Understanding the Effect of Curvature on the Magnetization Reversal of Three-Dimensional Nanohelices.

Comprehending the interaction between geometry and magnetism in three-dimensional (3D) nanostructures is important to understand the fundamental physics of domain wall (DW) formation and pinning. Here, we use focused-electron-beam-induced deposition to fabricate magnetic nanohelices with increasing helical curvature with height. Using electron tomography and Lorentz transmission electron microscopy, we reconstruct the 3D structure and magnetization of the nanohelices. The surface curvature, helical curvature, and torsion of the nanohelices are then quantified from the tomographic reconstructions. Furthermore, by using the experimental 3D reconstructions as inputs for micromagnetic simulations, we can reveal the influence of surface and helical curvature on the magnetic reversal mechanism. Hence, we can directly correlate the magnetic behavior of a 3D nanohelix to its experimental structure. These results demonstrate how the control of geometry in nanohelices can be utilized in the stabilization of DWs and control of the response of the nanostructure to applied magnetic fields.

ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth.

Multiple Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M (Palm M) block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared with Palm M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MAP kinase kinase (MEK) inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes as regulators of the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers.

Prediction of the Renal Organic Anion Transporter 1 (OAT1)- Mediated Drug Interactions for LY404039, the Active Metabolite of Pomaglumetad Methionil.

PURPOSE: The objective of this work was to demonstrate that clinical OAT1-mediated DDIs can be predicted using physiologically based pharmacokinetic (PBPK) modeling. METHODS: LY404039 is a metabotropic glutamate receptor 2/3 agonist and the active moiety of the prodrug pomaglumetad methionil (LY2140023). After oral administration, pomaglumetad methionil is rapidly taken up by enterocytes via PEPT1 and once absorbed, converted to LY404039 via membrane dehydropeptidase 1 (DPEP1). LY404039 is renally excreted by both glomerular filtration and active secretion and in vitro studies showed that the active secretion of LY404039 was mediated by the organic anion transporter 1 (OAT1). Both clinical and in vitro data were used to build a PBPK model to predict OAT1-mediated DDIs. RESULTS: In vitro inhibitory potencies (IC50) of the known OAT inhibitors, probenecid and ibuprofen, were determined to be 4.00 and 2.63 µM, respectively. Subsequently, clinical drug-drug interaction (DDI) study showed probenecid reduced the renal clearance of LY404039 by 30 to 40%. The PBPK bottom-up model, predicted a renal clearance that was approximately 20% lower than the observed one. The middle-out model, using an OAT1 relative activity factor (RAF) of 3, accurately reproduced the renal clearance of LY404039 and pharmacokinetic (PK) changes of LY404039 in the presence of probenecid. CONCLUSIONS: OAT1- mediated DDIs can be predicted using in vitro measured IC50 and PBPK modeling. The effect of ibuprofen was predicted to be minimal (AUC ratio of 1.15) and not clinically relevant.

Thermal Hysteresis and Ordering Behavior of Magnetic Skyrmion Lattices.

The physics of phase transitions in two-dimensional (2D) systems underpins research in diverse fields including statistical mechanics, nanomagnetism, and soft condensed matter. However, many aspects of 2D phase transitions are still not well understood, including the effects of interparticle potential, polydispersity, and particle shape. Magnetic skyrmions are chiral spin-structure quasi-particles that form two-dimensional lattices. Here, we show, by real-space imaging using in situ cryo-Lorentz transmission electron microscopy coupled with machine learning image analysis, the ordering behavior of Néel skyrmion lattices in van der Waals Fe3GeTe2. We demonstrate a distinct change in the skyrmion size distribution during field-cooling, which leads to a loss of lattice order and an evolution of the skyrmion liquid phase. Remarkably, the lattice order is restored during field heating and demonstrates a thermal hysteresis. This behavior is explained by the skyrmion energy landscape and demonstrates the potential to control the lattice order in 2D phase transitions.

Improving Research Dissemination to Black Sexual Minority Men: Development of a Community-Led and Theory-Based Dissemination Plan.

Background. Although research dissemination to participants and community stakeholders is a fundamental component of translational research, it rarely occurs. The objective of this study was to create a community-led, theory-based dissemination plan to engage local Black sexual minority men in an active dissemination process throughout a sexual health research study. Method. Seven focus groups (N = 38) were conducted with Black, cisgender sexual minority men aged 18 to 45 years. Findings were analyzed through thematic content analysis guided by McGuire's persuasive communication theory. Findings were used to draft a dissemination plan, which was then reviewed and edited by the study's community advisory board (CAB). The plan continues to be updated in response to community needs through CAB discussions. Results. Participants preferred messages concerning syphilis and other health concerns as well as information on local resources. Preferred sources included researchers working with trusted community organizations and leaders. Preferred channels included community events and social media, implemented with consistency. CAB feedback included expanding the target audience of dissemination efforts as well as the development of ideas for channels (i.e., events) and sources (i.e., community organizations and leaders). Additional revisions occurred in response to the COVID-19 pandemic. Conclusion. Given the continued lack of research dissemination to participant and community stakeholders, the process of developing a community-led, theory-based dissemination plan may benefit and help guide researchers to adopt this practice. It is critical that participant and community stakeholder dissemination become more highly prioritized as we strive for public health improvements and the elimination of health disparities.

Genetic disruption of N-RasG12D palmitoylation perturbs hematopoiesis and prevents myeloid transformation in mice.

Oncogenic RAS mutations pose substantial challenges for rational drug discovery. Sequence variations within the hypervariable region of Ras isoforms underlie differential posttranslational modification and subcellular trafficking, potentially resulting in selective vulnerabilities. Specifically, inhibiting the palmitoylation/depalmitoylation cycle is an appealing strategy for treating NRAS mutant cancers, particularly as normal tissues would retain K-Ras4b function for physiologic signaling. The role of endogenous N-RasG12D palmitoylation in signal transduction, hematopoietic differentiation, and myeloid transformation is unknown, and addressing these key questions will inform efforts to develop mechanism-based therapies. To evaluate the palmitoylation/depalmitoylation cycle as a candidate drug target in an in vivo disease-relevant model system, we introduced a C181S mutation into a conditional NrasG12D "knock-in" allele. The C181S second-site amino acid substitution abrogated myeloid transformation by NrasG12D, which was associated with mislocalization of the nonpalmitoylated N-Ras mutant protein, reduced Raf/MEK/ERK signaling, and alterations in hematopoietic stem and progenitor populations. Furthermore, hematologic malignancies arising in NrasG12D/G12D,C181S compound heterozygous mice invariably acquired revertant mutations that restored cysteine 181. Together, these studies validate the palmitoylation cycle as a promising therapeutic target in NRAS mutant cancers.

Exposure-response relationship of ramucirumab in RANGE, a randomized phase III trial in advanced urothelial carcinoma refractory to platinum therapy.

AIMS: Patients with advanced urothelial carcinoma (UC) who progress after platinum-based chemotherapy have a poor prognosis, and there is a medical need to improve current treatment options. Ramucirumab plus docetaxel significantly improved progression-free survival but not overall survival (OS) in platinum-refractory advanced UC (RANGE trial; NCT02426125). Here, we report the exposure-response (ER) of ramucirumab plus docetaxel using data from the RANGE trial. METHODS: Pharmacokinetic (PK) samples were collected (cycle 1-3, 5, 9 [day 1] and 30 days from treatment discontinuation), and PK data were analysed using population PK (popPK) analysis. The minimum ramucirumab concentration after first dose administration (Cmin,1 , or trough concentration immediately prior to the second dose) was derived by popPK analysis and used as the exposure parameter for ER analysis. Cox proportional hazards regression models and matched case-control analyses were used to evaluate the relationship between Cmin,1 and OS. The Cmin,1 relationship with safety was assessed descriptively. RESULTS: Several poor prognostic factors (ECOG 1, haemoglobin concentration <100 g/L, presence of liver metastases) appeared more frequently in the lower exposure quartiles, suggesting a possible disease-PK interaction. A significant association was identified between Cmin,1 and OS (P = .0108). Higher exposure quartiles were associated with longer survival and smaller hazard ratios compared to placebo. No new exposure-safety trends were observed within the exposure range (ramucirumab 10 mg/kg once every 3 weeks). CONCLUSIONS: This prespecified ER analyses suggests a positive relationship between efficacy and ramucirumab exposure, with an imbalance associated with disease prognostic factors. Further investigation may elucidate a possible disease-PK relationship.

Novel community health worker strategy for HIV service engagement in a hyperendemic community in Rakai, Uganda: A pragmatic, cluster-randomized trial.

BACKGROUND: Effective implementation strategies are needed to increase engagement in HIV services in hyperendemic settings. We conducted a pragmatic cluster-randomized trial in a high-risk, highly mobile fishing community (HIV prevalence: approximately 38%) in Rakai, Uganda, to assess the impact of a community health worker-delivered, theory-based (situated Information, Motivation, and Behavior Skills), motivational interviewing-informed, and mobile phone application-supported counseling strategy called "Health Scouts" to promote engagement in HIV treatment and prevention services. METHODS AND FINDINGS: The study community was divided into 40 contiguous, randomly allocated clusters (20 intervention clusters, n = 1,054 participants at baseline; 20 control clusters, n = 1,094 participants at baseline). From September 2015 to December 2018, the Health Scouts were deployed in intervention clusters. Community-wide, cross-sectional surveys of consenting 15 to 49-year-old residents were conducted at approximately 15 months (mid-study) and at approximately 39 months (end-study) assessing the primary programmatic outcomes of self-reported linkage to HIV care, antiretroviral therapy (ART) use, and male circumcision, and the primary biologic outcome of HIV viral suppression (<400 copies/mL). Secondary outcomes included HIV testing coverage, HIV incidence, and consistent condom use. The primary intent-to-treat analysis used log-linear binomial regression with generalized estimating equation to estimate prevalence risk ratios (PRR) in the intervention versus control arm. A total of 2,533 (45% female, mean age: 31 years) and 1,903 (46% female; mean age 32 years) residents completed the mid-study and end-study surveys, respectively. At mid-study, there were no differences in outcomes between arms. At end-study, self-reported receipt of the Health Scouts intervention was 38% in the intervention arm and 23% in the control arm, suggesting moderate intervention uptake in the intervention arm and substantial contamination in the control arm. At end-study, intention-to-treat analysis found higher HIV care coverage (PRR: 1.06, 95% CI: 1.01 to 1.10, p = 0.011) and ART coverage (PRR: 1.05, 95% CI: 1.01 to 1.10, p = 0.028) among HIV-positive participants in the intervention compared with the control arm. Male circumcision coverage among all men (PRR: 1.05, 95% CI: 0.96 to 1.14, p = 0.31) and HIV viral suppression among HIV-positive participants (PRR: 1.04, 95% CI: 0.98 to 1.12, p = 0.20) were higher in the intervention arm, but differences were not statistically significant. No differences were seen in secondary outcomes. Study limitations include reliance on self-report for programmatic outcomes and substantial contamination which may have diluted estimates of effect. CONCLUSIONS: A novel community health worker intervention improved HIV care and ART coverage in an HIV hyperendemic setting but did not clearly improve male circumcision coverage or HIV viral suppression. This community-based, implementation strategy may be a useful component in some settings for HIV epidemic control. TRIAL REGISTRATION: ClinicalTrials.gov NCT02556957.

Clinical Impact of a Shortened Infusion Duration of Ramucirumab in Japanese Patients -A Model-Based Approach.

AIM: We evaluated the safety and potential clinical impact of shortened ramucirumab infusion in Japanese patients from clinical studies. METHODS: Multivariate logistic regression analysis was used to assess any association between infusion rate and increased risk of an immediate infusion-related reaction(IRR). Population pharmacokinetic modeling was used to simulate concentration-time profiles and exposure parameters following a 30- or 60-minute infusion with ramucirumab. RESULTS: From 8 pooled ramucirumab clinical studies, 55 of 559(9.8%)Japanese patients experienced at least one immediate IRR(any grade). When grouped according to infusion rate quartile, the incidence of immediate any-grade IRR was similar across quartiles. Infusion rate was not significantly associated with an increased risk of an immediate IRR; odds ratio per 1 mg/min increase was 0.912, 95% confidence interval 0.724 to 1.149, p=0.436. Patients aged ≥65 years may have a reduced risk of an immediate IRR compared with those aged <65 years, and premedication use was also associated with a reduced risk. Ramucirumab pharmacokinetic profiles were comparable following a 30- or 60-minute infusion. CONCLUSIONS: A shortened infusion duration of ramucirumab is unlikely to affect the efficacy or safety profile in Japanese patients and may be clinically beneficial for patients and health care providers. CLINICAL TRIAL REGISTRATION: RAINBOW-NCT01170663, RAISE- NCT01183780, REACH-NCT01140347, REACH-2-NCT02435433, RAINFALL-NCT02314117, RANGE-NCT02426125, RELAY-NCT02411448, I4T-MC-JVCG-NCT01703091.

Phase I Study of Ramucirumab Plus Merestinib in Previously Treated Metastatic Colorectal Cancer: Safety, Preliminary Efficacy, and Pharmacokinetic Findings.

LESSONS LEARNED: The combination of the antivascular endothelial growth factor receptor 2 monoclonal antibody, ramucirumab, and the type II MET kinase inhibitor, merestinib, is tolerable. Preliminary efficacy data suggest that the combination may provide clinical benefit to patients with metastatic colorectal cancer (mCRC). Further development of this combination would likely necessitate the identification of subsets of patients with mCRC where the clinical benefit is of clinical relevance. BACKGROUND: This study evaluated safety, preliminary efficacy, and pharmacokinetics of ramucirumab plus merestinib in patients with MCR previously treated with oxaliplatin and/or irinotecan. METHODS: Open-label phase Ia/b study comprising 3+3 dose-limiting toxicity (DLT) observation and expansion parts. Treatment was ramucirumab 8 mg/kg on days 1 and 15 and merestinib 80 mg once daily (QD; 28-day cycle). Primary objective was safety and tolerability. Secondary objectives were pharmacokinetics and preliminary antitumor activity. Exploratory objective was biomarker associations. RESULTS: Safety findings: DLT (proteinuria) of 7 phase Ia patients (the expansion part started at the initial recommended dose level); 16 patients (70%) with grade ≥3 treatment-emergent adverse events (TEAEs); 10 patients (43%) with grade ≥3 treatment-related TEAEs. The most common grade ≥3 treatment-related TEAEs were fatigue (4 patients [17%]) and increased blood alkaline phosphatase, diarrhea, and hypertension (2 patients each [9%]). One patient discontinued treatment because of cholestatic hepatitis. Geometric mean trough concentrations at cycle 1, day 15, were ramucirumab, 24.8 µg/mL; merestinib, 130 ng/mL. No complete or partial response was seen; 12 patients (52%) achieved stable disease. Median progression-free survival was 3.3 months (95% confidence interval [CI]: 1.6-4.4). Median overall survival was 8.9 months (95% CI: 3.5-12.7). There were no associations between genetic alterations and efficacy. CONCLUSION: Ramucirumab plus merestinib is tolerable and may have clinical benefit in biomarker-unselected, heavily pretreated patients with mCRC.

The Association Between Social Support, Violence, and Social Service Needs Among a Select Sample of Urban Adults in Baltimore City.

Experiencing violence has been associated with negative health outcomes. The objectives of this study were to determine whether experiencing violence is associated increased support service needs and suboptimal general health indicators. In addition, we explore the relationship between these and perceived social support among a select sample of urban predominantly male adults in Baltimore City. A cross-sectional survey was conducted among 187 adults being seen in one of seven urban partner agencies participating in a parent HIV prevention and treatment demonstration project. Associations were examined using a multivariable logistic regression model, adjusting for the clinic site at which the client was being seen as well as age and gender identity. There was a significant amount of violence experienced by this population; 131 (72%) reported having seen someone be physically assaulted, and 89 (49%) had been physically assaulted without a weapon. Direct victimization from violence was associated with a threefold increased odds of needing housing and mental health/substance use services. Exposure to violence was associated with a threefold increase in needing housing and mental health/substance use services, and with sub-optimal health status. Perceived social support was associated with 30% decreased reports of experiencing violence. In conclusion, our select sample of urban adults report having experienced high rates of violence, and this is associated with increased support service needs as well as suboptimal perceived health status. Incorporating care for the effects of experiencing violence as well as social service needs are important in optimizing the health of urban populations.

Direct Evidence of Topological Defects in Electron Waves through Nanoscale Localized Magnetic Charge.

Topological concepts play an important role in, and provide unique insights into, many physical phenomena. In particular topological defects have become an active area of research due to their relevance to diverse systems including condensed matter and the early universe. These defects arise in systems during phase transitions or symmetry-breaking operations that lead to a specific configuration of the order parameter that is stable against external perturbations. In this work, we experimentally show that excitations or defects carrying magnetic charge in artificial spin ices introduce a topological defect in incident coherent electron waves. This results in the formation of a localized electron vortex beam carrying orbital angular momentum that is directly correlated with the magnetic charge. This work provides unique insight into the interaction of electrons with magnetically charged excitations and the effect on their topology thereby opening new possibilities to explore exotic scattering and quantum effects in nanoscale condensed-matter systems.

Phase I Dose-Escalation Study of Ramucirumab in Chinese Patients with Advanced Solid Tumors.

LESSONS LEARNED: Ramucirumab was well tolerated in Chinese patients with advanced solid tumors, and adverse events were manageable in this study.Pharmacokinetics characteristics in Chinese patients were similar to those in other populations. Immunogenicity was not detected.No efficacy conclusion could be drawn, and further randomized studies are warranted. BACKGROUND: This single-arm, nonrandomized, open-label, dose-escalation, phase I study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of ramucirumab in Chinese patients with advanced solid tumors that were resistant to standard therapy or no standard therapy was available. METHODS: Dose escalation was a 3 + 3 design, with expansion in Cohorts 2 and 3 for PK. Ramucirumab was given intravenously at three different dosages: 6 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, and 8 mg/kg every 2 weeks. Safety analyses included all patients. PK, immunogenicity, and antitumor activity were also assessed. RESULTS: Among 28 patients treated, 2 experienced dose-limiting toxicity, possibly related to ramucirumab. No maximum tolerated dose was determined. All patients experienced at least one treatment-emergent adverse event. Grade ≥3 adverse event was reported for 53.6% (n = 15) of patients. PK analyses indicated that ramucirumab had low clearance, small volume of distribution, and long half-life in Chinese patients, as in other populations. Immunogenicity was not detected. No patient had complete/partial response, and 64.3% (n = 18) had stable disease with a median duration of 5.55 months (95% confidence interval: 3.38-7.13 months). CONCLUSION: Ramucirumab appeared to be well tolerated in Chinese patients with advanced solid tumors. PK characteristics in Chinese patients were similar to those in other populations.

In Vitro and Clinical Evaluations of the Drug-Drug Interaction Potential of a Metabotropic Glutamate 2/3 Receptor Agonist Prodrug with Intestinal Peptide Transporter 1.

Despite peptide transporter 1 (PEPT1) being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design. In vitro investigations determined the prodrug (LY2140023 monohydrate) is a substrate of PEPT1 with Km value of approximately 30 µM, whereas the active moiety (LY404039) is not a PEPT1 substrate. In addition, among the eight known PEPT1 substrates evaluated in vitro, valacyclovir was the most potent inhibitor (IC50 = 0.46 mM) of PEPT1-mediated uptake of the prodrug. Therefore, a clinical drug interaction study was conducted to evaluate the potential interaction between the prodrug and valacyclovir in healthy subjects. No effect of coadministration was observed on the pharmacokinetics of the prodrug, valacyclovir, or either of their active moieties. Although in vitro studies showed potential for the prodrug and valacyclovir interaction via PEPT1, an in vivo study showed no interaction between these two drugs. PEPT1 does not appear to easily saturate because of its high capacity and expression in the intestine. Thus, a clinical interaction at PEPT1 is unlikely even with a compound with high affinity for the transporter.

Perceived Stress in Black and Latino Male Firefighters: Associations with Risk and Protective Factors.

Objective: To compare the prevalence of work-related protective and risk factors among Black and Latino male firefighters and to examine the association of these factors to perceived stress among both ethnic groups. Design Setting Participants: Participants included 1,036 male, career firefighters who self-identified as Black (n=477) or Latino (n=559) from a large fire department in a major metropolitan city in the southwestern United States. As part of a department-wide suicide prevention program conducted in 2008, participants completed an anonymous and voluntary mental health needs survey. Measures: The needs survey included questions regarding prevalence of work-related protective and risk factors, the RAPS-4 to assess substance abuse problems, and the 10-item Perceived Stress Scale. Results: Results of regression analyses indicated that for both Black and Latino male firefighters, alcohol abuse (ß =.13, ß =.22), self-reported good health (ß = -.23, ß =-.24) and a positive partner/spouse relationship (ß =-.14, ß = -.15) were related to perceived stress. In addition, having a second job (ß = .12) and a sense of life calling (ß =-.10) were related to perceived stress only among Latino firefighters. All associations were in the expected direction as indicated by the signs of the standardized beta coefficients (ß). Conclusion: Black and Latino male firefighters reported relatively high levels of perceived stress. However, there were both differences and similarities in the factors associated to perceived stress among the ethnic groups. Therefore, interventions to help firefighters reduce or manage stress need to take into account that factors associated with perceived stress may vary by ethnic group.