI3K) promotes cancer cell survival, migration, growth, and proliferation by generating phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the inner leaflet of the plasma membrane. PIP3 recruits pleckstrin homology (PH) domain-containing proteins to the membrane to activate oncogenic signaling cascades. Anti-cancer therapeutics targeting the PI3K/AKT/mTOR pathway are in clinical development. In a mass spectrometric screen to identify PIP3-regulated proteins in breast cancer cells, levels of the Rac activator PIP3-dependent Rac exchange factor 1 (P-REX1) increased in response to PI3K inhibition, and decreased upon loss of the PI3K antagonist PTEN. P-REX1 mRNA and protein levels were positively correlated with ER expression, and inversely correlated with PI3K pathway activation in breast tumors as assessed by gene expression and phosphoproteomic analyses. P-REX1 increased activation of Rac1, PI3K/AKT, and MEK/ERK signaling in a PTEN-independent manner, and promoted cell and tumor viability. Loss of P-REX1 or inhibition of Rac suppressed PI3K/AKT and MEK/ERK, and decreased viability. P-REX1 also promoted insulin-like growth factor-1 receptor (IGF-1R) activation, suggesting that P-REX1 provides positive feedback to activators upstream of PI3K. In support of a model where PIP3-driven P-REX1 promotes both PI3K/AKT and MEK/ERK signaling, high levels of P-REX1 mRNA (but not phospho-AKT or a transcriptomic signature of PI3K activation) were predictive of sensitivity to PI3K inhibitors among breast cancer cell lines. P-REX1 expression was highest in ER+ breast tumors compared to many other cancer subtypes, suggesting that neutralizing the P-REX1/Rac axis may provide a novel therapeutic approach to selectively abrogate oncogenic signaling in breast cancer cells.

Development of an RRAB increased residents' manuscript publication and poster presentation rates and facilitated the research process.

Purpose Phosphatidylinositol 3-kinase (PI3K) inhibitors are being developed for the treatment of estrogen receptor α (ER)-positive breast cancer in combination with anti-estrogens. Understanding the temporal response and pharmacodynamic effects of PI3K inhibition in ER+ breast cancer will provide rationale for treatment scheduling to maximize therapeutic index. Experimental Design Anti-estrogen-sensitive and -resistant ER+ human breast cancer cell lines, and mice bearing PIK3CA-mutant xenografts were treated with the anti-estrogen fulvestrant, the PI3K inhibitor GDC-0941 (pictilisib; varied doses/schedules that provided similar amounts of drug each week), or combinations. Cell viability, signaling pathway inhibition, proliferation, apoptosis, tumor volume, and GDC-0941 concentrations in plasma and tumors were temporally measured. Results Treatment with the combination of fulvestrant and GDC-0941, regardless of dose/schedule, was significantly more effective than single-agent treatments in fulvestrant-resistant tumors. Short-term, complete PI3K inhibition blocked cell growth in vitro more effectively than chronic, incomplete inhibition. Longer-term PI3K inhibition hypersensitized cells to growth factor signaling upon drug withdrawal. Different schedules of GDC-0941 elicited similar tumor responses. While weekly high-dose GDC-0941 with fulvestrant continuously suppressed PI3K signaling for 72 hours, inducing a bolus of apoptosis and inhibiting proliferation, PI3K reactivation upon GDC-0941 washout induced a proliferative burst. Fulvestrant with daily low-dose GDC-0941 metronomically suppressed PI3K for 6–9 hours/day, repeatedly inducing small amounts of apoptosis and temporarily inhibiting proliferation, followed by proliferative rebound compared to fulvestrant alone. Conclusions Continuous and metronomic PI3K inhibition elicit robust anti-cancer effects in ER+, PIK3CA-mutant breast cancer. Clinical exploration of alternate treatment schedules of PI3K inhibitors with anti-estrogens is warranted.

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. Respectively, symptoms of cognitive impairment were teased out of the multiple neurologic complications presented for each case and reported based on antimicrobial class. Articles were excluded if they focused solely on neuropsychiatric side effects such as seizures, psychosis, hallucinations, or mood disturbances, were conducted in animals, or involved antiretroviral medication therapies.Results:Of over 50 case reviews, case reports, retrospective chart reviews, and prospective cohort studies analyzed, 25 were deemed appropriate for purposes of this review. Common antimicrobial-induced cognitive side effects for all antimicrobial classes included confusion, delirium, encephalopathy, and impaired concentration or attention. Recurring risk factors included, but were not limited to, older age and renal impairment. Mechanisms of cognitive impairment were relatively specific to each antimicrobial class.Discussion:Awareness of the potential for antimicrobial-induced cognitive side effects, including the general time frame of symptom onset and symptom presentation, is critical in challenging patient cases. This review article aims to summarize the risk factors, clinical symptoms, mechanisms, and management of antimicrobial-induced cognitive side effects. Pharmacists can play a key role in prevention through adjustment of medications for renal or hepatic dysfunction, avoidance of polypharmacy, and knowledge of critical drug interactions that may precipitate cognitive decline.

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. The purpose of this innovative practice was to increase access to overdose education and naloxone distribution (OEND) to at-risk patients across urban and rural areas. Patient-specific factors were also examined among those receiving naloxone through the CVT clinic compared to other prescribers. During the first 6 months from the initiation of the clinic, 1 pharmacist prescribed 21% of the health care system's naloxone. These patients identified by the pharmacist-led CVT clinic were more likely to be considered high-risk due to concomitant use of opioids and benzodiazepines. In conclusion, the pharmacist-led CVT group clinic has been an efficient strategy to extend OEND services to high-risk patients beyond central, urban areas.