Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy.

BACKGROUND: Immunogenic cell death (ICD) is a crucial approach to turn immunosuppressive tumor microenvironment (ITM) into immune-responsive milieu and improve the response rate of immune checkpoint blockade (ICB) therapy. However, cancer cells show resistance to ICD-inducing chemotherapeutic drugs, and non-specific toxicity of those drugs against immune cells reduce the immunotherapy efficiency. METHODS: Herein, we propose cancer cell-specific and pro-apoptotic liposomes (Aposomes) encapsulating second mitochondria-derived activator of caspases mimetic peptide (SMAC-P)-doxorubicin (DOX) conjugated prodrug to potentiate combinational ICB therapy with ICD. The SMAC-P (AVPIAQ) with cathepsin B-cleavable peptide (FRRG) was directly conjugated to DOX, and the resulting SMAC-P-FRRG-DOX prodrug was encapsulated into PEGylated liposomes. RESULTS: The SMAC-P-FRRG-DOX encapsulated PEGylated liposomes (Aposomes) form a stable nanostructure with an average diameter of 109.1 ± 5.14 nm and promote the apoptotic cell death mainly in cathepsin B-overexpressed cancer cells. Therefore, Aposomes induce a potent ICD in targeted cancer cells in synergy of SMAC-P with DOX in cultured cells. In colon tumor models, Aposomes efficiently accumulate in targeted tumor tissues via enhanced permeability and retention (EPR) effect and release the encapsulated prodrug of SMAC-P-FRRG-DOX, which is subsequently cleaved to SMAC-P and DOX in cancer cells. Importantly, the synergistic activity of inhibitors of apoptosis proteins (IAPs)-inhibitory SMAC-P sensitizing the effects of DOX induces a potent ICD in the cancer cells to promote dendritic cell (DC) maturation and stimulate T cell proliferation and activation, turning ITM into immune-responsive milieu. CONCLUSIONS: Eventually, the combination of Aposomes with anti-PD-L1 antibody results in a high rate of complete tumor regression (CR: 80%) and also prevent the tumor recurrence by immunological memory established during treatments.

Antioxidative Hyaluronic Acid-Bilirubin Nanomedicine Targeting Activated Hepatic Stellate Cells for Anti-Hepatic-Fibrosis Therapy.

Liver fibrosis is a life-threatening and irreversible disease. The fibrosis process is largely driven by hepatic stellate cells (HSCs), which undergo transdifferentiation from an inactivated state to an activated one during persistent liver damage. This activated state is responsible for collagen deposition in liver tissue and is accompanied by increased CD44 expression on the surfaces of HSCs and amplified intracellular oxidative stress, which contributes to the fibrosis process. To address this problem, we have developed a strategy that combines CD44-targeting of activated HSCs with an antioxidative approach. We developed hyaluronic acid-bilirubin nanoparticles (HABNs), composed of endogenous bilirubin, an antioxidant and anti-inflammatory bile acid, and hyaluronic acid, an endogenous CD44-targeting glycosaminoglycan biopolymer. Our findings demonstrate that intravenously administered HABNs effectively targeted the liver, particularly activated HSCs, in fibrotic mice with choline-deficient l-amino acid-defined high-fat diet (CD-HFD)-induced nonalcoholic steatohepatitis (NASH). HABNs were able to inhibit HSC activation and proliferation and collagen production. Furthermore, in a murine CD-HFD-induced NASH fibrosis model, intravenously administered HABNs showed potent fibrotic modulation activity. Our study suggests that HABNs have the potential to serve as a targeted anti-hepatic-fibrosis therapy by modulating activated HSCs via CD44-targeting and antioxidant strategies. This strategy could also be applied to various ROS-related diseases in which CD44-overexpressing cells play a pivotal role.

Hyaluronic acid-bilirubin nanomedicine-based combination chemoimmunotherapy.

Despite significant advances in immune checkpoint blockade (ICB), immunosuppression mediated by tumor-associated myeloid cells (TAMCs) poses a major barrier to cancer immunotherapy. In addition, while immunogenic cell death (ICD) provides a viable approach to inducing anti-tumor immune response, it remains unknown how to effectively trigger ICD while addressing immunosuppressive TAMCs. Here, we show that SC144, a gp130 inhibitor that blocks the IL-6/gp130/STAT3 pathway, induces ICD of tumor cells and polarizes macrophages to M1-phenotype in vitro. However, as SC144 also induces killing of CD8+ T-cells, we sought to deliver SC144 selectively to tumor cells and TAMCs. Toward this goal, we have developed hyaluronic acid-bilirubin nanoparticles (HABN) that accumulate in CD44hi tumor cells and TAMCs. Systemic administration of SC144 loaded in HABN (SC144@HABN) induces apoptosis and ICD of tumor cells, increases the ratio of M1-like to M2-like macrophages, and decreases the frequency of myeloid-derived suppressor cells and CD4+ regulatory T-cells, while promoting anti-tumor CD8+ T-cells. Moreover, SC144@HABN combined with anti-PD-L1 ICB efficiently eliminates MC38 tumors and ICB-resistant 4T1 tumors. Overall, our work demonstrates a therapeutic strategy based on coordinated ICD induction and TAMC modulation and highlights the potential of combination chemoimmunotherapy.

Optic neuritis associated with seronegative autoimmune encephalitis: a case report.

Optic neuritis is an inflammatory demyelinating disorder that primarily affects the optic nerve and is often associated with multiple sclerosis. While it is rare for optic neuritis to be accompanied by autoimmune encephalitis, it can occur in some cases. A 65-year-old woman with bipolar disorder presented with a progressively altered mentality. Magnetic resonance imaging of the brain showed no definite abnormal findings. Electroencephalography revealed nonconvulsive status epilepticus. Cerebrospinal fluid study and autoimmune and paraneoplastic encephalitis antibodies were negative. The patient was diagnosed with seronegative autoimmune encephalitis and treated with methylprednisolone, intravenous immunoglobulin, and rituximab. Her condition gradually improved except for persistent blindness on the left side. This case highlights the importance of considering autoimmune encephalitis even in the absence of identifiable pathogenic antibodies when clinical manifestations and response to immunotherapy support such a diagnosis.

Oral Nanomedicines for siRNA Delivery to Treat Inflammatory Bowel Disease.

RNA interference (RNAi) therapies have significant potential for the treatment of inflammatory bowel diseases (IBD). Although administering small interfering RNA (siRNA) via an oral route is desirable, various hurdles including physicochemical, mucus, and cellular uptake barriers of the gastrointestinal tract (GIT) impede both the delivery of siRNA to the target site and the action of siRNA drugs at the target site. In this review, we first discuss various physicochemical and biological barriers in the GI tract. Furthermore, we present recent strategies and the progress of oral siRNA delivery strategies to treat IBD. Finally, we consider the challenges faced in the use of these strategies and future directions of oral siRNA delivery strategies.

Smart pH-responsive nanomedicines for disease therapy.

Background: Currently nanomedicines are the focus of attention from researchers and clinicians because of the successes of lipid-nanoparticles-based COVID-19 vaccines. Nanoparticles improve existing treatments by providing a number of advantages including protection of cargo molecules from external stresses, delivery of drugs to target tissues, and sustained drug release. To prevent premature release-related side effects, stable drug loading in nanoformulations is required, but the increased stability of the formulation could also lead to a poor drug-release profile at the target sites. Thus, researchers have exploited differences in a range of properties (e.g., enzyme levels, pH, levels of reduced glutathione, and reactive oxygen species) between non-target and target sites for site-specific release of drugs. Among these environmental stimuli, pH gradients have been widely used to design novel, responsive nanoparticles. Area covered: In this review, we assess drug delivery based on pH-responsive nanoparticles at the levels of tissues (tumor microenvironment, pH ~ 6.5) and of intracellular compartments (endosome and lysosome, pH 4.5-6.5). Upon exposure to these pH stimuli, pH-responsive nanoparticles respond with physicochemical changes to their material structure and surface characteristics. These changes include swelling, dissociation, or surface charge switching, in a manner that favors drug release at the target site (the tumor microenvironment region and the cytosol followed by endosomal escape) rather than the surrounding tissues. Expert opinion: Lastly, we consider the challenges involved in the development of pH-responsive nanomedicines.

Effectiveness of yoga training programs to reduce depression and improve resilience of single mothers.

Single mothers are vulnerable to mental health such as depression, but emotional support is insufficient. Yoga is known to be effective in reducing negative emotions and promoting resilience. This study was conducted in order to verify the effectiveness of yoga training programs in reducing depression and improving the resilience of single mothers. Participants in the study included 20 single mothers who belonged to the Single Mothers Association, who were randomly assigned to training (n=10) and nontraining (n=10) groups. The yoga training program for single mothers consisted of Asana yoga, meditation, and mind expression through expert meetings; a total of eight sessions were conducted once a week for 120 min. Testing for depression and resilience was performed before and after the program in order to verify the effectiveness of the program. According to the results of the study, depression in single mothers who participated in the yoga training program was significantly decreased, and resilience was significantly increased. Therefore, the effectiveness of the yoga training program in lowering the depression of single mothers and improving resilience was confirmed. In the future conduct of many studies will be required in order to help the mental health of single mothers.

Factors Affecting Post-Stroke Depression in Acute Ischemic Stroke Patients after 3 Months.

Post-stroke depression (PSD) affects approximately one-third of stroke patients. PSD not only impairs recovery and lowers quality of life, but has also serious neurological consequences, high mortality, and stroke recurrence risks. Studies on PSD-related prognostic factors are still lacking, especially environmental factors. Moreover, relieving factors after PSD in stroke patients has not been reported. This study aimed to investigate (study design 1) risk factors for PSD diagnosis after three months, and (study design 2) related factors for the relieving of early PSD after three months. This retrospective study included 227 patients hospitalized for acute ischemic stroke within three days at Jeonbuk National University Hospital from January to December 2019. The depressive status was assessed using the Hamilton Depression Rating Scale (HDRS) at admission and after three months. Clinical and laboratory data were analyzed for relevant prognostic factors. (Study design 1) HDRS score at admission (adjusted odds ratio (aOR) 1.22, 95% confidence interval (CI) 1.14-1.31; p < 0.001) and hospitalization period (aOR 1.11, 95% CI 1.02-1.20; p = 0.013) were confirmed as prognostic factors of PSD after three months. (Study design 2) The National Institute of Health Stroke Scale (NIHSS) score at discharge (aOR 0.80, 95% CI 0.68-0.94; p = 0.006) and HDRS score at admission (aOR 0.80, 95% CI 0.71-0.89; p < 0.001) were confirmed as prognostic factors of depression improvement after three months. In conclusion, environmental factors such as hospitalization period could be important in managing PSD. Factors related to PSD improvement are expected to be helpful in establishing a strategy for PSD recovery.

Oral nanomedicine for modulating immunity, intestinal barrier functions, and gut microbiome.

The gastrointestinal tract (GIT) affects not only local diseases in the GIT but also various systemic diseases. Factors that can affect the health and disease of both GIT and the human body include 1) the mucosal immune system composed of the gut-associated lymphoid tissues and the lamina propria, 2) the intestinal barrier composed of mucus and intestinal epithelium, and 3) the gut microbiota. Selective delivery of drugs, including antigens, immune-modulators, intestinal barrier enhancers, and gut-microbiome manipulators, has shown promising results for oral vaccines, immune tolerance, treatment of inflammatory bowel diseases, and other systemic diseases, including cancer. However, physicochemical and biological barriers of the GIT present significant challenges for successful translation. With the advances of novel nanomaterials, oral nanomedicine has emerged as an attractive option to not only overcome these barriers but also to selectively deliver drugs to the target sites in GIT. In this review, we discuss the GIT factors and physicochemical and biological barriers in the GIT. Furthermore, we present the recent progress of oral nanomedicine for oral vaccines, immune tolerance, and anti-inflammation therapies. We also discuss recent advances in oral nanomedicine designed to fortify the intestinal barrier functions and modulate the gut microbiota and microbial metabolites. Finally, we opine about the future directions of oral nano-immunotherapy.

Recent progress in development and applications of second near-infrared (NIR-II) nanoprobes.

Optical probes for near-infrared (NIR) light have clear advantages over UV/VIS-based optical probes, such as their low levels of interfering auto-fluorescence and high tissue penetration. The second NIR (NIR-II) window (1000-1350 nm) offers better light penetration, lower background signal, higher safety limit, and higher maximum permitted exposure than the first NIR (NIR-I) window (650-950 nm). Therefore, NIR-II laser-based photoacoustic (PA) and fluorescence (FL) imaging can offer higher sensitivity and penetration depth than was previously available, and deeper lesions can be treated in vivo by photothermal therapy (PTT) and photodynamic therapy (PDT) with an NIR-II laser than with an NIR-I laser. Advances in creation of novel nanomaterials have increased options for improving light-induced bioimaging and treatment. Nanotechnology can provide advantages such as good disease targeting ability and relatively long circulation times to supplement the advantages of optical technologies. In this review, we present recent progress in development and applications of NIR-II light-based nanoplatforms for FL, PA, image-guided surgery, PDT, and PTT. We also discuss recent advances in smart NIR-II nanoprobes that can respond to stimuli in the tumor microenvironment and inflamed sites. Finally, we consider the challenges involved in using NIR-II nanomedicine for effective diagnosis and treatment.

Synthesis of Tungsten-Doped Vanadium Dioxide Using a Modified Polyol Method Involving 1-Dodecanol.

The doping of tungsten into VO2 (M) via a polyol process that is based on oligomerization of ammonium metavanadate and ethylene glycol (EG) to synthesize a vanadyl ethylene glycolate (VEG) followed by postcalcination was carried out by simply adding 1-dodecanol and the tungsten source tungstenoxytetrachloride (WOCl4). Tungsten-doped VEGs (W-VEGs) and their calcinated compounds (WxVO2) were prepared with varying mixing ratios of EG to 1-dodecanol and WOCl4 concentrations. Characterizations of W-VEGs by powder X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and infrared and transmittance spectroscopy showed that tungsten elements were successfully doped into WxVO2, thereby decreasing the metal-insulator transition temperature from 68 down to 51 °C. Our results suggested that WOCl4 variously combined with 1-dodecanol might interrupt the linear growth of W-VEGs, but that such an interruption might be alleviated at the optimal 1:1 mixing ratio of EG to 1-dodecanol, resulting in the successful W doping. The difference in the solar modulations of a W0.0207VO2 dispersion measured at 20 and 70 °C was increased to 21.8% while that of a pure VO2 dispersion was 2.5%. It was suggested that WOCl4 coupled with both EG and 1-dodecanol at an optimal mixing ratio could improve the formation of W-VEG and WxVO2 and that the bulky dodecyl chains might act as defects to decrease crystallinity.

Preparation and Evaluation of Amino Acid Conjugates of Celecoxib as Prodrugs to Improve the Pharmacokinetic and Therapeutic Properties of Celecoxib.

Although celecoxib is quite effective in the management of inflammation-related diseases, especially arthritis, its use is limited by concerns including low bioavailability (BA), non-linear pharmacokinetic (PK) profile, and peak concentration-related toxicity. To overcome these issues, we designed and prepared hydrophilic celecoxib prodrugs, namely N-glycyl-aspart-1yl celecoxib (N-GA1C), glutam-1-yl celecoxib (G1C), and aspart-1yl celecoxib (A1C), for the sustained release of celecoxib in the intestine with limited systemic absorption. The celecoxib derivatives were converted to celecoxib in the intestinal contents. The conversion rates were in order of N-GA1C > G1C > A1C. Oral administration of the celecoxib derivatives (oral celecoxib derivatives) sustained the plasma concentration of celecoxib for 24 h, improving the BA and linearity of the PK profile of celecoxib. The peak concentrations (Cmax) of celecoxib after oral celecoxib derivatives were lower than that after oral celecoxib. In a carrageenan-induced rat paw edema model, oral N-GA1C exhibited greater anti-inflammatory activity for a longer duration compared with oral celecoxib. The order of efficacy of the celecoxib derivatives was N-GA1C > G1C > A1C. Taken together, the prodrug approach is a feasible strategy to improve the PK and therapeutic properties of celecoxib, and among the celecoxib derivatives, N-GA1C may be the most promising prodrug of celecoxib.

Interdigitated and Wave-Shaped Electrode-Based Capacitance Sensor for Monitoring Antibiotic Effects.

Label-free and real-time monitoring of the bacterial viability is essential for the accurate and sensitive characterization of the antibiotic effects. In the present study, we investigated the feasibility of the interdigitated and wave-shaped electrode (IWE) for monitoring the effect of tetracycline or kanamycin on Staphylococcus aureus (S. aureus) and methicillin-resistant S.aureus (MRSA). The electrical impedance spectra of the IWE immersed in the culture media for bacterial growth were characterized in a frequency range of 10 Hz to 1 kHz. The capacitance index (CI) (capacitance change relevant with the bacterial viability) was used to monitor the antibiotic effects on the S. aureus and MRSA in comparison to the traditional methods (disk diffusion test and optical density (OD) measurement). The experimental results showed that the percentage of change in CI (PCI) for the antibiotic effect on MRSA was increased by 51.58% and 57.83% in kanamycin and control, respectively. In contrast, the PCI value decreased by 0.25% for tetracycline, decreased by 52.63% and 37.66% in the cases of tetracycline and kanamycin-treated S. aureus, and increased 2.79% in the control, respectively. This study demonstrated the feasibility of the IWE-based capacitance sensor for the label-free and real-time monitoring of the antibiotic effects on S.aureus and MRSA.

Efficient Lymph Node-Targeted Delivery of Personalized Cancer Vaccines with Reactive Oxygen Species-Inducing Reduced Graphene Oxide Nanosheets.

Therapeutic cancer vaccines require robust cellular immunity for the efficient killing of tumor cells, and recent advances in neoantigen discovery may provide safe and promising targets for cancer vaccines. However, elicitation of T cells with strong antitumor efficacy requires intricate multistep processes that have been difficult to attain with traditional vaccination approaches. Here, a multifunctional nanovaccine platform has been developed for direct delivery of neoantigens and adjuvants to lymph nodes (LNs) and highly efficient induction of neoantigen-specific T cell responses. A PEGylated reduced graphene oxide nanosheet (RGO-PEG, 20-30 nm in diameter) is a highly modular and biodegradable platform for facile preparation of neoantigen vaccines within 2 h. RGO-PEG exhibits rapid, efficient (15-20% ID/g), and sustained (up to 72 h) accumulation in LNs, achieving >100-fold improvement in LN-targeted delivery, compared with soluble vaccines. Moreover, RGO-PEG induces intracellular reactive oxygen species in dendritic cells, guiding antigen processing and presentation to T cells. Importantly, a single injection of RGO-PEG vaccine elicits potent neoantigen-specific T cell responses lasting up to 30 days and eradicates established MC-38 colon carcinoma. Further combination with anti-PD-1 therapy achieved great therapeutic improvements against B16F10 melanoma. RGO-PEG may serve a powerful delivery platform for personalized cancer vaccination.

Prevalence and Duration of Acute Loss of Smell or Taste in COVID-19 Patients.

Initially, acute loss of smell (anosmia) and taste (ageusia) was not considered important symptoms for coronavirus disease 2019 (COVID-19). To determine the prevalence of these symptoms and to evaluate their diagnostic significance, we (approximately 150 physicians of the Daegu Medical Association) prospectively collected data of cases of anosmia and ageusia from March 8, 2020, via telephone interview among 3,191 patients in Daegu, Korea. Acute anosmia or ageusia was observed in 15.3% (488/3,191) patients in the early stage of COVID-19 and in 15.7% (367/2,342) patients with asymptomatic-to-mild disease severity. Their prevalence was significantly more common among females and younger individuals (P = 0.01 and P < 0.001, respectively). Most patients with anosmia or ageusia recovered within 3 weeks. The median time to recovery was 7 days for both symptoms. Anosmia and ageusia seem to be part of important symptoms and clues for the diagnosis of COVID-19, particularly in the early stage of the disease.

Incidental Diagnosis of Pediatric Arytenoid Cartilage Dislocation During Videofluoroscopic Swallowing Study: A Case Report.

Arytenoid cartilage dislocation is one of the most common mechanical causes of vocal fold immobility. The most common etiologies are intubation and external trauma, but its incidence is lower than 0.1%. Its symptoms include dysphonia, vocal fatigue, loss of vocal control, breathiness, odynophagia, dysphagia, dyspnea, and cough. Although there are some reports of arytenoid cartilage dislocation in adults, there are only few reports on its occurrence in children. It is particularly difficult to detect the symptoms of arytenoid cartilage dislocation in uncooperative pediatric patients with brain lesions without verbal output or voluntary expression. We report a case of arytenoid cartilage dislocation with incidental findings in a videofluoroscopic swallowing study performed to evaluate the swallowing function.

PEGylated Bilirubin-coated Iron Oxide Nanoparticles as a Biosensor for Magnetic Relaxation Switching-based ROS Detection in Whole Blood.

Rationale: Magnetic relaxation switching (MRSw) induced by target-triggered aggregation or dissociation of superparamagnetic iron oxide nanoparticles (SPIONs) have been utilized for detection of diverse biomarkers. However, an MRSw-based biosensor for reactive oxygen species (ROS) has never been documented. Methods: To this end, we constructed a biosensor for ROS detection based on PEGylated bilirubin (PEG-BR)-coated SPIONs (PEG-BR@SPIONs) that were prepared by simple sonication via ligand exchange. In addition, near infra-red (NIR) fluorescent dye was loaded onto PEG-BR@SPIONs as a secondary option for fluorescence-based ROS detection. Results: PEG-BR@SPIONs showed high colloidal stability under physiological conditions, but upon exposure to the model ROS, NaOCl, in vitro, they aggregated, causing a decrease in signal intensity in T2-weighted MR images. Furthermore, ROS-responsive PEG-BR@SPIONs were taken up by lipopolysaccharide (LPS)-activated macrophages to a much greater extent than ROS-unresponsive control nanoparticles (PEG-DSPE@SPIONs). In a sepsis-mimetic clinical setting, PEG-BR@SPIONs were able to directly detect the concentrations of ROS in whole blood samples through a clear change in T2 MR signals and a 'turn-on' signal of fluorescence. Conclusions: These findings suggest that PEG-BR@SPIONs have the potential as a new type of dual mode (MRSw-based and fluorescence-based) biosensors for ROS detection and could be used to diagnose many diseases associated with ROS overproduction.

Hyaluronic acid-bilirubin nanomedicine for targeted modulation of dysregulated intestinal barrier, microbiome and immune responses in colitis.

While conventional approaches for inflammatory bowel diseases mainly focus on suppressing hyperactive immune responses, it remains unclear how to address disrupted intestinal barriers, dysbiosis of the gut commensal microbiota and dysregulated mucosal immune responses in inflammatory bowel diseases. Moreover, immunosuppressive agents can cause off-target systemic side effects and complications. Here, we report the development of hyaluronic acid-bilirubin nanomedicine (HABN) that accumulates in inflamed colonic epithelium and restores the epithelium barriers in a murine model of acute colitis. Surprisingly, HABN also modulates the gut microbiota, increasing the overall richness and diversity and markedly augmenting the abundance of Akkermansia muciniphila and Clostridium XIVα, which are microorganisms with crucial roles in gut homeostasis. Importantly, HABN associated with pro-inflammatory macrophages, regulated innate immune responses and exerted potent therapeutic efficacy against colitis. Our work sheds light on the impact of nanotherapeutics on gut homeostasis, microbiome and innate immune responses for the treatment of inflammatory diseases.

Architectural Changes in the Medial Gastrocnemius on Sonography after Nerve Ablation in Healthy Adults.

Architectural changes in healthy muscle after denervation have not yet been reported. This study aimed to investigate architectural changes in the medial head of the gastrocnemius muscle (GCM) after aesthetic tibial nerve ablation in healthy adults using ultrasonography (US). The effects of tibial nerve ablation were verified by visual observation and surface electromyography analysis. US images of medial GCMs were taken by one trained physician using B-mode and real-time US with a linear-array probe before nerve ablation, at 1 week after nerve ablation and at 3 months after nerve ablation in an anatomic standing position with the feet about shoulder-width apart in 19 healthy adults (17 females and 2 males). Muscle thickness was significantly reduced on the left side at 1 week and 3 months after the procedure and on the right side at 3 months after the procedure (p<0.050). Although fascicle length was not significantly changed, pennation angle was significantly reduced on both sides at 3 months after the procedure (p<0.050). Muscle thickness and pennation angle of the muscle fascicle were significantly reduced, although fascicle length was not significantly changed, after tibial nerve ablation in the medial GCM of healthy adults.