Etrasimod: A Sphingosine-1-Phosphate Receptor Modulator for the Treatment of Ulcerative Colitis.

OBJECTIVE: To review the pharmacologic and clinical profile of etrasimod in the treatment of ulcerative colitis (UC). DATA SOURCES: A PubMed search was conducted from inception to November 2023 using the keywords etrasimod, ulcerative colitis, and sphingosine-1-phosphate receptor modulator. Information was also obtained from published abstracts and package insert. STUDY SELECTION AND DATA EXTRACTION: Phase 2 and 3 studies plus relevant literature on etrasimod pharmacologic and clinical profile were reviewed. DATA SYNTHESIS: Per ELEVATE, 2 phase 3 studies, a higher proportion of patients with moderately to severely active UC achieved clinical remission in the induction and maintenance phase with etrasimod compared with placebo. In addition, a higher proportion of patients achieved secondary endpoints of clinical response, endoscopic improvement-histologic remission, corticosteroid-free remission, and endoscopic improvement with etrasimod vs placebo. Common adverse events include anemia and headache. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Etrasimod is now the second orally administered sphingosine-1-phosphate modulator approved for UC, providing patients with additional treatment options. Efficacy rates of this treatment are in line with other UC medication options. Similar to other sphingosine-1-phosphate receptor modulators, various assessments are required at baseline and during treatment to ensure safe and appropriate use. CONCLUSION: Etrasimod is another possibility in the armamentarium of UC treatment, providing patients with more oral medication options. Prior to treatment initiation, several assessments relating to safety, drug interactions, and pharmacogenomics factors are advised.

Acute myeloid leukemia: Current understanding and management.

ABSTRACT: Although relatively rare, acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. AML is associated with poor 5-year overall survival and prompt treatment is critical. Classifying AML based on World Health Organization criteria is important for determining prognosis and applying a risk-adapted treatment approach. Throughout therapy, patients require comprehensive supportive care measures with blood product transfusions, antimicrobial treatment, and frequent monitoring for chemotherapy-related complications. This article provides an overview of AML and its treatments. Clinicians in all specialties must be able to recognize the early signs of AML and ensure their patients seek appropriate expert medical care with a hematologist/oncologist.

Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a lineage C betacoronavirus that since its emergence in 2012 has caused outbreaks in human populations with case-fatality rates of ∼36%. As in other coronaviruses, the spike (S) glycoprotein of MERS-CoV mediates receptor recognition and membrane fusion and is the primary target of the humoral immune response during infection. Here we use structure-based design to develop a generalizable strategy for retaining coronavirus S proteins in the antigenically optimal prefusion conformation and demonstrate that our engineered immunogen is able to elicit high neutralizing antibody titers against MERS-CoV. We also determined high-resolution structures of the trimeric MERS-CoV S ectodomain in complex with G4, a stem-directed neutralizing antibody. The structures reveal that G4 recognizes a glycosylated loop that is variable among coronaviruses and they define four conformational states of the trimer wherein each receptor-binding domain is either tightly packed at the membrane-distal apex or rotated into a receptor-accessible conformation. Our studies suggest a potential mechanism for fusion initiation through sequential receptor-binding events and provide a foundation for the structure-based design of coronavirus vaccines.

Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape.

Middle East respiratory syndrome coronavirus (MERS-CoV) causes a highly lethal pulmonary infection with ∼35% mortality. The potential for a future pandemic originating from animal reservoirs or health care-associated events is a major public health concern. There are no vaccines or therapeutic agents currently available for MERS-CoV. Using a probe-based single B cell cloning strategy, we have identified and characterized multiple neutralizing monoclonal antibodies (MAbs) specifically binding to the receptor-binding domain (RBD) or S1 (non-RBD) regions from a convalescent MERS-CoV-infected patient and from immunized rhesus macaques. RBD-specific MAbs tended to have greater neutralizing potency than non-RBD S1-specific MAbs. Six RBD-specific and five S1-specific MAbs could be sorted into four RBD and three non-RBD distinct binding patterns, based on competition assays, mapping neutralization escape variants, and structural analysis. We determined cocrystal structures for two MAbs targeting the RBD from different angles and show they can bind the RBD only in the "out" position. We then showed that selected RBD-specific, non-RBD S1-specific, and S2-specific MAbs given prophylactically prevented MERS-CoV replication in lungs and protected mice from lethal challenge. Importantly, combining RBD- and non-RBD MAbs delayed the emergence of escape mutations in a cell-based virus escape assay. These studies identify MAbs targeting different antigenic sites on S that will be useful for defining mechanisms of MERS-CoV neutralization and for developing more effective interventions to prevent or treat MERS-CoV infections.IMPORTANCE MERS-CoV causes a highly lethal respiratory infection for which no vaccines or antiviral therapeutic options are currently available. Based on continuing exposure from established reservoirs in dromedary camels and bats, transmission of MERS-CoV into humans and future outbreaks are expected. Using structurally defined probes for the MERS-CoV spike glycoprotein (S), the target for neutralizing antibodies, single B cells were sorted from a convalescent human and immunized nonhuman primates (NHPs). MAbs produced from paired immunoglobulin gene sequences were mapped to multiple epitopes within and outside the receptor-binding domain (RBD) and protected against lethal MERS infection in a murine model following passive immunization. Importantly, combining MAbs targeting distinct epitopes prevented viral neutralization escape from RBD-directed MAbs. These data suggest that antibody responses to multiple domains on CoV spike protein may improve immunity and will guide future vaccine and therapeutic development efforts.

Fine particulate matters: The impact of air quality standards on cardiovascular mortality.

BACKGROUND: In 1997 the U.S. Environmental Protection Agency set the first annual National Ambient Air Quality Standard (NAAQS) for fine particulate matter (PM2.5). Although the weight of scientific evidence has determined that a causal relationship exists between PM2.5 exposures and cardiovascular effects, few studies have concluded whether NAAQS-related reductions in PM2.5 led to improvements in public health. METHODS: We examined the change in cardiovascular (CV) mortality rate and the association between change in PM2.5 and change in CV-mortality rate before (2000-2004) and after implementation of the 1997 annual PM2.5 NAAQS (2005-2010) among U.S. counties. We further examined how the association varied with respect to two factors related to NAAQS compliance: attainment status and design values (DV). We used difference-in-differences and linear regression models, adjusted for sociodemographic confounders. FINDINGS: Across 619 counties, there were 1.10 (95% CI: 0.37, 1.82) fewer CV-deaths per year per 100,000 people for each 1µg/m3 decrease in PM2.5. Nonattainment counties had a twofold larger reduction in mean annual PM2.5, 2.1µg/m3, compared to attainment counties, 0.97µg/m3. CV-mortality rate decreased by 0.59 (95% CI: -0.54, 1.71) in nonattainment and 1.96 (95% CI: 0.77, 3.15) deaths per 100,000 people for each 1µg/m3 decrease in PM2.5 in attainment counties. When stratifying counties by DV, results were similar: counties with DV greater than 15µg/m3 experienced the greatest decrease in mean annual PM2.5 (2.29µg/m3) but the smallest decrease in CV-mortality rate per unit decrease in PM2.5, 0.73 (95% CI: -0.57, 2.02). INTERPRETATION: We report a significant association between the change in PM2.5 and the change in CV-mortality rate before and after the implementation of NAAQS and note that the health benefits per 1µg/m3 decrease in PM2.5 persist at levels below the current national standard. FUNDING: US EPA intermural research.

Resistance to two heterologous neurotropic oncolytic viruses, Semliki Forest virus and vaccinia virus, in experimental glioma.

Attenuated Semliki Forest virus (SFV) may be suitable for targeting malignant glioma due to its natural neurotropism, but its replication in brain tumor cells may be restricted by innate antiviral defenses. We attempted to facilitate SFV replication in glioma cells by combining it with vaccinia virus, which is capable of antagonizing such defenses. Surprisingly, we found parenchymal mouse brain tumors to be refractory to both viruses. Also, vaccinia virus appears to be sensitive to SFV-induced antiviral interference.

Systematic Review and Meta-analysis: The Association Between Serum Ustekinumab Trough Concentrations and Treatment Response in Inflammatory Bowel Disease.

BACKGROUND: Optimizing therapy and monitoring response are integral aspects of inflammatory bowel disease treatment. We conducted a systematic review and meta-analysis to determine whether serum ustekinumab trough concentrations during maintenance therapy were associated with ustekinumab treatment response in patients with inflammatory bowel disease. METHODS: A systematic review was performed to March 21, 2022, to identify studies using MEDLINE, EMBASE, and the Cochrane library. We included studies that reported the association between serum ustekinumab trough concentrations with clinical or endoscopic remission. Outcome measures were combined across studies using the random-effects model with an odds ratio (OR) for binary outcomes of endoscopic and clinical remission. RESULTS: We identified 14 observational studies that were included in the analysis for clinical remission (919 patients, 63% with Crohn's disease) or endoscopic remission (290 patients, all with Crohn's disease). Median ustekinumab trough concentrations were higher amongst individuals achieving clinical remission compared with those not achieving remission (mean difference, 1.6 ug/mL; 95% confidence interval [CI], 0.21-3.01 ug/mL). Furthermore, individuals with median serum trough concentration in the fourth quartile were significantly more likely to achieve clinical (OR, 3.61; 95% CI, 2.11-6.20) but not endoscopic remission (OR, 4.67; 95% CI, 0.86-25.19) compared with those with first quartile median trough concentrations. CONCLUSION: Based on the results of this meta-analysis primarily relating to patients with Crohn's disease on maintenance ustekinumab treatment, it appears that there is an association between higher ustekinumab trough concentration and clinical outcomes. Prospective studies are required to determine whether proactive dose adjustments of ustekinumab therapy provides additional clinical benefit.

This meta-analysis of 14 observational studies found an association between better clinical outcomes and higher trough ustekinumab levels for maintenance treatment in inflammatory bowel disease.

Discontinuation Syndrome With JAK2 Selective Agents: Case Presentation and Mechanistic Insights.

We report the first case of pacritinib-withdrawal syndrome with in vitro elucidation of underlying mechanisms.

Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus.

Interferon-inducible transmembrane proteins 1, 2, and 3 (IFITM1, 2, and 3) are recently identified viral restriction factors that inhibit infection mediated by the influenza A virus (IAV) hemagglutinin (HA) protein. Here we show that IFITM proteins restricted infection mediated by the entry glycoproteins (GP(1,2)) of Marburg and Ebola filoviruses (MARV, EBOV). Consistent with these observations, interferon-ß specifically restricted filovirus and IAV entry processes. IFITM proteins also inhibited replication of infectious MARV and EBOV. We observed distinct patterns of IFITM-mediated restriction: compared with IAV, the entry processes of MARV and EBOV were less restricted by IFITM3, but more restricted by IFITM1. Moreover, murine Ifitm5 and 6 did not restrict IAV, but efficiently inhibited filovirus entry. We further demonstrate that replication of infectious SARS coronavirus (SARS-CoV) and entry mediated by the SARS-CoV spike (S) protein are restricted by IFITM proteins. The profile of IFITM-mediated restriction of SARS-CoV was more similar to that of filoviruses than to IAV. Trypsin treatment of receptor-associated SARS-CoV pseudovirions, which bypasses their dependence on lysosomal cathepsin L, also bypassed IFITM-mediated restriction. However, IFITM proteins did not reduce cellular cathepsin activity or limit access of virions to acidic intracellular compartments. Our data indicate that IFITM-mediated restriction is localized to a late stage in the endocytic pathway. They further show that IFITM proteins differentially restrict the entry of a broad range of enveloped viruses, and modulate cellular tropism independently of viral receptor expression.

New Pneumococcal Vaccines for Prevention of Invasive Pneumococcal Disease in Adult Patients With Inflammatory Bowel Disease.

Patients with inflammatory bowel disease (IBD) are at a high risk of developing invasive pneumococcal infection both before and after they are diagnosed. The Advisory Committee on Immunization Practices now endorses use of 2 new pneumococcal conjugate vaccines, PCV15 (Vaxneuvance) and PCV20 (Prevnar 20), for patients who have never received a pneumococcal conjugate vaccine or those with unknown vaccination history. Previous studies have shown that pneumococcal vaccination can decrease the risk of developing severe pneumococcal disease; therefore, it is important that patients with IBD receive pneumococcal vaccination. This report aims to inform clinicians who care for patients with IBD about the changes in immunization practices, as it pertains to pneumococcal vaccination and provides appropriate direction on administering vaccination series.

Two new pneumococcal vaccines (PCV15 [Vaxneuvance], PCV20 [Prevnar 20]) are now recommended for patients who have not received a pneumococcal conjugate vaccine or those with unknown vaccination history. This report summarizes changes in immunization practices and provides direction on vaccination series for patients with inflammatory bowel disease.

Multi-institutional analysis of outcomes in acute myeloid leukemia patients with central nervous system involvement.

We evaluated outcomes of AML patients with central nervous system (CNS) involvement at two academic institutions. Fifty-two adult patients were identified. Neurologic symptoms were reported in 69% of patients, with headache the most common (33%). 84% (n = 42) of patients cleared their cerebrospinal fluid (CSF), with a median number of one dose of intrathecal (IT) chemotherapy. Of these patients, 21% (n = 9) had a CSF relapse, with 67% (n = 6) of those experiencing CSF relapse also having concurrent bone marrow relapse. Of the 36 patients with baseline neurologic symptoms, 69% had improvement in symptoms post-IT therapy. The median overall survival was 9.3 months and 3.5 months for patients with CNS involvement diagnosed before/during induction and at relapse, respectively. In this study, IT therapy was rapidly effective in clearing CSF blasts and improving neurologic symptoms in most patients. Few patients experienced CSF relapse, which predominantly occurred in the setting of concomitant bone marrow relapse.

Defining the Roles of Inflammatory Bowel Disease Clinical Pharmacists in the United States: A Systematic Review and National RAND/UCLA Consensus.

BACKGROUND: Given the complexity of inflammatory bowel disease (IBD) care, utilization of multidisciplinary teams is recommended to optimize outcomes. There is a growing recognition that clinical pharmacists should be an integral part of this care model. We sought to define the roles of IBD clinical pharmacists in the United States. METHODS: A national multidisciplinary expert panel of 12 gastroenterologists and clinical pharmacists practicing in IBD clinics was assembled. We used the RAND/University of California, Los Angeles appropriateness method, with a total of 281 statements generated based on a systematic literature review and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate in 2 rounds of voting. RESULTS: The number of publications evaluating the clinical pharmacists' roles in IBD is limited, primarily focusing on thiopurine initiation and monitoring, medication adherence, and switching to biosimilars. Medication education; medication initiation and monitoring; therapeutic drug monitoring; biosimilar management; health maintenance review; and transitions of care were deemed by the panel to be appropriate roles for IBD clinical pharmacists. In considering real-world settings, IBD clinical pharmacists should practice clinically under a predefined scope and primarily focus on complex treatments (eg, immunomodulators, biologics, and small molecules). Clinical pharmacists should also be included in practice settings with IBD specialized physicians. Additionally, clinical pharmacists caring for patients with IBD should be residency trained and board certified. CONCLUSIONS: This consensus defines IBD clinical pharmacists' roles and provides a framework for embedded clinical pharmacists in IBD care.

Infidelity of SARS-CoV Nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing.

Most RNA viruses lack the mechanisms to recognize and correct mutations that arise during genome replication, resulting in quasispecies diversity that is required for pathogenesis and adaptation. However, it is not known how viruses encoding large viral RNA genomes such as the Coronaviridae (26 to 32 kb) balance the requirements for genome stability and quasispecies diversity. Further, the limits of replication infidelity during replication of large RNA genomes and how decreased fidelity impacts virus fitness over time are not known. Our previous work demonstrated that genetic inactivation of the coronavirus exoribonuclease (ExoN) in nonstructural protein 14 (nsp14) of murine hepatitis virus results in a 15-fold decrease in replication fidelity. However, it is not known whether nsp14-ExoN is required for replication fidelity of all coronaviruses, nor the impact of decreased fidelity on genome diversity and fitness during replication and passage. We report here the engineering and recovery of nsp14-ExoN mutant viruses of severe acute respiratory syndrome coronavirus (SARS-CoV) that have stable growth defects and demonstrate a 21-fold increase in mutation frequency during replication in culture. Analysis of complete genome sequences from SARS-ExoN mutant viral clones revealed unique mutation sets in every genome examined from the same round of replication and a total of 100 unique mutations across the genome. Using novel bioinformatic tools and deep sequencing across the full-length genome following 10 population passages in vitro, we demonstrate retention of ExoN mutations and continued increased diversity and mutational load compared to wild-type SARS-CoV. The results define a novel genetic and bioinformatics model for introduction and identification of multi-allelic mutations in replication competent viruses that will be powerful tools for testing the effects of decreased fidelity and increased quasispecies diversity on viral replication, pathogenesis, and evolution.

Is Pet Health Insurance Able to Improve Veterinary Care? Why Pet Health Insurance for Dogs and Cats Has Limits: An Ethical Consideration on Pet Health Insurance.

BACKGROUND: Owners often feel the cost of veterinary care is too high, as there remains a limited understanding of the cost of health care in human and veterinary medicine alike. Pet health insurance is often seen as a universal solution. However, especially for patient owners with few financial resources, both the bill at the vet and the monthly premium for pet health insurance can become a challenge. HYPOTHESIS: Pet health insurance can prevent or ease many price discussions at the vet, but it does not offer a solution for patient owners with little financial means. METHODS: In order to verify for which patient owners pet health insurance can be a solution, four theoretical groups were formed depending on the patient owner's willingness to pay and his/her dispensable funds based on a theoretical model. RESULTS: Dispensable funds are a factor that cannot be influenced by the veterinary surgeon. However, low dispensable funds as a result of an insufficient willingness to save (whether due to a lack of financial education or a lack of will) can be solved by pet health insurance. Willingness to pay, on the other hand, can be influenced by empathetic communication from the veterinary surgeon and thus also from pet health insurance. Nevertheless, situations remain where pet health insurance is not a solution either, because owners can neither afford the veterinary costs nor a premium for a pet health insurance.

Synthetic recombinant bat SARS-like coronavirus is infectious in cultured cells and in mice.

Defining prospective pathways by which zoonoses evolve and emerge as human pathogens is critical for anticipating and controlling both natural and deliberate pandemics. However, predicting tenable pathways of animal-to-human movement has been hindered by challenges in identifying reservoir species, cultivating zoonotic organisms in culture, and isolating full-length genomes for cloning and genetic studies. The ability to design and recover pathogens reconstituted from synthesized cDNAs has the potential to overcome these obstacles by allowing studies of replication and pathogenesis without identification of reservoir species or cultivation of primary isolates. Here, we report the design, synthesis, and recovery of the largest synthetic replicating life form, a 29.7-kb bat severe acute respiratory syndrome (SARS)-like coronavirus (Bat-SCoV), a likely progenitor to the SARS-CoV epidemic. To test a possible route of emergence from the noncultivable Bat-SCoV to human SARS-CoV, we designed a consensus Bat-SCoV genome and replaced the Bat-SCoV Spike receptor-binding domain (RBD) with the SARS-CoV RBD (Bat-SRBD). Bat-SRBD was infectious in cell culture and in mice and was efficiently neutralized by antibodies specific for both bat and human CoV Spike proteins. Rational design, synthesis, and recovery of hypothetical recombinant viruses can be used to investigate mechanisms of transspecies movement of zoonoses and has great potential to aid in rapid public health responses to known or predicted emerging microbial threats.

Short-term medical service trips: what is the cost of patient care and student training?

BACKGROUND: Evaluations of the costs and effects of medical service trips (MSTs) are increasingly necessary. Estimates of costs can inform decision making to determine if participation is likely to be a wise use of resources. METHODS: This study estimates the costs and effects of a 1-week MST for 20 health professions students and seven providers to the Dominican Republic. Costs were defined as direct costs for students and providers and opportunity costs for providers. Effects were defined as the cost to treat one patient and the cost to train one student. Students were surveyed about their costs before and after the MST. Most provider costs were assumed to be the same as those of the students. RESULTS: The mean direct cost per student was US${\$}$1764 and US${\$}$2066 for providers. Total opportunity costs for seven providers was US${\$}$19 869. The total cost for the trip was US${\$}$69 612 to treat 464 patients. With and without provider opportunity costs, the cost to treat one patient was US${\$}$150 and US${\$}$107, and the cost to train one student was US${\$}$3481 and US${\$}$2487, respectively. CONCLUSIONS: Short-term MSTs may be more expensive than previously thought. The cost to treat one patient was similar to a medical office visit in the USA.

Short-term Experiences in Global Health: What is the Cost of Cultural Competence?

Students in a wide variety of health professions are increasingly interested in volunteering on a short-term experience in global health (STEGH). The literature suggests that STEGHs pose a variety of potential risks and benefits, and may carry a significant cost to plan and provide. One potential mitigating factor for any risks and costs is that student participation on a STEGH may enhance their cultural competence. Since monies spent on STEGHs are fungible, and there may be other opportunities to improve students' cultural competence, the objectives of this study were to determine if participation on a STEGH increased students' cultural competence and if so, what the cost for any such increase was. In this study, 20 students who participated on a 1-week STEGH to the Dominican Republic completed the Inventory for Assessing the Process of Cultural Competence Among Health Care Professionals - Student Version (IAPCC-SV) before and after the STEGH. The costs for all students and 7 supervising health professionals to volunteer for the STEGH were calculated, and the size of any increase in cultural competence was determined. The cost was divided by the change in cultural competence to ascertain the cost of the change. Students showed a measureable increase on the IAPCC-SV overall and on the subscales of knowledge and skill. The cost of a 1% overall increase in students' cultural competence ranged from $287 to $401. These results may allow schools offering STEGHs to determine if their offerings are cost-effective or not.

IL-33/IL1RL1 axis regulates cell survival through the p38 MAPK pathway in acute myeloid leukemia.

Acute myeloid leukemia (AML) is often characterized by the presence of specific and recurrent chromosomal abnormalities. Current treatments have greatly increased remission rate, but relapse still occurs. Therefore, novel therapeutic approaches are required. Previously, using a conditional Cbfb-MYH11 knockin mouse model, we showed that Cbfb-MYH11 induces the expression of a cytokine receptor, IL1RL1. Treatment with IL-33, the only known ligand of IL1RL1, promotes leukemia cell survival in vitro. We further found that IL1RL1+ cells survive better with chemotherapy than IL1RL1- population. However, the mechanism is not clear. Here, we show that IL-33 treatment decreased drug sensitivity in the human inv(16) AML cell line ME-1. By RT-PCR, we found that IL-33 increased the expression of IL-4 and IL-6 and led to the activation of both p38 MAPK and NF-κB. We also showed that IL-33 decreased apoptosis with increased phosphorylation of p38 MAPK. Moreover, pre-treatment with MAPK inhibitor attenuated the phosphorylation of p38 enhanced by IL-33 and reversed the anti-apoptotic effect by IL-33. Taken together, our findings give news insights into the potential mechanism of the anti-apoptotic effect by IL-33/IL1RL1 axis in AML which will help in future drug development.

Use of polymeric CXCR4 inhibitors as siRNA delivery vehicles for the treatment of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and is associated with poor long-term survival often owing to relapse. Current treatments for AML are associated with considerable toxicity and are frequently not effective after relapse. Thus, it is important to develop novel therapeutic strategies. Short interfering RNA (siRNA)-based therapeutics targeting key oncogenes have been proposed as treatments for AML. We recently developed novel siRNA delivery polycations (PCX) based on AMD3100 (plerixafor), an FDA-approved inhibitor of the CXC chemokine receptor 4 (CXCR4). Inhibitors of CXCR4 have been shown to sensitize leukemia cells to chemotherapy. Therefore, PCX has the potential to target leukemia cells via two mechanisms: inhibition of CXCR4 and delivery of siRNAs against critical genes. In this report, we show that PCX exerts a cytotoxic effect on leukemia cells more effectively than other CXCR4 inhibitors, including AMD3100. In addition, we show that PCX can deliver siRNAs against the transcription factor RUNX1 to mouse and human leukemia cells. Overall, our study provides the first evidence that dual-function PCX/siRNA nanoparticles can simultaneously inhibit CXCR4 and deliver siRNAs, targeting key oncogenes in leukemia cells and that PCX/siRNA has clinical potential for the treatment of AML.

Nuclear localization of cytoplasmic poly(A)-binding protein upon rotavirus infection involves the interaction of NSP3 with eIF4G and RoXaN.

Rotavirus nonstructural protein NSP3 interacts specifically with the 3' end of viral mRNAs, with the eukaryotic translation initiation factor eIF4G, and with RoXaN, a cellular protein of yet-unknown function. By evicting cytoplasmic poly(A) binding protein (PABP-C1) from translation initiation complexes, NSP3 shuts off the translation of cellular polyadenylated mRNAs. We show here that PABP-C1 evicted from eIF4G by NSP3 accumulates in the nucleus of rotavirus-infected cells. Through modeling of the NSP3-RoXaN complex, we have identified mutations in NSP3 predicted to interrupt its interaction with RoXaN without disturbing the NSP3 interaction with eIF4G. Using these NSP3 mutants and a deletion mutant unable to associate with eIF4G, we show that the nuclear localization of PABP-C1 not only is dependent on the capacity of NSP3 to interact with eIF4G but also requires the interaction of NSP3 with a specific region in RoXaN, the leucine- and aspartic acid-rich (LD) domain. Furthermore, we show that the RoXaN LD domain functions as a nuclear export signal and that RoXaN tethers PABP-C1 with RNA. This work identifies RoXaN as a cellular partner of NSP3 involved in the nucleocytoplasmic localization of PABP-C1.