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Recent evidence suggests that imagined auditory and visual sensory stimuli can be integrated with real sensory information from a different sensory modality to change the perception of external events via cross-modal multisensory integration mechanisms. Here, we explored whether imagined voluntary movements can integrate visual and proprioceptive cues to change how we perceive our own limbs in space. Participants viewed a robotic hand wearing a glove repetitively moving its right index finger up and down at a frequency of 1 Hz, while they imagined executing the corresponding movements synchronously or asynchronously (kinesthetic-motor imagery); electromyography (EMG) from the participants’ right index flexor muscle confirmed that the participants kept their hand relaxed while imagining the movements. The questionnaire results revealed that the synchronously imagined movements elicited illusory ownership and a sense of agency over the moving robotic hand—the moving rubber hand illusion—compared with asynchronously imagined movements; individuals who affirmed experiencing the illusion with real synchronous movement also did so with synchronous imagined movements. The results from a proprioceptive drift task further demonstrated a shift in the perceived location of the participants’ real hand toward the robotic hand in the synchronous versus the asynchronous motor imagery condition. These results suggest that kinesthetic motor imagery can be used to replace veridical congruent somatosensory feedback from a moving finger in the moving rubber hand illusion to trigger illusory body ownership and agency, but only if the temporal congruence rule of the illusion is obeyed. This observation extends previous studies on the integration of mental imagery and sensory perception to the case of multisensory bodily awareness, which has potentially important implications for research into embodiment of brain–computer interface controlled robotic prostheses and computer-generated limbs in virtual reality.

Background: Vancomycin requires therapeutic drug monitoring (TDM) based on its pharmacokinetic properties, and guidelines have shifted to analyzing area under the curve over 24 hours (AUC24) rather than trough concentrations due to nephrotoxicity concerns and correlation to efficacy. Obesity is an established risk factor for vancomycin-induced nephrotoxicity due to increased drug exposure based on dosing calculations and volume of distribution estimation. The aim of this study is to assess the relationship between AUC-based versus trough-based dosing and nephrotoxicity among obese patients receiving vancomycin. Methods: This research project was conducted as a retrospective, observational, single-centered study which included obese adults who received at least 48 hours of vancomycin. The electronic medical record provided data for patients with vancomycin pharmacokinetic consults either evaluated with trough-only or AUC-based dosing. The primary objective was to compare the development of nephrotoxicity after vancomycin initiation, while secondary objectives included vancomycin loading dose exposure, total daily dose of vancomycin, and whether target TDM was attained. Nominal data were evaluated utilizing the chi-square test and continuous data using the independent samples t-test or Mann-Whitney test. The a priori level of significance was .05. Data analysis was performed using Microsoft Excel and SAS statistical software. Results: Two hundred fifty-four patients were included in the primary analysis. Four patients in the AUC cohort (6.3%) developed nephrotoxicity compared to 32 (17.4%) in the trough cohort ( P = .035). Both cohorts received a median of 4 days of therapy; however, the median loading dose per actual body weight in the AUC cohort was 20 mg/kg as compared to 16 mg/kg in the trough cohort. Of the 130 patients with available TDM in the trough cohort, 97 (74.6%) did not meet target attainment as compared to 15 of the 57 in the AUC cohort (26.3%) ( P

Transplant renal artery stenosis (TRAS) after renal transplantation is a common cause of graft dysfunction and failure. Endovascular intervention in the form of percutaneous transluminal angioplasty (PTA) and stenting has rapidly become the dominant treatment modality for the TRAS. There is a paucity of clinical data on the use of drug-eluting stent (DES) for TRAS. We investigated the outcomes of patients with clinically significant TRAS undergoing DES placement.A retrospective review of patients with clinically significant TRAS undergoing PTA with DES placement from June 2014 to April 2021 was conducted. Patients treated for TRAS exhibited uncontrolled hypertension and/or unexplained allograft dysfunction. Patient demographics, procedural details, and follow-up outcomes were collected. Primary endpoints were the in-stent primary patency and graft survival. Secondary endpoints were freedom from reintervention, primary-assisted patency, and access-related complications.Thirteen TRAS in 12 patients with graft function alteration were treated with DES. The median age was 57 years (interquartile range (IQR), 48-63 years), and 9 (70%) patients were male. The median follow-up was 9 months (IQR, 4-52 months). The most common comorbidity was hypertension (100%), coronary artery disease (83%), and diabetes. The median time from deceased donor transplant to intervention was 5.8 months (IQR, 3.5-6.7 months). TRAS was most commonly found at the juxta-ostial segment (77%). The procedure was performed with carbon dioxide angiography with minimal amount of iodinated contrast (median, 3 mL) under local anesthesia in 9 (69%), and general anesthesia in 4 (31%) patients. The median stent diameter was 4.5 mm (IQR, 4-5 mm), and the median stent length was 15 mm (IQR, 15-18 mm). No intraoperative complications occurred. The rates of stenosis-free primary patency of the DES and graft survival were 76% and 100%, respectively. All 3 reinterventions for restenosis resulted from the kinking of the transplant renal artery proximal to the DES, which were treated by extending the stent more proximally 1-2 mm into the external iliac artery. There were no access-related complications. The median time to reintervention was 0.9 months (range, 0.23-2 months). Freedom from reintervention and primary-assisted patency were 76% and 100%, respectively.Our study demonstrates that DES is a safe and effective treatment modality in patients with TRAS at short to mid-term follow-up. As all reinterventions after DES were performed due to kinking of the transplant renal artery proximal to the stent, bridging of the DES 1-2 mm into the external iliac artery is recommended.

PURPOSE: Many cancer centers engage in multidisciplinary tumor board meetings to determine the optimal approach to complex cancer care. With the onset of the COVID-19 pandemic, many institutions changed the format of these meetings from in-person to virtual. The aim of this study was to determine if the change to a virtual meeting format had an impact on attendance and cases presented. METHODS: Tumor board records were analyzed to obtain attendance and case presentation information at a National Cancer Institute–designated Comprehensive Cancer Center. Twelve-month in-person tumor board data were compared with 12-month virtual tumor board data to assess for difference in attendance and case presentation patterns. RESULTS: Seven separate weekly tumor board meetings at the beginning of the study (breast, GI, gynecology, liver, lung, melanoma, and urology) were expanded to nine meetings on the virtual platform (+endocrine and pancreas). Overall attendance increased by 46% on the virtual platform compared with in-person meetings (4,030 virtual attendances v 2,753 in-person, P < .001). Increased attendance was present across all specialties on the virtual platform. In addition, the number of patient cases discussed increased from 2,127 in in-person meeting to 2,656 on the virtual platform (a 20% increase, P < .001). CONCLUSION: A significant increase was observed in overall tumor board attendance and in case presentations per meeting, requiring the expansion of additional weekly meetings. Furthermore, in a major cancer center with multiple community affiliates, virtual tumor boards may encourage increased participation from remote sites with the benefit of obtaining expert specialist advice as compared with geographically challenging in-person meetings.

Background: Antimicrobial stewardship programs have made large efforts to minimize the inappropriate use of antibiotics. Implementation of these programs can be challenging, since many institutions have limited resources. Utilizing resources that already exist may be beneficial, including medication reconciliation pharmacist (MRP) programs. This study aims to evaluate the impact of a MRP program on appropriateness of community-acquired pneumonia (CAP) treatment durations at hospital discharge. Methods: This study was a retrospective, observational, single-center study comparing the total days of antibiotic therapy for CAP in the preintervention period (9/2020-11/2020) versus the post-intervention period (9/2021-11/2021). Implementation of a new clinical intervention occurred between the 2 periods and included education to MRPs on appropriate CAP treatment durations and on documentation of recommendations. Data was collected utilizing a chart review of the electronic medical record of patients diagnosed with CAP using ICD-10 codes. The primary objective of this study was to compare the total days of antibiotic therapy in the pre-intervention period versus the postintervention period. Results: One-hundred fifty-five patients were included in the primary analysis. When observing total days of antibiotic therapy, there was no change from the pre-intervention period at 8 days compared to the postintervention period ( P = .109). When analyzing antibiotic days of therapy at discharge, there was a decrease from 4.55 days in the preintervention period compared to 3.8 days in the post-intervention period ( P = .109). The incidence of those with appropriate treatment durations, defined as 5 to 7 days of antibiotic therapy, was higher in the post-intervention period (26.5% in the pre-intervention group vs 37.9% in the post-intervention group, P = .460). Conclusions: There was a non-statistically significant decrease in median days of antimicrobial therapy for CAP at hospital discharge after implementation of a new clinical intervention targeting antibiotic days of therapy. Though median total antibiotic days of therapy were similar between both time periods, patients had an overall increase in incidence of appropriate duration of therapy, defined as 5 to 7 days, after intervention. Further studies are necessary to show how MRPs have a positive impact on improving outpatient antibiotic prescribing at hospital discharge.

To evaluate risk factors associated with vasopressor use and development of hospital-acquired pressure injuries (HAPIs).The researchers conducted a retrospective chart review in a 12-bed medical ICU at a community hospital. A total of 123 patients who received a minimum of 24 hours of continuous vasopressor administration between January 2017 and January 2019 were included. The primary outcomes assessed were vasopressor dose and HAPI incidence, with a subgroup analysis based on type. Secondary outcomes included quantity of vasopressors, duration, mean arterial pressure, mechanical ventilation, time to injury, severity, and location.The overall incidence of HAPIs was 20.3%, with 17% incidence in the low-dose cohort and 22.4% in the high-dose cohort ( P = .317). There were no differences in the subgroup analysis based on vasopressor type. The most common locations for injuries were the sacrum and coccyx, with the majority being stage 1 or 2 based on the National Pressure Injury Advisory Panel severity staging. No correlations were found between HAPI incidence and factors such as multiple vasopressors use, mechanical ventilation, mean arterial pressure, or duration of vasopressor administration. The documentation of time to injury was significantly shorter in the high-dose cohort compared with the low-dose cohort (157.58 vs 330.86 hours, P.05).The incidence of HAPIs did not differ between the low- and high-dose vasopressor cohorts. However, patients who received higher doses of vasopressors had documented pressure injuries sooner than the low-dose cohort, emphasizing the importance of close monitoring for HAPIs in patients receiving vasopressors.

While practitioners discuss the phenomena of sustainability, cities, and entrepreneurship, such as living labs and smart cities, alongside sustainable entrepreneurial ecosystems at length, researchers tend to reduce the complexity by considering these phenomena from the perspective of one discipline or by merging two research disciplines at best. This study intends to provide guidance on what is required for the emergence of a transdisciplinary research stream of sustainability, urban studies, and entrepreneurship. By applying design science involving practitioners and scientific experts, we designed a relevant and rigorous future research agenda that considered phenomena, research design, and theoretical foundations. Starting from the basis that sustainable entrepreneurial ecosystems are promising, the agenda integrates the knowledge base and establishes a multifaceted and comprehensive perspective on sustainable entrepreneurship in cities. Furthermore, implementing the research agenda has strong practical implications for realizing the common vision of a transition that ensures the quality of life on Earth.

Supplemental Figure 1: PLX8394 does not alter CRAF or c-Src phosphorylation; Supplemental Figure 2. Treatment of xenograft-derived tumor pieces in an ex vivo explant system; Supplemental Figure 3: Patient sample extended data; Supplemental Figure 4: Parallel ex vivo dosing and homodimerization of vemurafenib and PLX8394 treatments; Supplemental Figure 5: PBRT characterization; Supplemental Figure 6: Targeting AKT and PDGFRβ in PBRT cell lines does not resensitize to PLX8394; Supplemental Figure 7: BRAF V600E splice variant analysis of PBRT cell lines and signaling and growth response of second-line therapies; Supplemental Methods.

FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K–mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox-breaking RAF inhibitor (PLX8394) has been designed. Here, we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenib-resistant BRAF splice variant–expressing tumors and reduced splice variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test the efficacy of therapeutic agents. Mol Cancer Ther; 17(1); 84–95. ©2017 AACR.

Table S1: KLF5 E419Q-gained super-enhancers and the nearest genes

Figure S1. Super-enhancers near the KLF5 gene are focally amplified in cancer cell lines;Figure S2. The regulatory potential of the KLF5/KLF12 intervening region;Figure S3. Expression level of KLF12, DIS3 and PIBF1 after repression of KLF5 superenhancers;Figure S4. Genomic analysis of KLF5 binding sites in BICR31 cells;Figure S5. Target genes of KLF5 in head and neck squamous cell carcinomas;Figure S6. The effect of KLF5 silencing on H3K27ac profile;Figure S7. Mutation hotspots in KLF5;Figure S8. Mutation profile in FBXW7 in colorectal cancers; Figure S9. Ectopic expression of KLF5 mutants in HEK293T cells; Figure S10. Ectopic expression of KLF5 E419Q in HCC95 cells

Table S2: Oligos used in the study

Combinations of BRAF inhibitors and MEK inhibitors (BRAFi + MEKi) are FDA-approved to treat BRAFV600E/K-mutant melanoma. Efficacy of BRAFi + MEKi associates with cancer cell death and alterations in the tumor immune microenvironment; however, the links are poorly understood. We show that BRAFi + MEKi caused durable melanoma regression in an immune-mediated manner. BRAFi + MEKi treatment promoted cleavage of gasdermin E (GSDME) and release of HMGB1, markers of pyroptotic cell death. GSDME-deficient melanoma showed defective HMGB1 release, reduced tumor-associated T cell and activated dendritic cell infiltrates in response to BRAFi + MEKi, and more frequent tumor regrowth after drug removal. Importantly, BRAFi + MEKi–resistant disease lacked pyroptosis markers and showed decreased intratumoral T-cell infiltration but was sensitive to pyroptosis-inducing chemotherapy. These data implicate BRAFi + MEKi–induced pyroptosis in antitumor immune responses and highlight new therapeutic strategies for resistant melanoma.Significance:Targeted inhibitors and immune checkpoint agents have advanced the care of patients with melanoma; however, detailed knowledge of the intersection between these two research areas is lacking. We describe a molecular mechanism of targeted inhibitor regulation of an immune-stimulatory form of cell death and provide a proof-of-principle salvage therapy concept for inhibitor-resistant melanoma.See related commentary by Smalley, p. 176.This article is highlighted in the In This Issue feature, p. 161

Supplementary Figures and Legends.

Supplemental Table 1: Patient data and treatment history Supplemental Table 2: PBRT #15 Ion Torrent results Supplemental Table 3: PBRT #16 Ion Torrent results

The Krüppel-like family of transcription factors plays critical roles in human development and is associated with cancer pathogenesis. Krüppel-like factor 5 gene (KLF5) has been shown to promote cancer cell proliferation and tumorigenesis and to be genomically amplified in cancer cells. We recently reported that the KLF5 gene is also subject to other types of somatic coding and noncoding genomic alterations in diverse cancer types. Here, we show that these alterations activate KLF5 by three distinct mechanisms: (i) Focal amplification of superenhancers activates KLF5 expression in squamous cell carcinomas; (ii) Missense mutations disrupt KLF5–FBXW7 interactions to increase KLF5 protein stability in colorectal cancer; (iii) Cancer type–specific hotspot mutations within a zinc-finger DNA binding domain of KLF5 change its DNA binding specificity and reshape cellular transcription. Utilizing data from CRISPR/Cas9 gene knockout screening, we reveal that cancer cells with KLF5 overexpression are dependent on KLF5 for their proliferation, suggesting KLF5 as a putative therapeutic target.Significance: Our observations, together with previous studies that identified oncogenic properties of KLF5, establish the importance of KLF5 activation in human cancers, delineate the varied genomic mechanisms underlying this occurrence, and nominate KLF5 as a putative target for therapeutic intervention in cancer. Cancer Discov; 8(1); 108–25. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1

Supplemental Fig. S1. ErbB3 and ErbB2 are phosphorylated in the majority of WT/WT melanoma patient. Supplemental Fig. S2. Melanoma cells utilized in this study do not express NRG1. Supplemental Fig. S3. NRG1 rescues the inhibitory effects of MEK inhibitor on melanoma cell growth. Supplemental Fig. S4. Trametinib induces adaptive activation of ErbB2/ErbB3 dimer following NRG1 treatment. Supplemental Fig. S5. ERK1/2 phosphorylation modulates ErbB2 activation. Supplemental Fig. S7. LJM716 and pertuzumab reverse the protective effects provided by CAF-derived NRG1 in MEK inhibited melanoma cells and increase the efficacy of MEK inhibitors in vivo.

Cell culture-Inhibitor-Sequencing-Additional siRNA-Statistical analysis

MEK–ERK1/2 signaling is elevated in melanomas that are wild-type for both BRAF and NRAS (WT/WT), but patients are insensitive to MEK inhibitors. Stromal-derived growth factors may mediate resistance to targeted inhibitors, and optimizing the use of targeted inhibitors for patients with WT/WT melanoma is a clinical unmet need. Here, we studied adaptive responses to MEK inhibition in WT/WT cutaneous melanoma. The Cancer Genome Atlas data set and tumor microarray studies of WT/WT melanomas showed that high levels of neuregulin-1 (NRG1) were associated with stromal content and ErbB3 signaling. Of growth factors implicated in resistance to targeted inhibitors, NRG1 was effective at mediating resistance to MEK inhibitors in patient-derived WT/WT melanoma cells. Furthermore, ErbB3/ErbB2 signaling was adaptively upregulated following MEK inhibition. Patient-derived cancer-associated fibroblast studies demonstrated that stromal-derived NRG1 activated ErbB3/ErbB2 signaling and enhanced resistance to a MEK inhibitor. ErbB3- and ErbB2-neutralizing antibodies blocked the protective effects of NRG1 in vitro and cooperated with the MEK inhibitor to delay tumor growth in both cell line and patient-derived xenograft models. These results highlight tumor microenvironment regulation of targeted inhibitor resistance in WT/WT melanoma and provide a rationale for combining MEK inhibitors with anti-ErbB3/ErbB2 antibodies in patients with WT/WT cutaneous melanoma, for whom there are no effective targeted therapy options.Significance: This work suggests a mechanism by which NRG1 regulates the sensitivity of WT NRAS/BRAF melanomas to MEK inhibitors and provides a rationale for combining MEK inhibitors with anti-ErbB2/ErbB3 antibodies in these tumors. Cancer Res; 78(19); 5680–93. ©2018 AACR.

Chemical structures of compounds used in study

Article File and Figures

Supplementary Methods. Supplementary Figure 1. Somatic alterations in PPARG and RXRA are hallmarks of luminal bladder cancer. Supplementary Figure 2. PPARG pathway is activated by overexpression of RXRA S427F/S427Y, but not other mutant alleles in bladder cancer cells. Supplementary Figure 3. Representation of the effects of ligand-dependent modulation on the PPARG interactome. Supplementary Figure 4. Downregulation of FABP4 protein by treatment of PPARG-activated bladder cancer cell lines by inverse-agonist T0070907. Supplementary Figure 5. Genome engineering scheme for generating reporter cell line. Supplementary Figure 6. Basal expression of FABP4 is reduced by PPARG inverse agonists, but not antagonists. Supplementary Figure 7. Lipid metabolism genes are inhibited by PPARG inverse-agonists. Supplementary Figure 8. PPARG inverse-agonists inhibit proliferation of PPARG activated bladder cancer cell lines in clonogenic assays. Supplementary Figure 9. PPARG inverse-agonists, but not antagonists, inhibit proliferation of PPARG-activated bladder cancer cell lines. Supplementary Figure 10. Somatic alterations in RXRA and PPARG.

The PPARG gene encoding the nuclear receptor PPARγ is activated in bladder cancer, either directly by gene amplification or mutation, or indirectly by mutation of the RXRA gene, which encodes the heterodimeric partner of PPARγ. Here, we show that activating alterations of PPARG or RXRA lead to a specific gene expression signature in bladder cancers. Reducing PPARG activity, whether by pharmacologic inhibition or genetic ablation, inhibited proliferation of PPARG-activated bladder cancer cells. Our results offer a preclinical proof of concept for PPARG as a candidate therapeutic target in bladder cancer. Cancer Res; 77(24); 6987–98. ©2017 AACR.

PDF file - 3777K, TWIST1 expression is not regulated by RSK, STAT3, AKT, or by protein stability in mutant B-RAF cell lines

PDF file - 1510K, TWIST1 is positively regulated by active ERK1/2 signaling in N-RAS mutant melanoma cells

PDF file - 2984K, Oligonucleotide and primer sequences