Targeting the mutant p53 secretome

While p53 is the most highly mutated and perhaps best studied tumor suppressor protein related to cancer, it remains refractory to targeted therapeutic strategies. In this issue of the JCI, Tan and colleagues investigated the mechanistic basis of the mutant p53 secretome in preclinical models of lung adenocarcinoma. The authors uncovered miR-34a as a regulator of a conventional protein secretion axis, which is mediated by three proteins: the Golgi reassembly and stacking protein 55 kDa (GRASP55), basic leucine zipper nuclear factor 1, and myosin IIA. Inhibition of GRASP55 in TP53-deficient lung adenocarcinoma suppressed protumorigenic secretion of osteopontin/secreted phosphoprotein 1 and insulin-like growth factor binding protein 2 and reduced tumor growth and metastases in mice as well as in patient-derived xenografts. These results provide a therapeutic opportunity to target downstream effects of p53 loss.     

Ventricular tachyarrhythmias in patients receiving an implantable cardioverter-defibrillator for primary versus secondary prophylaxis indications

Introduction: Data on the mechanisms of sudden cardiac death are limited and may be biased by delays in rhythm recording and selection bias in survivors. As a result, the relative contributions of monomorphic ventricular tachycardia (VT) (cycle length [CL] > 260 ms), monomorphic fast VT (FVT) (CL ≤ 260 ms), and polymorphic VT (PMVT)/ventricular fibrillation (VF) have not been well characterized nor compared in patients with and without prior arrhythmic events. Methods: A retrospective cohort study of implantable cardioverter‐defibrillator (ICD) recipients with primary or secondary implant indications was used to evaluate intracardiac electrograms (EGMs) for the first spontaneous VT/VF resulting in appropriate ICD therapy. EGMs were categorized into VT, FVT, and PMVT/VF based on CL and morphologic criteria. Results: Of 616 implants, 145 patients (58 [40%] primary indications) received appropriate ICD therapy for VT/VF over mean follow‐up of 3.8 ± 3.2 years. Primary implants had more diabetes (28% vs 12%; P = 0.02) and less antiarrhythmic use (15% vs 33%; P = 0.02). In those patients with spontaneous arrhythmia, PMVT/VF occurred in 20.7% of primary versus 21.8% of secondary implants, FVT in 19.0% versus 21.8%, and VT in 60.3% versus 56.4%, respectively (P = 0.88). Spontaneous VT CL was similar regardless of implant indication (284 ± 56 [primary] vs 286 ± 67 ms [secondary]; P = 0.92). Conclusions: Monomorphic VT is the most common cause of appropriate ICD therapy regardless of implant indication. These results provide insight into the mechanisms of sudden cardiac death and have implications for the use of interventions designed to limit ICD shocks. (PACE 2011; 34:571–576)     

Wide Variability in Prethrombectomy Workflow Practices in the United States: A Multicenter Survey

BACKGROUND AND PURPOSE:Clinical outcomes in patients with acute ischemic stroke caused by large vessel occlusion depend on the speed and quality of workflows leading to mechanical thrombectomy. In the absence of universally accepted best practices for workflow, developing stroke hospitals can benefit from improved awareness of real-world workflows in effect at experienced centers. To this end, we surveyed prethrombectomy workflow practices at stroke centers throughout the United States.MATERIALS AND METHODS:E-mail and phone interviews were conducted with neurointerventional team members at 30 experienced, endovascular-capable stroke centers. Questions were chosen to reflect workflow components of triage, team activation, transport, case setup, and anesthesia.RESULTS:There is wide variation in prethrombectomy workflows. At 53% of institutions, nonphysician staff respond to stroke alerts alongside physicians. Imaging triage involves noninvasive angiography or perfusion imaging at 97% and 63% of institutions, respectively. Neurointerventional consultation is initiated before the completion of neuroimaging at 86% of institutions, and the team is activated before a final treatment decision at 59%. The neurointerventional team most commonly arrives within 30 minutes. Patients may be transported to the neuroangiography suite before team arrival at 43% of institutions. Procedural trays are set up in advance of team arrival at 13% of centers; additional thrombectomy devices are centrally stored at 54%. A power injector for angiographic runs is consistently used at 43% of institutions. Anesthesiology routinely supports thrombectomies at 67% of institutions.CONCLUSIONS:Prethrombectomy workflows vary widely between experienced centers. Improved awareness of real-world workflows and their variations may help to guide institutions in designing their own protocols of care.

Recent clinical trials have conclusively demonstrated the outcome benefit of mechanical thrombectomy in selected patients with acute ischemic stroke caused by large vessel occlusion (LVO).^1–5 For these patients, the likelihood of a good neurologic outcome depends on the time elapsed between symptom onset and revascularization.^6–11 Indeed, the negative results of 3 earlier clinical trials^12–14 may be attributed in part to prolonged treatment delays.^8,15–17These developments have sparked considerable interest in designing efficient workflows for diagnosis and treatment that can reduce the time between patient presentation and thrombectomy.^7,18–20 Although many of these efforts have been successful, there is currently no broadly accepted consensus for optimal prethrombectomy workflow. In the absence of such consensus, individual centers have implemented a heterogeneous assortment of workflows that may be influenced by individual physician preference, institution-specific factors, or incomplete awareness of effective solutions at competing institutions.Given the overall importance of prethrombectomy workflow on time to treatment, improved guidance is needed for hospitals looking to redesign their own systems to care for patients with LVO. Understanding the range of current practice patterns is an important first step toward that goal. In this work, we aimed to attain a broader perspective on prethrombectomy workflow practices by conducting a nationwide survey of practices in effect at experienced stroke centers, identify highly consistent workflow steps that may indicate general agreement on best practices in real-world conditions, and recognize areas of greater workflow variability that may suggest that such a consensus has yet to emerge.     

Tuberculosis and HIV co-infection: screening and treatment strategies

Globally, tuberculosis (TB) and HIV interact in deadly synergy. The high burden of TB among HIV-infected individuals underlies the importance of TB diagnosis, treatment and prevention for clinicians involved in HIV care. Despite expanding access to antiretroviral therapy (ART) to treat HIV infection in resource-limited settings, many individuals in need of therapy initiate ART too late and have already developed clinically significant TB by the time they present for care. Many co-infected individuals are in need of concurrent ART and anti-TB therapy, which dramatically improves survival, but also raises several management challenges, including drug interactions, shared drug toxicities and TB immune reconstitution inflammatory syndrome (IRIS). Due to the survival benefits of promptly initiating ART among all HIV-infected individuals, including those with TB, it is recommended that co-infected individuals receive treatment for both diseases, regardless of CD4+ cell count. We review current screening and treatment strategies for TB and HIV co-infection. Recent findings and ongoing studies will assist clinicians in managing the prevention and treatment of TB and HIV co-infection, which remains a major global health challenge.     

Interactions of HIV, other sexually transmitted diseases, and genital tract inflammation facilitating local pathogen transmission and acquisition

Despite several decades of clinical trials assessing the impact of etiological treatment of sexually transmitted diseases (STDs) to decrease HIV acquisition and transmission, almost all of these trials have not proven to be efficacious. Increasing evidence suggests that specific STD treatment alone may not be sufficient to alter the genital tract inflammatory milieu that is created by STDs. This paper examines the associations between STDs and HIV susceptibility and infectiousness, and considers the role of chronic and refractory inflammation to create an environment that potentiates HIV and STD transmission and acquisition by reviewing biological, observational, and clinical trial data.     

Effect of nicotine on feeding and body weight in rats: involvement of cocaine- and amphetamine-regulated transcript peptide

Memantine, a noncompetitive NMDA receptor blocker, has been demonstrated to be neuroprotective against various neurotoxins. Aluminum, a well-known neurotoxin, has been suggested to be a contributing factor in Alzheimer's disease. In this study we investigated the possible effect of memantine on aluminum-induced cognitive impairment in rats. Rats were exposed to aluminum chloride (100 mg/kg/day) and memantine (5, 10 and 20 mg/kg/day) for 60 days. Cognitive functions were evaluated using three tests: Morris water maze, radial arm maze and passive avoidance tests. Results showed that memantine failed at low doses to have any significant influence on aluminum-induced memory deficit, but the 20 mg/kg dose was found to cause significant enhancement of memory in the aluminum-exposed rats. This is the first study to demonstrate the protective role of memantine against aluminum-induced neuronal dysfunction. Biochemical and histological investigations are highly indicated to clarify the possible pharmacodynamic basis.