Extracellular Vesicles Derived from Adipose Stem Cells Alleviate Systemic Sclerosis by Inhibiting TGF-ß Pathway.

Systemic sclerosis is an autoimmune disease characterized by inflammatory reactions and fibrosis. Myofibroblasts are considered therapeutic targets for preventing and reversing the pathogenesis of fibrosis in systemic sclerosis. Although the mechanisms that differentiate into myofibroblasts are diverse, transforming growth factor ß (TGF-ß) is known to be a key mediator of fibrosis in systemic sclerosis. This study investigated the effects of extracellular vesicles derived from human adipose stem cells (ASC-EVs) in an in vivo systemic sclerosis model and in vitro TGF-ß1-induced dermal fibroblasts. The therapeutic effects of ASC-EVs on the in vivo systemic sclerosis model were evaluated based on dermal thickness and the number of α-smooth muscle actin (α-SMA)- expressing cells using hematoxylin and eosin staining and immunohistochemistry. Administration of ASC-EVs decreased both the dermal thickness and α-SMA expressing cell number as well as the mRNA levels of fibrotic genes, such as Acta2, Ccn2, Col1a1 and Comp. Additionally, we discovered that ASC-EVs can decrease the expression of α-SMA and CTGF and suppress the TGF-ß pathway by inhibiting the activation of SMAD2 in dermal fibroblasts induced by TGF-ß1. Finally, TGF-ß1-induced dermal fibroblasts underwent selective death through ASC-EVs treatment. These results indicate that ASC-EVs could provide a therapeutic approach for preventing and reversing systemic sclerosis.

Hemodynamic changes in the prone position according to fluid loading after anaesthesia induction in patients undergoing lumbar spine surgery: a randomized, assessor-blind, prospective study.

INTRODUCTION: A change from the supine to prone position causes hemodynamic alterations. We aimed to evaluate the effect of fluid preloading in the supine position, the subsequent hemodynamic changes in the prone position and postoperative outcomes. PATIENTS AND METHODS: This prospective, assessor-blind, randomized controlled trial was conducted between March and June 2023. Adults scheduled for elective orthopaedic lumbar surgery under general anaesthesia were enrolled. In total, 80 participants were randomly assigned to fluid maintenance (M) or loading (L) groups. Both groups were administered intravenous fluid at a rate of 2 ml/kg/h until surgical incision; Group L was loaded with an additional 5 ml/kg intravenous fluid for 10 min after anaesthesia induction. The primary outcome was incidence of hypotension before surgical incision. Secondary outcomes included differences in the mean blood pressure (mBP), heart rate, pleth variability index (PVi), stroke volume variation (SVV), pulse pressure variation (PPV), stroke volume index and cardiac index before surgical incision between the two groups. Additionally, postoperative complications until postoperative day 2 and postoperative hospital length of stay were investigated. RESULTS: Hypotension was prevalent in Group M before surgical incision and could be predicted by a baseline PVi >16. The mBP was significantly higher in Group L immediately after fluid loading. The PVi, SVV and PPV were lower in Group L after fluid loading, with continued differences at 2-3 time points for SVV and PPV. Other outcomes did not differ between the two groups. CONCLUSION: Fluid loading after inducing general anaesthesia could reduce the occurrence of hypotension until surgical incision in patients scheduled for surgery in the prone position. Additionally, hypotension could be predicted in patients with a baseline PVi >16. Therefore, intravenous fluid loading is strongly recommended in patients with high baseline PVi to prevent hypotension after anaesthesia induction and in the prone position. TRIAL NUMBER: KCT0008294 (date of registration: 16 March 2023).

Fluid preloading could reduce the occurrence of hypotension in the prone position. Hypotension could be predicted in patients with a baseline PVi >16. Intravenous fluid preloading is strongly recommended in patients with high baseline PVi to prevent hypotension after anaesthesia induction and in the prone position.

Novel Personalized Cancer Vaccine Using Tumor Extracellular Vesicles with Attenuated Tumorigenicity and Enhanced Immunogenicity.

Cancer vaccines offer a promising avenue in cancer immunotherapy by inducing systemic, tumor-specific immune responses. Tumor extracellular vesicles (TEVs) are nanoparticles naturally laden with tumor antigens, making them appealing for vaccine development. However, their inherent malignant properties from the original tumor cells limit their direct therapeutic use. This study introduces a novel approach to repurpose TEVs as potent personalized cancer vaccines. The study shows that inhibition of both YAP and autophagy not only diminishes the malignancy-associated traits of TEVs but also enhances their immunogenic attributes by enriching their load of tumor antigens and adjuvants. These revamped TEVs, termed attenuated yet immunogenically potentiated TEVs (AI-TEVs), showcase potential in inhibiting tumor growth, both as a preventive measure and a possible treatment for recurrent cancers. They prompt a tumor-specific and enduring immune memory. In addition, by showing that AI-TEVs can counteract cancer growth in a personalized vaccine approach, a potential strategy is presented for developing postoperative cancer immunotherapy that's enduring and tailored to individual patients.

Clinical outcomes according to the timing of the first tracheostomy tube change.

Purpose: The first tracheostomy tube replacement is a critical procedure that can cause various complications, but there are few studies on the optimal timing of tracheostomy tube replacement in adult patients. This study aimed to evaluate the appropriate timing to replace the first tracheostomy tube to improve outcomes in adult patients. Materials and methods: This study was a retrospective cohort study that included 3957 patients aged ≥18 years who underwent the first tracheostomy tube change from January 2010 to February 2021. The primary outcome was all-cause mortality after the first tracheostomy tube change. Results: The all-cause mortality was statistically significantly lower in group changing the first tracheostomy tube between 7 and 9 days than in other groups (42.1%, P = 0.001). After adjustments in the multivariable analyses, early first tracheostomy tube change within 6 days was independently associated with increased all-cause mortality. The hospital stay, ICU stay, and post-procedural pulmonary complications seemed to increase as the replacement time was delayed. Conclusions: The timing of the first tracheostomy tube change between 7 and 9 days after tracheostomy was associated with improved clinical outcomes, including all-cause mortality. Further prospective investigations are needed to determine whether the optimal timing of the first tracheostomy tube change can reduce mortality.

Borohydride and halide dual-substituted lithium argyrodites.

Solid electrolyte is a crucial component of all-solid-state batteries, with sulphide solid electrolytes such as lithium argyrodite being closest to commercialization due to their high ionic conductivity and formability. In this study, borohydride/halide dual-substituted argyrodite-type electrolytes, Li7-α-ßPS6-α-ß(BH4)αXß (X = Cl, Br, I; α + ß ≤ 1.8), have been synthesized using a two-step ball-milling method without post-annealing. Among the various compositions, Li5.35PS4.35(BH4)1.15Cl0.5 exhibits the highest ionic conductivity of 16.4 mS cm-1 at 25 °C when cold-pressed, which further improves to 26.1 mS cm-1 after low temperature sintering. The enhanced conductivity can be attributed to the increased number of Li vacancies resulting from increased BH4 and halide occupancy and site disorder. Li symmetric cells with Li5.35PS4.35(BH4)1.15Cl0.5 demonstrate stable Li plating and stripping cycling for over 2,000 hours at 1 mA cm-2, along with a high critical current density of 2.1 mA cm-2. An all-solid-state battery prepared using Li5.35PS4.35(BH4)1.15Cl0.5 as the electrolyte and pure Li as the anode exhibits an initial coulombic efficiency of 86.4%. Although these electrolytes have limited thermal stability, it shows a wide compositional range while maintaining high ionic conductivity.

Half-Bridge Silicon Strain Gauges with Arc-Shaped Piezoresistors.

Half-bridge silicon strain gauges are widely used in the fabrication of diaphragm-type high-pressure sensors, but in some applications, they suffer from low output sensitivity because of mounting position constraints. Through a special design and fabrication approach, a new half-bridge silicon strain gauge comprising one arc gauge responding to tangential strain and another linear gauge measuring radial strain was developed using Silicon-on-Glass (SiOG) substrate technology. The tangential gauge consists of grid patterns, such as the reciprocating arc of silicon piezoresistors on a thin glass substrate. When two half-bridges are connected to form a full bridge with arc-shaped gauges that respond to tangential strain, they have the advantage of providing much higher output sensitivity than a conventional half-bridge. Pressure sensors tested under pressure ranging from 0 to 50 bar at five different temperatures indicate a linear output with a typical sensitivity of approximately 16 mV/V/bar, a maximum zero shift of 0.05% FS, and a span shift of 0.03% FS. The higher output level of pressure sensing gauges will provide greater signal strength, thus maintaining a better signal-to-noise ratio than conventional pressure sensors. The offset and span shift curves are quite linear across the operating temperature range, giving the end user the advantage of using very simple algorithms for temperature compensation of offset and span shift.

A Study on the O2 Plasma Etching Method of Spray-Formed SWCNT Films and Their Utilization as Electrodes for Electrochemical Sensors.

In this study, we analyzed the morphological changes and molecular structure changes on the surface of single-walled carbon nanotube (SWCNT) films during oxygen plasma (O2) etching of SWCNT surfaces formed by the spray method and analyzed their potential use as electrochemical electrodes. For this purpose, a SWCNT film was formed on the surface of a glass substrate using a self-made spray device using SWCNT powder prepared with DCB as a solvent, and SEM, AFM, and XPS analyses were performed as the SWCNT film was O2 plasma etched. SEM images and AFM measurements showed that the SWCNT film started etching after about 30 s under 50 W of O2 plasma irradiation and was completely etched after about 300 s. XPS analysis showed that as the O2 plasma etching of the SWCNT film progressed, the sp2 bonds representing the basic components of graphite decreased, the sp3 bonds representing defects increased, and the C-O, C=O, and COO peaks increased simultaneously. This result indicates that the SWCNT film was etched by the O2 plasma along with the oxygen species. In addition, electrochemical methods were used to verify the damage potential of the remaining SWCNTs after O2 plasma etching, including cyclic voltammetry, Randles plots, and EIS measurements. This resulted in a reversible response based on perfect diffusion control in the cyclic voltammetry, and an ideal linear curve in the Randles plot of the peak current versus square root scan rate curve. EIS measurements also confirmed that the charge transfer resistance of the remaining SWCNTs after O2 plasma etching is almost the same as before etching. These results indicate that the remaining SWCNTs after O2 plasma etching do not lose their unique electrochemical properties and can be utilized as electrodes for biosensors and electrochemical sensors. Our experimental results also indicate that the ionic conductivity enhancement by O2 plasma can be achieved additionally.

Evaluation of mechanical properties of triple-junction-free polycrystalline graphene.

Although chemical vapor deposition (CVD) has emerged as an important method for producing large-scale and relatively high-quality graphene, CVD-grown graphene inherently contains grain boundaries (GBs), which degrade its mechanical properties. To compensate for these characteristics, various studies have been conducted to maintain the mechanically superior properties by controlling the density of defects and GBs. In this study, the mechanical properties of triple junction (TJ)-free polycrystalline graphene, which is expected to exhibit excellent properties, were investigated through molecular dynamics simulations because TJ is well-known as a crack nucleation site due to stress concentration. We adopted the phase-field crystal method to model CVD-grown graphene-containing TJ-free polycrystalline materials. From a series of numerical simulations, we found that the fracture strength increases as the density of the GB increases. This trend is consistent with that presented in a previous experimental study measured by nanoindentation. It was determined that the variation in the fracture strength is related to the discontinuous density of 5-7 pairs, which act as stress-concentration sites. Additionally, we observed that the fracture strength was higher than that of polycrystalline graphene with TJ. We believe that these results have a higher mechanical advantage compared to the low strength of TJs shown in previous studies and will be important for future structural reliability-based graphene applications.

Reciprocating Arc Silicon Strain Gauges.

Currently, silicon-strain-gauge-based diaphragm pressure sensors use four single-gauge chips for high-output sensitivity. However, the four-single-gauge configuration increases the number of glass frit bonds and the number of aluminum wire bonds, reducing the long-term stability, reliability, and yield of the diaphragm pressure sensor. In this study, a new design of general-purpose silicon strain gauges was developed to improve the sensor output voltage while reducing the number of bonds. The new gauges consist grid patterns with a reciprocating arc of silicon piezoresistors on a thin glass backing. The gauges make handling easier in the bonding process due to the use of thin glass for the gauge backing. The pressure sensors were tested under pressure ranging from 0 to 50 bar at five different temperatures, with a linear output with a typical sensitivity of approximately 16 mV/V/bar and an offset shift of -6 mV to 2 mV. The new approach also opens the possibility to extend arc strain gauges to half-bridge and full-bridge configurations to further reduce the number of glass frit and Al wire bonds in the diaphragm pressure sensor.

Mucus-inspired organogel as an efficient absorbent and retention agent for volatile organic compounds.

Nasal mucus plays a key role in the sense of smell by absorbing and transporting chemicals to olfactory receptors. Inspired by the physical properties of mucus that enable it to transport molecules despite its high viscosity, we developed a polymeric organogel with similar viscosity and analyzed its general performance. Through qualitative and quantitative analysis, we confirmed that the matrix viscosity mainly affects the absorption and retention of volatile organic compounds (VOCs) and not their diffusion inside the matrix. Additionally, the vapor pressure of VOCs influences the absorption and retention efficiencies of the matrix. Finally, a detailed understanding of the properties of mucus along with the use of sol-gel transition enabled us to create an efficient VOC absorbent and retention agent.

A performance improvement of enzyme-based electrochemical lactate sensor fabricated by electroplating novel PdCu mediator on a laser induced graphene electrode.

A lactate sensor for lactate sensing using porous laser-induced graphene (LIG) electrodes with an electrodeposited PdCu catalyst was developed in this study. CO2 laser was used to convert the polyimide film surface to multilayered LIG. The morphology and composition of LIG were analyzed through field-emission scanning electron microscopy and Raman spectroscopy, respectively, to confirm that the fabricated LIG electrode was composed of porous and stacked graphene layers. PdCu was electrodeposited on the LIG electrode and lactate oxidase (LOx) was immobilized on the LIG surface to create a LOx/PdCu/LIG structure. According to the Randles-Sevcík equation, the calculated active surface area of the fabricated PdCu/LIG electrode was ∼12.8 mm2, which was larger than the apparent area of PdCu/LIG (1.766 mm2) by a factor of 7.25. The measured sensitivities of the fabricated lactate sensors with the LOx/PdCu/LIG electrode were -51.91 µA/mM·cm2 (0.1-5 mM) and -17.18 µA/mM·cm2 (5-30 mM). The calculated limit of detection was 0.28 µM. The selectivity of the fabricated lactate sensor is excellent toward various potentially interfering materials such as ascorbic acid, uric acid, lactose, sucrose, K+ and Na+.

When self comes to a wandering mind: Brain representations and dynamics of self-generated concepts in spontaneous thought.

Self-relevant concepts are major building blocks of spontaneous thought, and their dynamics in a natural stream of thought are likely to reveal one's internal states that are important for mental health. Here, we conducted a functional magnetic resonance imaging experiment (n = 62) to examine brain representations and dynamics of self-generated concepts in the context of spontaneous thought using a newly developed free association-based thought sampling task. The dynamics of conceptual associations were predictive of individual differences in general negative affectivity, replicating across multiple datasets (n = 196). Reflecting on self-generated concepts strongly engaged brain regions linked to autobiographical memory, conceptual processes, emotion, and autonomic regulation, including the medial prefrontal and medial temporal subcortical structures. Multivariate pattern-based predictive modeling revealed that the neural representations of valence became more person-specific as the level of perceived self-relevance increased. Overall, this study sheds light on how self-generated concepts in spontaneous thought construct inner affective states and idiosyncrasies.

Efficacy and safety of thread embedding acupuncture for knee osteoarthritis: A randomized controlled pilot trial.

BACKGROUND: Thread embedding acupuncture (TEA) is a widely used clinical procedure for the treatment of musculoskeletal pain. However, few clinical studies have been conducted on the efficacy and safety of TEA for knee osteoarthritis (KOA), and data from randomized controlled trials are lacking. This randomized controlled pilot study aimed to assess the feasibility of conducting large-scale studies on the efficacy and safety of TEA for KOA. METHODS: Forty participants were included in the study and randomly divided into 2 groups (TEA and acupuncture) of 20 each. The intervention period was 6 weeks. The experimental group received TEA once a week (total of 6 sessions) on 14 defined knee areas, and the control group received acupuncture twice a week (total of 12 sessions) on 9 defined acupuncture points. The primary outcome measure was the visual analogue scale score, and the secondary outcome measures were the short-form McGill pain questionnaire, and Western Ontario and McMaster Universities Osteoarthritis Index scores. Participants were assessed prior to the intervention (baseline) and at 3, 6, and 10 weeks (4 weeks after the end of intervention). The adverse effects of TEA and acupuncture were documented. Hematological examination and biochemical tests were performed at the screening and at 6 weeks. RESULTS: Of the 40 participants, 37 completed the study and 3 participants dropped out. Both the TEA and acupuncture groups showed a significant improvement in the visual analogue scale, short-form McGill Pain Questionnaire, and Western Ontario and McMaster Universities Osteoarthritis Index scores in a time-dependent manner. However, there was no significant interaction between group and time. No serious adverse events were reported in the groups, and no clinically significant changes were observed in the hematological and biochemical parameters. CONCLUSION: This pilot study suggests that TEA is a safe and effective procedure for relieving pain in patients with KOA. The results of this study provide basic data and indicate the feasibility of large-scale clinical studies to evaluate the efficacy and safety of TEA for KOA.

Engineered small extracellular vesicles displaying ACE2 variants on the surface protect against SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry is mediated by the interaction of the viral spike (S) protein with angiotensin-converting enzyme 2 (ACE2) on the host cell surface. Although a clinical trial testing soluble ACE2 (sACE2) for COVID-19 is currently ongoing, our understanding of the delivery of sACE2 via small extracellular vesicles (sEVs) is still rudimentary. With excellent biocompatibility allowing for the effective delivery of molecular cargos, sEVs are broadly studied as nanoscale protein carriers. In order to exploit the potential of sEVs, we design truncated CD9 scaffolds to display sACE2 on the sEV surface as a decoy receptor for the S protein of SARS-CoV-2. Moreover, to enhance the sACE2-S binding interaction, we employ sACE2 variants. sACE2-loaded sEVs exhibit typical sEVs characteristics and bind to the S protein. Furthermore, engineered sEVs inhibit the entry of wild-type (WT), the globally dominant D614G variant, Beta (K417N-E484K-N501Y) variant, and Delta (L452R-T478K-D614G) variant SARS-CoV-2 pseudovirus, and protect against authentic SARS-CoV-2 and Delta variant infection. Of note, sACE2 variants harbouring sEVs show superior antiviral efficacy than WT sACE2 loaded sEVs. Therapeutic efficacy of the engineered sEVs against SARS-CoV-2 challenge was confirmed using K18-hACE2 mice. The current findings provide opportunities for the development of new sEVs-based antiviral therapeutics.

The conceptual building blocks of everyday thought: Tracking the emergence and dynamics of ruminative and nonruminative thinking.

How do thoughts arise, unfold, and change over time? Are the contents and dynamics of everyday thought rooted in conceptual associations within one's semantic networks? To address these questions, we developed the Free Association Semantic task (FAST), whereby participants generate dynamic chains of conceptual associations in response to seed words that vary in valence. Ninety-four adults from a community sample completed the FAST task and additionally described and rated six of their most frequently occurring everyday thoughts. Text analysis and valence ratings revealed similarities in thematic and affective content between FAST concept chains and recurrent autobiographical thoughts. Dynamic analyses revealed that individuals higher in rumination were more strongly attracted to negative conceptual spaces and more likely to remain there longer. Overall, these findings provide quantitative evidence that conceptual associations may act as a semantic scaffold for more complex everyday thoughts, and that more negative and less dynamic conceptual associations in ruminative individuals mirror maladaptive repetitive thoughts in daily life. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Rho-Kinase as a Target for Cancer Therapy and Its Immunotherapeutic Potential.

Cancer immunotherapy is fast rising as a prominent new pillar of cancer treatment, harnessing the immune system to fight against numerous types of cancer. Rho-kinase (ROCK) pathway is involved in diverse cellular activities, and is therefore the target of interest in various diseases at the cellular level including cancer. Indeed, ROCK is well-known for its involvement in the tumor cell and tumor microenvironment, especially in its ability to enhance tumor cell progression, migration, metastasis, and extracellular matrix remodeling. Importantly, ROCK is also considered to be a novel and effective modulator of immune cells, although further studies are needed. In this review article, we describe the various activities of ROCK and its potential to be utilized in cancer treatment, particularly in cancer immunotherapy, by shining a light on its activities in the immune system.

Extracellular vesicles from adipose tissue-derived stem cells alleviate osteoporosis through osteoprotegerin and miR-21-5p.

Osteoporosis is one of the most common skeletal disorders caused by the imbalance between bone formation and resorption, resulting in quantitative loss of bone tissue. Since stem cell-derived extracellular vesicles (EVs) are growing attention as novel cell-free therapeutics that have advantages over parental stem cells, the therapeutic effects of EVs from adipose tissue-derived stem cells (ASC-EVs) on osteoporosis pathogenesis were investigated. ASC-EVs were isolated by a multi-filtration system based on the tangential flow filtration (TFF) system and characterized using transmission electron microscopy, dynamic light scattering, zeta potential, flow cytometry, cytokine arrays, and enzyme-linked immunosorbent assay. EVs are rich in growth factors and cytokines related to bone metabolism and mesenchymal stem cell (MSC) migration. In particular, osteoprotegerin (OPG), a natural inhibitor of receptor activator of nuclear factor-κB ligand (RANKL), was highly enriched in ASC-EVs. We found that the intravenous administration of ASC-EVs attenuated bone loss in osteoporosis mice. Also, ASC-EVs significantly inhibited osteoclast differentiation of macrophages and promoted the migration of bone marrow-derived MSCs (BM-MSCs). However, OPG-depleted ASC-EVs did not show anti-osteoclastogenesis effects, demonstrating that OPG is critical for the therapeutic effects of ASC-EVs. Additionally, small RNA sequencing data were analysed to identify miRNA candidates related to anti-osteoporosis effects. miR-21-5p in ASC-EVs inhibited osteoclast differentiation through Acvr2a down-regulation. Also, let-7b-5p in ASC-EVs significantly reduced the expression of genes related to osteoclastogenesis. Finally, ASC-EVs reached the bone tissue after they were injected intravenously, and they remained longer. OPG, miR-21-5p, and let-7b-5p in ASC-EVs inhibit osteoclast differentiation and reduce gene expression related to bone resorption, suggesting that ASC-EVs are highly promising as cell-free therapeutic agents for osteoporosis treatment.

Alzheimer's disease-causing presenilin-1 mutations have deleterious effects on mitochondrial function.

Mitochondrial dysfunction and oxidative stress are frequently observed in the early stages of Alzheimer's disease (AD). Studies have shown that presenilin-1 (PS1), the catalytic subunit of γ-secretase whose mutation is linked to familial AD (FAD), localizes to the mitochondrial membrane and regulates its homeostasis. Thus, we investigated how five PS1 mutations (A431E, E280A, H163R, M146V, and Δexon9) observed in FAD affect mitochondrial functions. Methods: We used H4 glioblastoma cell lines genetically engineered to inducibly express either the wild-type PS1 or one of the five PS1 mutants in order to examine mitochondrial morphology, dynamics, membrane potential, ATP production, mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), oxidative stress, and bioenergetics. Furthermore, we used brains of PS1M146V knock-in mice, 3xTg-AD mice, and human AD patients in order to investigate the role of PS1 in regulating MAMs formation. Results: Each PS1 mutant exhibited slightly different mitochondrial dysfunction. Δexon9 mutant induced mitochondrial fragmentation while A431E, E280A, H163R, and M146V mutants increased MAMs formation. A431E, E280A, M146V, and Δexon9 mutants also induced mitochondrial ROS production. A431E mutant impaired both complex I and peroxidase activity while M146V mutant only impaired peroxidase activity. All PS1 mutants compromised mitochondrial membrane potential and cellular ATP levels were reduced by A431E, M146V, and Δexon9 mutants. Through comparative profiling of hippocampal gene expression in PS1M146V knock-in mice, we found that PS1M146V upregulates Atlastin 2 (ATL2) expression level, which increases ER-mitochondria contacts. Down-regulation of ATL2 after PS1 mutant induction rescued abnormally elevated ER-mitochondria interactions back to the normal level. Moreover, ATL2 expression levels were significantly elevated in the brains of 3xTg-AD mice and AD patients. Conclusions: Overall, our findings suggest that each of the five FAD-linked PS1 mutations has a deleterious effect on mitochondrial functions in a variety of ways. The adverse effects of PS1 mutations on mitochondria may contribute to MAMs formation and oxidative stress resulting in an accelerated age of disease onset in people harboring mutant PS1.

Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer.

BACKGROUND: Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors. METHODS: The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment. RESULTS: Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models. CONCLUSIONS: Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity.

Liquid-to-Solid Phase Transitions of Imidazolium-Based Zwitterionic Polymers Induced by Hofmeister Anions.

In this study, we compared the responses of two different types of zwitterionic polymers (ZPs), polyvinylimidzole sulfobetaine (poly(SBVI)) and polymethacrylate sulfobetaine (poly(SBMA)) to Hofmeister anions. Although the anions of the two ZPs were the same as the sulfonate anions and only the types of their cations were different from each other, the aggregation behavior of each in the salt aqueous solution was remarkably different. Consequently, poly(SBVI) exhibited both salting-in and salting-out effects depending on the type and concentration of salt, while poly(SBMA) only exhibited the anti-polyelectrolyte effect. The results of this study provide a deeper understanding of the behavior of zwitterionic polymers in salt solutions and will greatly expand their applications.