Comprehensive Characterization of Cancer Driver Genes and Mutations.

Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%-85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors.

Cancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases.

The phosphoinositide 3-kinase regulatory subunit p85α is a key regulator of kinase signaling and is frequently mutated in cancers. In the present study, we showed that in addition to weakening the inhibitory interaction between p85α and p110α, a group of driver mutations in the p85α N-terminal SH2 domain activated EGFR, HER2, HER3, c-Met, and IGF-1R in a p110α-independent manner. Cancer cells expressing these mutations exhibited the activation of p110α and the AKT pathway. Interestingly, the activation of EGFR, HER2, and c-Met was attributed to the ability of driver mutations to inhibit HER3 ubiquitination and degradation. The resulting increase in HER3 protein levels promoted its heterodimerization with EGFR, HER2, and c-Met, as well as the allosteric activation of these dimerized partners; however, HER3 silencing abolished this transactivation. Accordingly, inhibitors of either AKT or the HER family reduced the oncogenicity of driver mutations. The combination of these inhibitors resulted in marked synergy. Taken together, our findings provide mechanistic insights and suggest therapeutic strategies targeting a class of recurrent p85α mutations.

Biophysical Principles and Computational Modeling of Deep Brain Stimulation.

BACKGROUND: Deep brain stimulation (DBS) has revolutionized the treatment of neurological disorders, yet the mechanisms of DBS are still under investigation. Computational models are important in silico tools for elucidating these underlying principles and potentially for personalizing DBS therapy to individual patients. The basic principles underlying neurostimulation computational models, however, are not well known in the clinical neuromodulation community. OBJECTIVE: In this study, we present a tutorial on the derivation of computational models of DBS and outline the biophysical contributions of electrodes, stimulation parameters, and tissue substrates to the effects of DBS. RESULTS: Given that many aspects of DBS are difficult to characterize experimentally, computational models have played an important role in understanding how material, size, shape, and contact segmentation influence device biocompatibility, energy efficiency, the spatial spread of the electric field, and the specificity of neural activation. Neural activation is dictated by stimulation parameters including frequency, current vs voltage control, amplitude, pulse width, polarity configurations, and waveform. These parameters also affect the potential for tissue damage, energy efficiency, the spatial spread of the electric field, and the specificity of neural activation. Activation of the neural substrate also is influenced by the encapsulation layer surrounding the electrode, the conductivity of the surrounding tissue, and the size and orientation of white matter fibers. These properties modulate the effects of the electric field and determine the ultimate therapeutic response. CONCLUSION: This article describes biophysical principles that are useful for understanding the mechanisms of neurostimulation.

Focused Ultrasound Thalamotomy for Tremor in Parkinson's Disease: Outcomes in a Large, Prospective Cohort.

BACKGROUND: Magnetic resonance guided focused ultrasound (MRgFUS) is United States Food and Drug Administration approved for the treatment of tremor-dominant Parkinson's disease (TdPD), but only limited studies have been described in practice. OBJECTIVES: To report the largest prospective experience of unilateral MRgFUS thalamotomy for the treatment of medically refractory TdPD. METHODS: Clinical outcomes of 48 patients with medically refractory TdPD who underwent MRgFUS thalamotomy were evaluated. Tremor outcomes were assessed using the Fahn-Tolosa-Marin scale and adverse effects were categorized using a structured questionnaire and clinical exam at 1 month (n = 44), 3 months (n = 34), 1 year (n = 22), 2 years (n = 5), and 3 years (n = 2). Patients underwent magnetic resonance imaging <24 hours post-procedure. RESULTS: Significant tremor control persisted at all follow-ups (P < 0.001). All side effects were mild. At 3 months, these included gait imbalance (38.24%), sensory deficits (26.47%), motor weakness (17.65%), dysgeusia (5.88%), and dysarthria (5.88%), with some persisting at 1 year. CONCLUSIONS: MRgFUS thalamotomy is an effective treatment for sustained tremor control in patients with TdPD. © 2023 International Parkinson and Movement Disorder Society.

High risk and low prevalence diseases: Toxic alcohol ingestion.

INTRODUCTION: Toxic alcohol ingestion is a rare but serious condition that carries with it a high rate of morbidity and mortality. OBJECTIVE: This review highlights the pearls and pitfalls of toxic alcohol ingestion, including presentation, diagnosis, and management in the emergency department (ED) based on current evidence. DISCUSSION: Toxic alcohols include ethylene glycol, methanol, isopropyl alcohol, propylene glycol, and diethylene glycol. These substances can be found in several settings including hospitals, hardware stores, and the household, and ingestion can be accidental or intentional. Toxic alcohol ingestion presents with various degrees of inebriation, acidemia, and end-organ damage depending on the substance. Timely diagnosis is critical to prevent irreversible organ damage or death and is based primarily on clinical history and consideration of this entity. Laboratory evidence of toxic alcohol ingestion includes worsening osmolar gap or anion-gap acidemia and end organ injury. Treatment depends on the ingestion and severity of illness but includes alcohol dehydrogenase blockade with fomepizole or ethanol and special considerations for the initiation of hemodialysis. CONCLUSIONS: An understanding of toxic alcohol ingestion can assist emergency clinicians in diagnosing and managing this potentially deadly disease.

The Role of FAS Receptor Methylation in Osteosarcoma Metastasis.

Osteosarcoma is the most frequent primary malignant bone tumor with an annual incidence of about 400 cases in the United States. Osteosarcoma primarily metastasizes to the lungs, where FAS ligand (FASL) is constitutively expressed. The interaction of FASL and its cell surface receptor, FAS, triggers apoptosis in normal cells; however, this function is altered in cancer cells. DNA methylation has previously been explored as a mechanism for altering FAS expression, but no variability was identified in the CpG island (CGI) overlapping the promoter. Analysis of an expanded region, including CGI shores and shelves, revealed high variability in the methylation of certain CpG sites that correlated significantly with FAS mRNA expression in a negative manner. Bisulfite sequencing revealed additional CpG sites, which were highly methylated in the metastatic LM7 cell line but unmethylated in its parental non-metastatic SaOS-2 cell line. Treatment with the demethylating agent, 5-azacytidine, resulted in a loss of methylation in CpG sites located within the FAS promoter and restored FAS protein expression in LM7 cells, resulting in reduced migration. Orthotopic implantation of 5-azacytidine treated LM7 cells into severe combined immunodeficient mice led to decreased lung metastases. These results suggest that DNA methylation of CGI shore sites may regulate FAS expression and constitute a potential target for osteosarcoma therapy, utilizing demethylating agents currently approved for the treatment of other cancers.

Transcriptome visualization and data availability at the Saccharomyces Genome Database.

The Saccharomyces Genome Database (SGD; www.yeastgenome.org) maintains the official annotation of all genes in the Saccharomyces cerevisiae reference genome and aims to elucidate the function of these genes and their products by integrating manually curated experimental data. Technological advances have allowed researchers to profile RNA expression and identify transcripts at high resolution. These data can be configured in web-based genome browser applications for display to the general public. Accordingly, SGD has incorporated published transcript isoform data in our instance of JBrowse, a genome visualization platform. This resource will help clarify S. cerevisiae biological processes by furthering studies of transcriptional regulation, untranslated regions, genome engineering, and expression quantification in S. cerevisiae.

Effect of Therapeutic Drug Monitoring and Cytochrome P450 2C19 Genotyping on Clinical Outcomes of Voriconazole: A Systematic Review.

OBJECTIVES: To examine current knowledge on the clinical utility of therapeutic drug monitoring (TDM) in voriconazole therapy, the impact of CYP2C19 genotype on voriconazole plasma concentrations, and the role of CYP2C19 genotyping in voriconazole therapy. DATA SOURCES: Three literature searches were conducted for original reports on (1) TDM and voriconazole outcomes and (2) voriconazole and CYP2C19 polymorphisms. Searches were conducted through EMBASE, MEDLINE/PubMed, Scopus, and Cochrane Central Register of Controlled Trials from inception to June 2020. STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials, cohort studies, and case series with ≥10 patients were included. Only full-text references in English were eligible. DATA SYNTHESIS: A total of 63 studies were reviewed. TDM was recommended because of established concentration and efficacy/toxicity relationships. Voriconazole trough concentrations ≥1.0 mg/L were associated with treatment success; supratherapeutic concentrations were associated with increased neurotoxicity; and hepatotoxicity associations were more prevalent in Asian populations. CYP2C19 polymorphisms significantly affect voriconazole metabolism, but no relationship with efficacy/safety were found. Genotype-guided dosing with TDM was reported to increase chances of achieving therapeutic range. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Genotype-guided dosing with TDM is a potential solution to optimizing voriconazole efficacy while avoiding treatment failures and common toxicities. CONCLUSIONS: Voriconazole plasma concentrations and TDM are treatment outcome predictors, but research is needed to form a consensus target therapeutic range and dosage adjustment guidelines based on plasma concentrations. CYP2C19 polymorphisms are a predictor of voriconazole concentrations and metabolism, but clinical implications are not established. Large-scale, high-methodological-quality trials are required to investigate the role for prospective genotyping and establish CYP2C19-guided voriconazole dosing recommendations.

Intramuscular cobinamide as an antidote to methyl mercaptan poisoning.

BACKGROUND: Methyl mercaptan occurs naturally in the environment and is found in a variety of occupational settings, including the oil, paper, plastics, and pesticides industries. It is a toxic gas and deaths from methyl mercaptan exposure have occurred. The Department of Homeland Security considers it a high threat chemical agent that could be used by terrorists. Unfortunately, no specific treatment exists for methyl mercaptan poisoning. METHODS: We conducted a randomized trial in 12 swine comparing no treatment to intramuscular injection of the vitamin B12 analog cobinamide (2.0 mL, 12.5 mg/kg) following acute inhalation of methyl mercaptan gas. Physiological and laboratory parameters were similar in the control and cobinamide-treated groups at baseline and at the time of treatment. RESULTS: All six cobinamide-treated animals survived, whereas only one of six control animals lived (17% survival) (p = 0.0043). The cobinamide-treated animals returned to a normal breathing pattern by 3.8 ± 1.1 min after treatment (mean ± SD), while all but one animal in the control group had intermittent gasping, never regaining a normal breathing pattern. Blood pressure and arterial oxygen saturation returned to baseline values within 15 minutes of cobinamide-treatment. Plasma lactate concentration increased progressively until death (10.93 ± 6.02 mmol [mean ± SD]) in control animals, and decreased toward baseline (3.79 ± 2.93 mmol [mean ± SD]) by the end of the experiment in cobinamide-treated animals. CONCLUSION: We conclude that intramuscular administration of cobinamide improves survival and clinical outcomes in a large animal model of acute, high dose methyl mercaptan poisoning.

A retrospective study of antithrombotic therapy use in an outpatient haemodialysis unit.

WHAT IS KNOWN AND OBJECTIVE: Patients on haemodialysis (HD) are at increased risk of both bleeding and thrombotic events, due to comorbidities and nature of dialysis treatment. However, there is a lack of research on evidence-based treatment strategies and prescribing patterns for antithrombotic therapies (ATT) in this population. To characterize ATT use and its main indications in an outpatient HD unit. METHODS: A single-centre retrospective chart review was conducted in a Toronto outpatient HD unit (n = 329). Medical histories, number of ATTs and corresponding indications were collected from adult patients prescribed at least one ATT from 1 October 2019 to 31 December 2019, inclusive. RESULTS AND DISCUSSION: Of 329 patients in the unit, a total of 135 (41%) patients were on at least one ATT. Of these 135 patients, 80% were on monotherapy (55% antiplatelet, 25.1% anticoagulant), 12.6% were on dual antiplatelet therapy (DAPT), and 7.4% were on a antiplatelet and anticoagulant combination. Primary indications for ATT in our cohort were coronary artery disease (CAD; 55%), atrial fibrillation (18.5%) and venous thromboembolism (VTE; 17%). Described ATT use was in-line with current clinical guidelines. Monotherapy was primarily used in our HD cohort, whereas few patients were on dual therapy. Low-dose aspirin was the most common antiplatelet prescribed for secondary prevention of cardiovascular events. Warfarin monotherapy was primarily indicated for VTE, and DAPT aspirin/clopidogrel was the most commonly prescribed for CAD. WHAT IS NEW AND CONCLUSION: Our characterization of ATT use in this HD cohort demonstrates that ATT is often prescribed for a number of different CVD reasons. Overlapping and confounding indications for prescribing ATTs, lack of randomized controlled trials and unclear clinical guidelines mean that individualized risk-benefit assessments for ATT use are still needed to provide care for these high-risk patients. More research to address the safety and efficacy of ATTs is warranted to develop more robust evidence-based treatment guidelines for the HD population.

Pediatric Prehospital Intraosseous Access During Combat Operations in Iraq and Afghanistan.

BACKGROUND: Vascular access in critically ill pediatric patients can be challenging with delays potentially leading to worse outcomes. Intraosseous (IO) access has a low rate of complications and can be utilized to administer lifesaving medications. Combat medics are trained to treat adults but may also be required to treat children in the deployed setting. Vascular access in children can be challenging, especially in a hypovolemic state. There are limited data on prehospital lifesaving interventions in children in the combat setting. We sought to characterize the use of IO access in pediatric patients who sustained trauma in the combat setting. METHODS: We queried the Department of Defense Trauma Registry for all pediatric patients admitted to fixed-facilities and forward surgical teams in Iraq and Afghanistan from January 2007 to January 2016. Within that population, we searched for all subjects with a documented prehospital IO or intravenous (IV) access obtained. Subjects with both an IO and IV documented were placed into the IO category. We separated subjects by age groupings: younger than 1, 1 to 4, 5 to 9, 10 to 14, and 15 to 17 years. RESULTS: During the study period, there were 3439 subjects 17 years or younger. There were 177 in the IO cohort and 803 in the IV cohort. Most subjects in the IO cohort were in the 10- to 14-year-old age group (35.6%), male (79.1%), located in Afghanistan (95.5%), and injured by explosive (52.0%), with lower survival rates than the IV cohort (68.9% vs 90.7%, P < 0.001). Hemostatic dressing application, tourniquet application, intubation, cardiopulmonary resuscitation, sedative administration, ketamine administration, and paralytic administration were all higher in the IO cohort. CONCLUSIONS: Pediatric IO placement in the prehospital setting occurred infrequently. Pediatric subjects receiving an IO had higher injury severity scores and higher mortality rates compared with those who received an IV only. Intraosseous use appears to be used more often in critically ill pediatric subjects.

Lower opioid and higher adjuvant analgesic use in patients on haemodialysis: A single-centre cross-sectional study.

WHAT IS KNOWN: Opioids are often used to treat chronic non-cancer pain (CNCP) in patients on haemodialysis. Altered pharmacokinetics in this population increases risk for opioid-related adverse events. Although useful in pain management, there is a lack of opioid prescribing guidance for end-stage kidney disease. OBJECTIVE: To characterize opioid usage for CNCP in an outpatient haemodialysis unit. METHODS: Cross-sectional, single-centre, retrospective cohort study of 272 patients receiving outpatient haemodialysis between 01 June and 31 December 2017. Prevalence of prescription or non-prescription opioids, formulation, indication, dosing, prescriber type and therapeutic effectiveness were evaluated. RESULTS: A total of 27 (10%, aged 58 + 12.1 years, 59% women) patients received opioids for CNCP during the study period. Pain aetiology was diverse; 14 (52%) patients experienced multiple concurrent chronic pain conditions. Hydromorphone (55%) and oxycodone (37%) were the most common prescriptions. A majority (85%) of patients used non-opioid analgesics as adjunct therapy, while half (48%) used benzodiazepines or zopiclone concurrently. Patients who completed a pain scale (n = 10) reported a median pain intensity of 6.8/10 ([IQR], 4.5-7.3). DISCUSSION: Opioid usage was lower than expected despite a higher prevalence of concurrent chronic pain conditions. Though this was within opioid usage guidelines, pain may not be sufficiently controlled. High concomitant use of benzodiazepines and Z-drugs introduces the potential for additive adverse effects. Judicious opioid usage can be facilitated with stewardship to effectively treat pain while avoiding associated harms and manage potential drug-drug interactions with common concomitant medications. WHAT IS NEW AND CONCLUSION: The prevalence of chronic opioid use for non-cancer pain in haemodialysis patients was lower than expected at our centre. Despite following the recommended guidelines, pain management was relatively ineffective, and concomitant use of non-opioid analgesics was widespread. Opioid stewardship is recommended to optimize pain treatment and mitigate drug interaction risks.

Efficacy of Oral Administration of Sodium Thiosulfate and Glycine in a Large, Swine Model of Oral Cyanide Toxicity.

STUDY OBJECTIVE: Cyanide is a deadly poison, particularly with oral exposure, in which larger doses can occur before any symptoms develop. Multiple governmental agencies highlight oral cyanide as an agent that can be used in a terrorist attack because it can be easily weaponized and is readily available. Currently, there are no Food and Drug Administration-approved antidotes specifically for oral cyanide. An oral countermeasure that can neutralize and prevent absorption of cyanide from the gastrointestinal tract after oral exposure is needed. The objective of this study is to determine if the combination of glycine and sodium thiosulfate administered orally is effective in reducing mortality in a large, swine model of oral cyanide toxicity. METHODS: Nine swine (45 to 55 kg) were instrumented, sedated, and stabilized. Potassium cyanide (at 8 mg/kg) in saline solution was delivered as a onetime bolus through an orogastric tube. Three minutes after cyanide administration, animals that were randomized to the treatment group received sodium thiosulfate (508.2 mg/kg, 3.25-M solution) and glycine (30 mg/kg, 3.5-M solution) through an orogastric tube. Survival at 60 minutes was the primary outcome. We compared survival between groups by log-rank Mantel-Cox analysis and trended laboratory results and vital signs. RESULTS: At baseline and treatment, all animals were similar. Survival at 60 minutes was 100% in treated animals compared with 0% in the control group (P=.003). By the study end, defined as death or 60 minutes after cyanide administration, there was a significant difference in the lactate concentration between the treatment and control groups (control 9.43 mmol/L [SD 4.08]; treatment 1.66 mmol/L [SD 0.82]; difference between means 7.69 mmol/L [SD 2.07]; 95% confidence interval difference -14.05 to -1.32). Mean arterial pressure was significantly different between the treatment and control groups at study end (control 26 mm Hg [SD 6.7]; treatment 81 mm Hg [SD 14]; difference between means 55.2 mm Hg [SD 7.1]; 95% confidence interval difference 37.8 to 72.6). pH and oxygen saturation were also significantly different between the treatment and control groups at study end. CONCLUSION: The combination of oral sodium thiosulfate and glycine significantly improved survival and physiologic parameters in a large-animal model of oral cyanide toxicity.

Idiopathic acute eosinophilic pneumonia: A rare cause of hypoxic respiratory failure.

Idiopathic Acute Eosinophilic Pneumonia (IAEP) is a life-threatening cause of hypoxic respiratory failure. IAEP is challenging to diagnose as it may mimic infectious pneumonia or acute respiratory distress syndrome. Distinguishing IAEP from these alternatives is important; the mainstay of treatment for IAEP is corticosteroids, a therapy which might not otherwise be indicated. Patients treated appropriately usually experience a full recovery. In this case report we describe the presentation, evaluation, and management of a 19-year old male who presented to the emergency department (ED) in respiratory failure from IAEP. The patient was a military trainee who recently moved to the United States from Saudi Arabia. He also recently began smoking cigarettes for the first time, a known risk factor for IAEP. Upon initial presentation, the patient was in respiratory distress and had an oxygen saturation of 82% on room air. His ED diagnostic workup included chest X-ray showing diffuse interstitial thickening and chest computed tomography that demonstrated diffuse nodular opacification of pulmonary parenchyma. The patient was admitted to the intensive care unit (ICU) where bronchoscopy yielded cytology with 30% eosinophilia. The patient ultimately required 3 days of extra corporeal membrane oxygenation (ECMO) due to worsening hypoxic respiratory failure. After both intravenous and outpatient oral steroid treatments, the patient went on to have a full recovery with no ongoing respiratory issues. To our knowledge, this is the first case of IAEP requiring ECMO reported in the emergency medicine literature.

Acetaminophen and Acetylsalicylic Acid Exposure in a Preterm Infant after Maternal Overdose.

Here, we review the case of a 26 1/7 weeks' gestation premature female infant born to a mother who intentionally ingested a large quantity of Tylenol, aspirin, quetiapine, and prenatal vitamins. The neonate subsequently had markedly elevated levels of both Tylenol and aspirin when checked on the first day of life. While overall clinically stable, the neonate did demonstrate coagulopathy as evidenced by abnormal coagulation studies. Both poison control and a pediatric gastroenterologist/hepatologist were consulted. She successfully tolerated a course of N-acetylcysteine; her subsequent Tylenol level was markedly decreased and the neonate exhibited no further effects of toxicity. The salicylate level decreased on its own accord. To our knowledge, this is the first report of a neonate at 26 weeks' gestation that has been successfully managed for supratherapeutic concentrations of acetaminophen and acetylsalicylic acid secondary to maternal ingestion. While rare, this case may serve as a reference for the effectiveness of N-acetylcysteine in premature infants in such instances.

Lacosamide Overdose: A Case of QRS Prolongation and Seizure.

BACKGROUND: Lacosamide is a third-generation antiepileptic drug. Its likely mechanism of action is via neuronal sodium channel blockade, via a unique manner compared with other antiepileptic drugs that block sodium channels. A paucity of information exists regarding lacosamide overdosage. Lacosamide overdosage is thought to cause QRS prolongation and seizures, due to its effect of sodium channel blockade. The potential efficacy of sodium bicarbonate to reverse the effects of lacosamide has not been well studied. Furthermore, prior reports of lacosamide toxicity have occurred in the setting of concomitant polypharmacy. Thus, the isolated toxic effects of the drug have not been well elucidated. CASE REPORT: We report a case of a suspected, single-ingestion overdose on lacosamide. The patient developed signs of cardiotoxicity and seizure. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: After lacosamide overdosage, the emergency physician must be capable of acute management of subsequent lacosamide toxicity. Understanding the mechanisms of action causing toxicity due to this drug can help the clinician to anticipate the interventions that may be needed or useful to treat this potentially toxic ingestion.

Latrodectus Facies After Latrodectus Hesperus Envenomation in a Pediatric Patient.

BACKGROUND: Black widow spider (Latrodectus spp) envenomation represents the most medically significant spider envenomation in the United States, prompting more than 2500 calls to poison centers annually. The female spider, which is responsible for symptomatic envenomations, is classically described as a shiny black spider with a red hourglass-shaped marking on the ventral abdomen. Clinical features of envenomation include painful muscle cramping, abdominal pain, and autonomic disturbances, such as tachycardia, hypertension, and diaphoresis. "Latrodectus facies" or "facies latrodectismica" is an additional distinctive but rarely described clinical finding characterized by periorbital edema, lacrimation, and blepharospasm. CASE REPORT: A 6-year-old female developed the typical clinical features of Latrodectus envenomation after being found in bed with a Western black widow spider (Latrodectus hesperus) with no ventral marking. She initially improved with opioid analgesia, but 6 h later her symptoms worsened again, and concurrent with this worsening she developed Latrodectus facies. She received additional opioid analgesia and all her symptoms resolved within 24 h. Her mother provided informed and written consent for the acquisition and publication of the facial photographs presented. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: A high degree of clinical suspicion is necessary to correctly diagnose Latrodectus envenomation, especially when the spider escapes unnoticed or in young children in whom the bite is not witnessed. To our knowledge, Latrodectus facies has not been reported previously in a young child, and recognition of this finding will aid clinicians in limiting unnecessary interventions and administering appropriate therapy.

AKT isoform-specific expression and activation across cancer lineages.

BACKGROUND: Aberrant AKT activation is prevalent across human cancer lineages, providing an important therapeutic target. AKT comprises three isoforms that mediate critical non-redundant, even opposing functions in cancer pathophysiology. Therefore, targeting specific AKT isoforms in particular cancers may be more effective than pan-AKT inhibition while avoiding disadvantages of pan-AKT inhibition. Currently, AKT isoform-specific expression and activation in cancer are not clearly characterized. METHODS: We systematically characterized AKT isoform-specific expression and activation in 211 cancer cell lines derived from different lineages and genetic backgrounds using a reverse-phase protein array platform. RESULTS: We found that phosphorylation, but not expression, of AKT1 and AKT2 was coordinated in most but not all cells. Different cancer lineages displayed differential AKT1 and AKT2 expression and phosphorylation. A PIK3CA hotspot mutation H1047R but not E545K was associated with selective activation of AKT2 but not AKT1. CONCLUSIONS: Our study identified and validated AKT isoform-specific expression and phosphorylation in certain cell lines and demonstrated that genetic changes can affect AKT isoform-specific activation. These results provide a more precise understanding of AKT isoform-specific signaling and, in addition, facilitate AKT isoform targeting for personalized cancer therapies.

Aromatherapy Versus Oral Ondansetron for Antiemetic Therapy Among Adult Emergency Department Patients: A Randomized Controlled Trial.

STUDY OBJECTIVE: We compare aromatherapy with inhaled isopropyl alcohol versus oral ondansetron for treating nausea among emergency department (ED) patients not requiring immediate intravenous access. METHODS: In a randomized, blinded, placebo-controlled trial, we enrolled a convenience sample of adults presenting to an urban tertiary care ED with chief complaints including nausea or vomiting. We randomized subjects to 1 of 3 arms: inhaled isopropyl alcohol and 4 mg oral ondansetron, inhaled isopropyl alcohol and oral placebo, and inhaled saline solution placebo and 4 mg oral ondansetron. The primary outcome was mean nausea reduction measured by a 0- to 100-mm visual analog scale from enrollment to 30 minutes postintervention. Secondary outcomes included receipt of rescue antiemetic medications and adverse events. RESULTS: We enrolled 122 subjects, of whom 120 (98.3%) completed the study. Of randomized subjects, 40 received inhaled isopropyl alcohol and oral ondansetron, 41 received inhaled isopropyl alcohol and oral placebo, and 41 received inhaled saline solution placebo and oral ondansetron. The mean decrease in nausea visual analog scale score in each arm was 30 mm (95% confidence interval [CI] 22 to 37 mm), 32 mm (95% CI 25 to 39 mm), and 9 mm (95% CI 5 to 14 mm), respectively. The proportions of subjects who received rescue antiemetic therapy in each arm were 27.5% (95% CI 14.6% to 43.9%), 25.0% (95% CI 12.7% to 41.2%), and 45.0% (95% CI 29.3% to 61.5%), respectively. There were no adverse events. CONCLUSION: Among ED patients with acute nausea and not requiring immediate intravenous access, aromatherapy with or without oral ondansetron provides greater nausea relief than oral ondansetron alone.