Technological advancements allow embodied and synchronous communication via social virtual reality (VR), where multiple users interact as avatars in a shared virtual space. However, the affordances ...of social VR and how users interact with them have been underexplored. We expand the discourse on media affordances by emphasizing user agency in strategic media choices for overcoming constraints in physical and virtual worlds. We qualitatively investigated user experiences of a social VR platform. Findings from semi-structured interviews (N = 28) revealed that media selection is determined through a dynamic relationship between platforms designed to encourage action possibilities and users strategically leveraging media affordances to overcome situational constraints of their physical environment.
Aims/hypothesis
IL-6 is a proinflammatory cytokine associated with the pathogenesis of hepatic diseases. Metformin is an anti-diabetic drug used for the treatment of type 2 diabetes, and orphan ...nuclear receptor small heterodimer partner (SHP, also known as NR0B2), a transcriptional co-repressor, plays an important role in maintaining metabolic homeostasis. Here, we demonstrate that metformin-mediated activation of AMP-activated protein kinase (AMPK) increases SHP protein production and regulates IL-6-induced hepatic insulin resistance.
Methods
We investigated metformin-mediated SHP production improved insulin resistance through the regulation of an IL-6-dependent pathway (involving signal transducer and activator of transcription 3 STAT3 and suppressor of cytokine signalling 3 SOCS3) in both
Shp
knockdown and
Shp
null mice.
Results
IL-6-induced STAT3 transactivation and SOCS3 production were significantly repressed by metformin, adenoviral constitutively active AMPK (Ad-CA-AMPK), and adenoviral SHP (Ad-SHP), but not in
Shp
knockdown, or with the adenoviral dominant negative form of AMPK (Ad-DN-AMPK). Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP) and protein localisation studies showed that SHP inhibits DNA binding of STAT3 on the
Socs3
gene promoter via interaction and colocalisation within the nucleus. Upregulation of inflammatory genes and downregulation of hepatic insulin signalling by acute IL-6 treatment were observed in wild-type mice but not in
Shp
null mice. Finally, chronic IL-6 exposure caused hepatic insulin resistance, leading to impaired insulin tolerance and elevated gluconeogenesis, and these phenomena were aggravated in
Shp
null mice.
Conclusions/interpretation
Our results demonstrate that SHP upregulation by metformin may prevent hepatic disorders by regulating the IL-6-dependent pathway, and that this pathway can help to ameliorate the pathogenesis of cytokine-mediated metabolic dysfunction.
Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety ...and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody.
Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25–75 mg p.o. twice a day; continuous or intermittent), savolitinib (600–800 mg p.o. once a day), or durvalumab (3–10 mg/kg intravenous every 2 weeks).
At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n = 36), savolitinib (n = 18), or durvalumab (n = 23). Most common adverse events (any grade), occurring in ≥20% of patients across dose groups, were: selumetinib arm—diarrhea (75%), rash (58%), nausea (47%); savolitinib arm—nausea (67%), rash (56%), vomiting (50%); durvalumab arm—rash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n = 1), 50 mg (n = 1), and 75 mg (n = 4) continuous-dose groups, savolitinib 600 mg (n = 1) and 800 mg dose groups (n = 2), and durvalumab 10 mg/kg (n = 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively.
Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated.
NCT02143466.
•Patients with advanced EGFR-mutant NSCLC received osimertinib 80 mg combined with selumetinib, savolitinib or durvalumab.•Feasible dosing strategies were identified for osimertinib plus selumetinib or savolitinib.•Osimertinib plus durvalumab was not feasible due to increased reporting of interstitial lung disease.•Responses were seen in all treatment arms, warranting further analysis of the feasible combinations identified.•Osimertinib-based combinations represent a compelling approach now being investigated broadly to further improve outcomes.
Low cost, locally available biomaterial was tested for its ability to remove reactive dyes from aqueous solution. Granules prepared from dried activated sludge (DAS) were utilized as a sorbent for ...the uptake of Rhodamine-B (Rh-B) dye. The effects of various experimental parameters (dye concentration, sludge concentrations, swelling, pretreatment and other factors) were investigated and optimal experimental conditions were ascertained. Nearly 15
min was required for the equilibrium adsorption, and Rh-B dyes could be removed effectively. Dye removal performance of Rh-B and DAS increased with increasing concentrations. The acid pretreated biomass exhibited a slightly better biosorption capacity than alkali pretreated or non-pretreated biomass. The optimum swelling time for dye adsorption of the DAS within the swelling time range studied was 12
h. Both the Freundlich and Langmuir isotherm models could describe the adsorption equilibrium of the reactive dye onto the activated sludge with the Langmuir isotherm showing the better agreement of the two. Second-order kinetic models confirmed the agreement.
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer (MBC) was ...published in 2021. A special, hybrid guidelines meeting was convened by ESMO and the Korean Society of Medical Oncology (KSMO) in collaboration with nine other Asian national oncology societies in May 2022 in order to adapt the ESMO 2021 guidelines to take into account the differences associated with the treatment of MBC in Asia. These guidelines represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with MBC representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). The voting was based on the best available scientific evidence and was independent of drug access or practice restrictions in the different Asian countries. The latter were discussed when appropriate. The aim of these guidelines is to provide guidance for the harmonisation of the management of patients with MBC across the different regions of Asia, drawing from data provided by global and Asian trials whilst at the same time integrating the differences in genetics, demographics and scientific evidence, together with restricted access to certain therapeutic strategies.
•This article provides ESMO recommendations adapted for the treatment of MBC in Asian patients.•Evidence-based medicine and the availability to molecular diagnostic tests and treatments in Asian countries are discussed.•The aim is to encourage harmonisation of the management of MBC patients and to facilitate drug registration, across Asia.
Summary
Improving dendritic cell (DC) functions is highly promising for therapeutic intervention of diverse diseases, including cancer. Immunosuppressive cytokines such as interleukin (IL)‐10 ...produced by DCs themselves (autocrine) and other regulatory immune cells (paracrine) down‐regulate functional profiles of DCs through specific cell surface receptors such as IL‐10R. Here, we tried to improve DC functions using small interfering RNA (siRNA) technology to block an IL‐10R‐mediated immunosuppressive axis. DCs modified with siRNA targeting against IL‐10R or IL‐10 (DC/siIL‐10R or DC/siIL‐10) led to up‐regulation of major histocompatibility complex (MHC) class II, CD40 co‐stimulatory molecule, and IL‐12 proinflammatory cytokine after lipopolysacharide (LPS) stimulation compared to DC/siGFP. Notably, the LPS‐induced functional profiles of DC/siIL‐10R were strongly resistant to the addition of recombinant IL‐10, which mimicked paracrine IL‐10. In contrast, those of DC/siIL‐10 were reversed by adding exogenous IL‐10. Consistently, DC/siIL‐10R generated more human papilloma virus (HPV) E7‐specific CD8+ T cells and stronger anti‐tumour effects against E7‐expressing TC‐1 tumour cells in vaccinated mice than DC/siGFP, as well as DC/siIL‐10. Taken together, these results provide the groundwork for future clinical translation of siRNA‐mediated strategy targeting IL‐10R to enhance DC‐based vaccine potency.
The increasing prevalence of multidrug-resistant organism (MDRO) carriage poses major challenges to medicine as healthcare costs increase. Recently, faecal microbiota transplantation (FMT) has been ...discussed as a novel and effective method for decolonizing MDRO.
To compare the efficacy of different FMT methods to optimize the success rate of decolonization in patients with MDRO carriage.
This prospective cohort study enrolled patients with MDRO carriages from 2018 to 2021. Patients underwent FMT via one of the following methods: oral capsule, oesophagogastroduodenoscopy (EGD), colonoscopy, or gastric tube.
A total of 57 patients underwent FMT for MDRO decolonization. The colonoscopy group required the shortest time for decolonization, whereas the EGD group required the longest (24.9 vs 190.4 days, P = 0.022). The decolonization rate in the oral capsule group was comparable to that in the EGD group (84.6% vs 85.7%, P = 0.730). An important clinical factor associated with decolonization failure was antibiotic use after FMT (odds ratio = 6.810, P = 0.008). All four groups showed reduced proportions of MDRO species in microbiome analysis after FMT.
Compared to other conventional methods, the oral capsule is an effective FMT method for patients who can tolerate an oral diet. The discontinuation of antibiotics after FMT is a key factor in the success of decolonization.
Summary
Bone disorder is a common complication of chronic kidney disease (CKD). The clinical usefulness of bone mineral density (BMD) in CKD is not well known. Our study shows that low BMD is ...associated with physical activity and dietary Na/K intake ratio and can predict poor renal outcome in non-dialysis CKD.
Purpose
Despite evidence of a link between bone mineral disorders and chronic kidney disease (CKD), the clinical implications of bone mineral density (BMD) in CKD are not well established. We investigated risk factors and renal outcomes of low BMD in CKD.
Methods
We analyzed data from the KNOW-CKD. BMD measured by dual-energy x-ray absorptiometry was classified by
T
score: normal (
T
score ≥ − 1.0), osteopenia (− 1.0 >
T
score > − 2.5), and osteoporosis (
T
score ≤ − 2.5) of the lumbar spine, hip, or femoral neck. Logistic regression analysis to assess risk factors of low BMD (
T
score < − 1.0) and Cox proportional hazards models to estimate risk of incident end-stage renal disease (ESRD).
Results
Low BMD was prevalent (osteopenia 33%; osteoporosis 8%) in 2128 adults with CKD (age 54 ± 12 years; male 61%). Over a median follow-up of 4.3 years, there were 521 cases of incident ESRD. Lower BMD was associated with female sex, older age, low eGFR, low BMI, and lifestyle factors of physical activity (odds ratio (OR) = 0.62, 95% confidence interval (0.49–0.77)) and spot urine Na/K ratio (1.07 (1.00–1.15)). In adjusted Cox models, low BMD was associated with increased incident ESRD (hazard ratio (HR) = 1.14 (0.92–1.41) for osteopenia; 1.43 (1.01–2.04) for osteoporosis,
P
for trend < 0.05) compared with the reference of normal BMD. The association between low BMD and ESRD was similar according to
T
score discordance classification.
Conclusions
Low BMD was associated with modifiable lifestyle factors including low physical activity and high dietary Na/K intake ratio. The presence of low BMD is associated with poor renal outcomes in non-dialysis CKD.
Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. We assessed the efficacy and tolerability of pemetrexed and cisplatin combination ...therapy in patients with refractory bone and soft tissue sarcoma (STS).
Patients were included in this multicenter, phase II study (ClinicalTrials.gov identifier NCT03809637) if they progressed after receiving one or more chemotherapy regimens containing an anthracycline and/or ifosfamide. Pemetrexed was first administered intravenously, followed by cisplatin, over a cycle of 21 days, for a maximum of six cycles. The primary endpoint was a progression-free rate (PFR) at 3 months (3-month PFR).
From January 2017 to September 2019, we enrolled 37 patients; of these, 73% had previously undergone three or more rounds of chemotherapy. Five patients (13.5%) exhibited objective responses, including two patients (2/6, 33.3%) with malignant peripheral nerve sheath tumors, one patient (1/4, 25%) with synovial sarcoma, one patient (1/4, 25%) with undifferentiated pleomorphic sarcoma, and one patient (1/4, 25%) with angiosarcoma. The median progression-free survival was 2.6 months, and the 3-month PFR was 45.9% (n = 17). None of the four patients with osteosarcoma exhibited objective responses or were progression free at 3 months. The most frequent treatment-related grade 3-4 toxicities included neutropenia (16.2%), anemia (13.5%), thrombocytopenia (13.5%), and fatigue (8.1%). Among 26 patients (70.3%) available for immunohistochemical assessments, patients in the low-excision repair cross-complementation group 1 (ERCC1) and low-thymidylate synthase expression groups showed a tendency for longer overall survival.
Combination therapy with pemetrexed and cisplatin was associated with clinically meaningful and sustained responses among patients with advanced and refractory STS. The combination therapy met its predefined primary study endpoint.
•Pemetrexed and cisplatin show promising efficacy for advanced sarcoma treatment, particularly as a salvage therapy option.•The combination therapy met its predefined primary endpoint, with a 3-month PFR of 45.9%.•Pemetrexed and cisplatin showed acceptable toxicity in heavily treated sarcoma patients.
Reports detailing the response of hypertensive patients to renal denervation (RDN) in Asian patients are limited. We evaluated 6- and 12-month outcomes after RDN in an Asian population and compared ...outcomes to a primarily Caucasian population. The Global SYMPLICITY Registry (GSR) is a prospective, all-comer, worldwide registry that evaluates the safety and effectiveness of RDN and includes the Korean registry substudy (GSR Korea) and a Caucasian subset (GSR Caucasian). Given differences in baseline characteristics among GSR Korea (n=93) as compared with GSR Caucasian (n=169) patients, including lower baseline office systolic blood pressure (SBP), lower body mass index and differences in medications, propensity score adjustment was performed when comparing the change in SBP between subsets. The 6- and 12-month change in SBP in GSR Korea was -19.4±17.2 and -27.2±18.1 mm Hg, respectively (P<0.001 for both vs baseline). GSR Caucasian had a SBP change similar to GSR Korea at 6 months (-20.9±21.4 mm Hg, unadjusted P=0.547, adjusted P=0.998), whereas at 12 months the change was significantly less pronounced (-20.1±23.9 mm Hg, unadjusted P=0.004, adjusted P=0.002). There were no protocol-defined procedure-related adverse events and no chronic adverse events associated with the device in an Asian population. RDN provided a significant reduction in 6- and 12-month office SBP among Asian patients, with a favorable safety profile. The 12-month SBP reduction was larger than that observed in Caucasian patients.
PDF
