Adverse effects of methylphenidate for apathy in patients with Alzheimer's disease (ADMET2 trial).

OBJECTIVES: To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia. METHODS: The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo-controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6 months. AEs, including insomnia, falls, and cardiovascular events, were reported at every visit by participants and families using a symptom checklist. RESULTS: The study included 98 participants in the MPH group and 101 in the placebo group. Participants in the MPH group experienced greater weight loss on average than the placebo through the 6-month follow-up, with a difference in change between MPH and placebo of 2.8 lb (95% confidence interval, CI: 0.7, 4.9 lb). No treatment group differences in change during the trial were found in systolic and diastolic blood pressure. More participants in the MPH group reported falls during the follow-up, 10 versus 6 in MPH and placebo groups, respectively. No differences in post-baseline insomnia were observed between the treatment groups. No participants reported instances of myocardial infarction, congestive heart failure, arrhythmia, stroke, or cardiomyopathy throughout the study period. CONCLUSIONS: MPH use in AD patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population. There was a statistically significant but modest weight loss associated with MPH use, and clinicians are thus advised to monitor weight during MPH treatment.

Analysis of long noncoding RNAs and messenger RNAs expression profiles in the hearts of mice with acute viral myocarditis.

Acute viral myocarditis (AVMC) is a common acute myocardial inflammation caused by viral infections, which can lead to severe cardiac dysfunction. Several long noncoding RNAs (lncRNAs) with aberrant expression have been identified in the pathogenesis of AVMC. However, the expression profiles and functions of lncRNAs in AVMC have not been fully elucidated. In the present study, we constructed AVMC mouse models by intraperitoneal injection of coxsackievirus B3 (CVB3) and performed RNA sequencing (RNA-seq) on heart tissues to investigate the differences in lncRNAs and messenger RNAs (mRNAs) expression profiles. Based on the cutoff criteria of adjusted p-values (padj) <0.05 and |log2FoldChange| >1, a total of 1122 differentially expressed lncRNAs (DElncRNAs) and 3186 differentially expressed mRNAs (DEmRNAs) were screened, including 734 upregulated and 388 downregulated lncRNAs, 1821 upregulated and 1365 downregulated mRNAs. RT-qPCR analysis validated that the expression patterns of 12 randomly selected genes (6 DElncRNAs and 6 DEmRNAs) were highly consistent with those in RNA-seq, proving the reliability of the RNA-seq data. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that differentially expressed genes were mainly involved in metabolic and immune-related processes. Furthermore, co-expression networks between DElncRNAs and DEmRNAs in cytokine-cytokine receptor interaction, MAPK signaling pathway, and PI3K-Akt signaling pathway were constructed to study the molecular interactions of these molecules. Our study, for the first time, reveals the expression profiles of lncRNAs and mRNAs associated with AVMC, which may shed light on the roles of lncRNAs in disease pathogenesis and aid in discovering new therapeutic targets.

LncGBP9 knockdown alleviates myocardial inflammation and apoptosis in mice with acute viral myocarditis via suppressing NF-κB signaling pathway.

BACKGROUND: Myocardial inflammation and apoptosis are key processes in coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVMC). Accumulating evidence reveals the essential roles of long noncoding RNAs (lncRNAs) in the pathogenesis of AVMC. Here, we aimed to evaluate the biological functions of a novel lncRNA guanylate-binding protein 9 (lncGBP9) in AVMC progression and further explore its underlying mechanisms. METHODS: Initially, mouse models of AVMC were constructed by CVB3 infection. The expression and localization of lncGBP9 in heart tissues were analyzed using RT-qPCR and FISH. Adeno-associated virus serotype 9 (AAV9)-mediated lncGBP9 knockdown was then employed to clarify its roles in survival, cardiac function, and myocardial inflammation and apoptosis. Moreover, the mRNA and protein levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) were detected by RT-qPCR and ELISA, and the regulation of lncGBP9 knockdown on the NF-κB signaling pathway was investigated by Western blotting. Using an in vitro model of HL-1 cardiomyocytes exposed to CVB3 infection, the effects of lncGBP9 knockdown on cell viability, inflammation, and apoptosis were further evaluated in vitro. RESULTS: Increased lncGBP9 expression was detected in the heart tissues of AVMC mice and CVB3-infected HL-1 cells, and was mainly located in the cytoplasm. Knockdown of lncGBP9 remarkably alleviated the severity of AVMC in CVB3-infected mice, as verified by improved cardiac function, and reduced myocardial inflammation and apoptosis. Additionally, lncGBP9 knockdown suppressed the NF-κB signaling pathway and consequently reduced productions of pro-inflammatory cytokines in vivo. In vitro functional assays further confirmed that lncGBP9 knockdown promoted cell viability, inhibited cell apoptosis, and reduced pro-inflammatory cytokines release in CVB3-infected HL-1 cells through suppressing NF-κB activation. CONCLUSIONS: Collectively, lncGBP9 knockdown exerts anti-inflammatory and anti-apoptotic effects in CVB3-induced AVMC, which may be mediated in part via NF-κB signaling pathway. These findings highlight lncGBP9 as an attractive target for therapeutic interventions.

Probing Dynamic Behavior of Chemical Enhancers Passing In and Out of the Stratum Corneum and Modulation by Biodegradable Enhancer.

Chemical enhancers (CEs) decreased the barrier of the stratum corneum (SC) to enhance drug permeation. This was a "dynamic" behavior, which involved three processes including passing in, acting on, and passing out of the SC. However, compared with mature "static" researches about acting on the SC, the other two processes were poorly understood. This work aimed to probe the dynamic behavior of CEs and modulate it for satisfactory effectiveness. The investigating method of CEs' dynamic behavior was established to obtain the rate of CEs passing in and out of the SC. An analysis attribution was conducted to obtain the possible reasons for the quite different dynamic behavior of CEs based on log P, solubility parameter, and minimum binging energy. It demonstrated the rate of CEs passing in and out of the SC was dependent on CE affinity with the SC and the interaction between CEs and the SC, respectively. The relevance between CEs' dynamic behavior and the extent of decreasing SC barrier was confirmed by transepidermal water loss (TEWL). The higher rate of CE passing in the SC and a lower rate of passing out of the SC may contribute to an increased concentration of CEs in the SC, leading to a stronger ability to decrease the SC barrier. More importantly, two biodegradable CEs (Leu-Dod and Ser-Dod) of dodecanol were synthesized and achieved a modulation of its dynamic behavior to obtain more satisfactory effectiveness of enhancing drug permeation. This work was meaningful for the guidance of rationally promoting CEs' effectiveness from a dynamic perspective, which was an unprecedented attempt in this field.

Unconventional Passive Enhancement of Transdermal Drug Delivery: toward a Mechanistic Understanding of Penetration Enhancers Releasing from Acrylic Pressure-Sensitive Adhesive of Patches.

PURPOSE: Penetration enhancers (PEs) enhancing efficacy depends on two processes: PEs release from patches and action on skin. Compared with their action on skin, PEs release process was poorly understood. Therefore, the purpose of this study was to make a mechanistic understanding of PEs release from acrylic pressure-sensitive adhesive of patches and propose an unconventional enhancement of PEs efficacy. METHODS: PEs efficacy was evaluated both in drug permeation study and drug pharmacokinetic study. Confocal Raman spectroscopy was employed to observe PEs release behavior by mapping PEs dynamic distribution in skin. The mechanism of PEs release behavior was provided from molecular interaction and rheology using FT-IR, molecular docking, molecular dynamic simulation and rheometer, separately. RESULTS: The release behavior of PEs themselves greatly restricted their efficacy. By using PEG 400, an improvement of oleic acid (OA) release behavior was achieved, and the efficacy of OA was significantly enhanced with enhancing ratio (ER) from 2.69 to 4.10 and AUClast from 1574 ± 87 to 2664 ± 249 ng·h/mL, separately. The improvement of OA release behavior was primarily resulted from reduction of the interaction between OA and adhesive, which was caused by other small molecules with a strong ability in forming hydrogen bonds with adhesive. Also, the rigidity of adhesive was a factor in affecting PEs release behavior. CONCLUSIONS: An unconventional passive enhancement of transdermal drug delivery was achieved via improving PEs themselves releasing from acrylic pressure-sensitive adhesive. Graphical abstract Influence of PEs release behavior on drug permeation through skin and molecular mechanism.

Pathogenesis investigation of miR-199-5p in oral submucous fibrosis based on bioinformatics analysis.

OBJECTIVES: Fibrosis diseases are one of the leading causes of suffering and death. However, no systematic investigation has been carried out on fibrosis-related genes. MATERIALS AND METHODS: By querying PubMed using keywords "fibrosis" and "gene" or "protein," we identified fibrosis-related genes in the last decade. Bioinformatics analysis was performed by MAS 3.0 software. Key miRNA was selected to assess its relationship with oral submucous fibrosis (OSF) and fibroblast functions. RESULTS: A total of 1,310 genes related to fibrosis were identified. TGF-ß1, CTGF, MMP9, HSP47, and S1P were found to be associated with mainly fibrotic organs. In total, 244 cellular components terms, 595 molecular function terms, 1,816 cellular component terms, and 136 KEGG pathway annotations were predicted. miR-199-5p was selected as the key miRNA, which has higher level in OSF. Upregulated miR-199-5p was significantly related to OSF duration and OSF histological grade (p = 0.028 and 0.012, respectively). Overexpressive miR-199-5p reduced proliferation and induced apoptosis in buccal fibroblasts. Additionally, expression levels of collagen I (COL I) and III (COL III) were promoted by overexpressive miR-199-5p in buccal fibroblasts. CONCLUSION: These results indicate that fibrosis-related genes are related to a series of complex mechanisms. The characteristics of miR-199-5p may supply important clues for developing therapeutic strategy for OSF.

Tripaddled Anterolateral Thigh Flap for the Reconstruction of Extensively Full-Thickness Cheek Defects by Stacking Two Skin Paddles as Kiss Pattern.

Extended anterolateral thigh (ALT) flap can provide a large amount of skin to reconstruct the extensively full-thickness defects of cheek. However when the width of 1 skin paddle exceeds 8 cm, it always results in that the donor site cannot be closed primarily and need to be covered by split-thickness skin grafting, which delivers lots of impacts on the functional and cosmetic outcome of the thigh. The aim of this study was to introduce the authors' modification of stacking 2 skin paddles of the tripaddled ALT flap to reconstruct the extensive full-thickness defects in the cheek after the radical ablasion of advanced buccal squamous cell carcinoma. Ten patients of advanced buccal squamous cell carcinoma between March 2014 and December 2016 were enrolled in the authors' hospital. All the patients were received the soft-tissue reconstructions for the extensively full-thickness cheek defects by using the tripaddled ALT chimeric flaps. Among 3 skin paddles, the distal paddle was used to reconstruct the inner mucosa defect, and the other 2 large skin paddles were stacked side by side for outer mega cheek defect. The mean area of the intraoral defect was 32.2 cm and the mean area of the extraoral defect was 106.34 cm. The mean width of the outer skin defect was 9.5 cm. All the flaps survived and all the donor sites were closed primarily. So, stacking 2 skin paddles of a tripaddled ALT flap as a kiss pattern is a novel modification on conventional flap design to provide customized coverage for extensive and full-thickness buccal defects while minimizing donor-site morbidity.

Bifidobacterium adolescentis protects against necrotizing enterocolitis and upregulates TOLLIP and SIGIRR in premature neonatal rats.

BACKGROUND: Necrotizing enterocolitis (NEC) is a serious gastrointestinal disorder that is often seen in premature infants. Probiotics decrease the risk of NEC; however, the mechanism by which probiotics work is not clear. The goal of this study was to evaluate the preventive effect of Bifidobacterium adolescentis in an NEC rat model. METHODS: Sprague-Dawley neonatal rats were obtained by caesarean section after 20-21 d gestation and randomly divided into the following 3 groups: dam fed (DF), formula fed (FF), and formula + B. adolescentis (FB). Those in the FF and FB groups developed NEC after exposure to asphyxia and cold stress. All rats were sacrificed 72 h after birth and intestinal injury and mRNA expression of TLR4, TOLLIP and SIGIRR were assessed. RESULTS: B. adolescentis significantly increased the 72-h survival rate from 56.3% in the FF group to 86.7% in the FB group. B. adolescentis significantly reduced the histological score from a median of 3.0 in the FF group to a median of 1.0 in the FB group,and significantly decreased the rate of NEC-like intestinal injury from 77.8% in the FF group to 23.1% in the FB group. The mRNA expression of TLR4 increased 3.6 fold in the FF group but decreased by 2 fold from B. adolescentis treatment. mRNA expression of TOLLIP and SIGIRR decreased 4.3 and 3.7 fold, respectively, in the FF group. B. adolescentis significantly increased mRNA expression of TOLLIP and SIGIRR by 3.7 fold and 2.6 fold, respectively. CONCLUSIONS: This study demonstrated B. adolescentis prevents NEC in preterm neonatal rats and that the mechanism for this action might be associated with the alteration of TLR4, TOLLIP, and SIGIRR expression.

Vascularized Fascia Lata for Prevention of Postoperative Parotid Fistula Arising From Partial Parotidectomy During Neck Dissection.

PURPOSE: Postoperative parotid fistula can occur after partial parotidectomy, which is a routine surgical procedure during neck dissection of oral cancers arising from or close to the oropharyngeal area. The aim of this study was to evaluate the reliability of vascularized fascia lata for the prevention of postoperative parotid fistula after neck dissection. MATERIALS AND METHODS: A retrospective review was conducted of patients with oral cancer who underwent ablative resection involving the parotid tail and reconstruction using the anterolateral thigh (ALT) flap with a vascularized fascia lata paddle. The vascularized fascia lata paddle was used to seal off the parotid stump by tightly suturing the edges of the fascia lata and parotid wound together. RESULTS: Twenty-three patients (18 men and 5 women) with primary oral cancer arising from or close to the oropharyngeal area were enrolled. The mean area of parotid defect was 16.7 cm2 and the mean area of fascia lata harvested was 21.8 cm2. All flaps survived. Pressure dressing or anticholinergic drugs were not used in any case. During the follow-up period, there was no clinical evidence of the development of parotid fistula. CONCLUSION: The vascularized fascia lata paddle is a reliable option for the prevention of postoperative parotid fistula after neck dissection of oral cancer.

The Chinese prescription lianhuaqingwen capsule exerts anti-influenza activity through the inhibition of viral propagation and impacts immune function.

BACKGROUND: Lianhuaqingwen Capsule (LH-C) is a traditional Chinese medicine (TCM) formula used to treat respiratory tract infectious diseases in Chinese. The aim of this study was to determine the antiviral activity of LH-C and its immunomodulatory effects on viral infection. METHOD: The in vitro cytotoxicity and antiviral activity of LH-C was determined by MTT and Plaque reduction assays. Time course study under single-cycle virus growth conditions were used to determine which stage of viral replication was blocked. The effect of LH-C on the nuclear export of the viral nucleoprotein was examined using an indirect immunofluorescence assay. The regulation to different signaling transduction events and cytokine/chemokine expression of LH-C was evaluated using Western blotting and real-time RT-PCR. After virus inoculation, BALB/c mice were administered with LH-C of different concentrations for 5 days. Body-weight, viral titers and lung pathology of the mice were measured, the level of inflammatory cytokines were also examined using real-time RT-PCR. RESULTS: LH-C inhibited the proliferation of influenza viruses of various strain in vitro, with the 50% inhibitory concentration (IC50) ranging from 0.35 to 2 mg/mL. LH-C blocked the early stages (0-2 h) of virus infection, it also suppressed virus-induced NF-kB activation and alleviated virus-induced gene expression of IL-6, IL-8, TNF-a, IP-10, and MCP-1 in a dose-dependent manner. LH-C treatment efficiently impaired the nuclear export of the viral RNP. A decrease of the viral titers in the lungs of mice were observed in groups administered with LH-C. The level of inflammatory cytokines were also decreased in the early stages of infection. CONCLUSIONS: LH-C, as a TCM prescription, exerts broad-spectrum effects on a series of influenza viruses, including the newly emerged H7N9, and particularly regulates the immune response of virus infection. Thus, LH-C might be a promising option for treating influenza virus infection.

Radix isatidis Polysaccharides Inhibit Influenza a Virus and Influenza A Virus-Induced Inflammation via Suppression of Host TLR3 Signaling In Vitro.

Influenza remains one of the major epidemic diseases worldwide, and rapid virus replication and collateral lung tissue damage caused by excessive pro-inflammatory host immune cell responses lead to high mortality rates. Thus, novel therapeutic agents that control influenza A virus (IAV) propagation and attenuate excessive pro-inflammatory responses are needed. Polysaccharide extract from Radix isatidis, a traditional Chinese herbal medicine, exerted potent anti-IAV activity against human seasonal influenza viruses (H1N1 and H3N2) and avian influenza viruses (H6N2 and H9N2) in vitro. The polysaccharides also significantly reduced the expression of pro-inflammatory cytokines (IL-6) and chemokines (IP-10, MIG, and CCL-5) stimulated by A/PR/8/34 (H1N1) at a range of doses (7.5 mg/mL, 15 mg/mL, and 30 mg/mL); however, they were only effective against progeny virus at a high dose. Similar activity was detected against inflammation induced by avian influenza virus H9N2. The polysaccharides strongly inhibited the protein expression of TLR-3 induced by PR8, suggesting that they impair the upregulation of pro-inflammatory factors induced by IAV by inhibiting activation of the TLR-3 signaling pathway. The polysaccharide extract from Radix isatidis root therefore has the potential to be used as an adjunct to antiviral therapy for the treatment of IAV infection.

Quantitative proteomic analysis for novel biomarkers of buccal squamous cell carcinoma arising in background of oral submucous fibrosis.

BACKGROUND: In South and Southeast Asian, the majority of buccal squamous cell carcinoma (BSCC) can arise from oral submucous fibrosis (OSF). BSCCs develop in OSF that are often not completely resected, causing local relapse. The aim of our study was to find candidate protein biomarkers to detect OSF and predict prognosis in BSCCs by quantitative proteomics approaches. METHODS: We compared normal oral mucosa (NBM) and paired biopsies of BSCC and OSF by quantitative proteomics using isobaric tags for relative and absolute quantification (iTRAQ) to discover proteins with differential expression. Gene Ontology and KEGG networks were analyzed. The prognostic value of biomarkers was evaluated in 94 BSCCs accompanied with OSF. Significant associations were assessed by Kaplan-Meier survival and Cox-proportional hazards analysis. RESULTS: In total 30 proteins were identified with significantly different expression (false discovery rate < 0.05) among three tissues. Two consistently upregulated proteins, ANXA4 and FLNA, were validated. The disease-free survival was negatively associated with the expression of ANXA4 (hazard ratio, 3.4; P = 0.000), FLNA (hazard ratio, 2.1; P = 0.000) and their combination (hazard ratio, 8.8; P = 0.002) in BSCCs. CONCLUSION: The present study indicates that iTRAQ quantitative proteomics analysis for tissues of BSCC and OSF is a reliable strategy. A significantly up-regulated ANXA4 and FLNA could be not only candidate biomarkers for BSCC prognosis but also potential targets for its therapy.

Favorable effects of open surgery on patients with extensive skull base osteoradionecrosis through a personalized sequential approach: A case series.

The present study aimed to investigate outcomes following open surgery for extensive skull base ORN. Open surgery through a personalized sequential approach was employed to deal with five cases of extensive skull base ORN. Two patients with mild cases underwent regional debridement and sequestrectomy, and three patients with severe cases underwent extensive resection with reconstruction using free anterolateral thigh (ALT) flap. Biological glues and vascularized flaps were used for obturation of the skull base bony defect to prevent postoperative cerebrospinal fluid (CSF) leakage. The infections were controlled by antibiotic administrations which strictly followed the principles of antimicrobial stewardship (AMS). As results, both regional debridement plus sequestrectomy and extensive resection achieved satisfied outcomes in all patients. No severe complications and delayed hospitalization occurred. During the follow-up period (8-19 months), all patients were alive, pain free, without crusting or purulent discharge, and no sequestration or CSF leakage occurred. In conclusion, a personalized sequential approach including open surgery, pedicled/vascularized free flap reconstruction and AMS was advocated for patients with extensive skull base ORN.

Exploring amyotrophic lateral sclerosis patients' experiences of psychological distress during the disease course in China: a qualitative study.

OBJECTIVE: This study aims to explore the psychological distress course of Chinese amyotrophic lateral sclerosis (ALS) patients after the onset of the disease and to provide targeted nursing guidance. DESIGN: The interview content was analysed qualitatively. We used seven steps of Colaizzi's method to analyse the participants' data. SETTING: Wuhan, China, Traditional Chinese Medicine Hospital. PARTICIPANTS: A semistructured face-to-face interview were performed among 22 people with ALS from the motor neuron disease rehabilitation centre of a tertiary Chinese medicine hospital in China. RESULT: This study included a total of 22 participants, from whom three main themes regarding the psychological distress trajectory of ALS patients were extracted from the interview data: 'Time begins to run out' include tormented and restless waiting and shock and doubt in ALS disease confirmation, 'Family out of control' include the burden of stigma and function loss, the burden of missing family roles, the burden of marriage's emotional needs and the burden of offspring health, 'Way forward' include struggle between live and death and struggle between quality of life and the value of life. CONCLUSION: This study outlines the psychologically distressing journey of ALS patients. Studies have pointed out the need for targeted care to address patients' various sources of psychological distress to improve their quality of life and coping ability, increase their psychological resilience and reconstruct their life beliefs.

Effects of Fe(II) bio-oxidation rate and alkali control on schwertmannite microstructure and adsorption of oxyanions: Characteristics, performance and mechanism.

Schwertmannite has attracted increasing interest for its excellent sorption of oxyanions such as AsO43-, CrO42-, and Sb(OH)6-. Controlling biomineralization by adjusting the Fe(II) oxidation rate and implementing alkali control can enhance the yield and adsorption performance of schwertmannite. However, the adsorption improvement mechanism is still unclear. The morphology, crystallinity, specific surface area (SSA) and oxyanion adsorption of schwertmannite synthesized with alkali control of solution pH and different Fe(II) oxidation rates were analyzed in this study. The differences in the adsorption mechanisms of As(V), Cr(VI) and Sb(V) on schwertmannite obtained under different synthesis conditions were also studied. Reducing the Fe(II) oxidation rate or maintaining the solution pH through alkali control significantly increased the SSA of schwertmannite and the proportion of outer-sphere sulfate. Alkali-controlled schwertmannite (Sch-C) exhibited superior As(V) and Sb(V) adsorption performance and slightly greater Cr(VI) adsorption than non-alkali-controlled schwertmannite. The As(V) and Sb(V) adsorption capacities of Sch-C greatly improved because the ultra-high SSA increased the surface hydroxyl content and reduced the passivation effect of amorphous precipitates on the mineral surface, allowing continuous sulfate exchange at inner mineral sites. An increased surface hydroxyl content had little effect on Cr(VI) adsorption, but an increased proportion of outer-sphere sulfate caused a slight increase in Cr(VI) adsorption. Sb(V) has a stronger hydroxyl exchange ability than As(V), but due to its octahedral structure, it exchanges only with outer-sphere sulfate on schwertmannite and hardly exchanges with inner-sphere sulfate.

A Lactate-Depleting metal organic framework-based nanocatalyst reinforces intratumoral T cell response to boost anti-PD1 immunotherapy.

Infiltration and activation of intratumoral T lymphocytes are critical for immune checkpoint blockade (ICB) therapy. Unfortunately, the low tumor immunogenicity and immunosuppressive tumor microenvironment (TME) induced by tumor metabolic reprogramming cooperatively hinder the ICB efficacy. Herein, we engineered a lactate-depleting MOF-based catalytic nanoplatform (LOX@ZIF-8@MPN), encapsulating lactate oxidase (LOX) within zeolitic imidazolate framework-8 (ZIF-8) coupled with a coating of metal polyphenol network (MPN) to reinforce T cell response based on a "two birds with one stone" strategy. LOX could catalyze the degradation of the immunosuppressive lactate to promote vascular normalization, facilitating T cell infiltration. On the other hand, hydrogen peroxide (H2O2) produced during lactate depletion can be transformed into anti-tumor hydroxyl radical (•OH) by the autocatalytic MPN-based Fenton nanosystem to trigger immunogenic cell death (ICD), which largely improved the tumor immunogenicity. The combination of ICD and vascular normalization presents a better synergistic immunopotentiation with anti-PD1, inducing robust anti-tumor immunity in primary tumors and recurrent malignancies. Collectively, our results demonstrate that the concurrent depletion of lactate to reverse the immunosuppressive TME and utilization of the by-product from lactate degradation via cascade catalysis promotes T cell response and thus improves the effectiveness of ICB therapy.

An Immunocompetent Hafnium Oxide-Based STING Nanoagonist for Cancer Radio-immunotherapy.

cGAS-STING signaling plays a critical role in radiotherapy (RT)-mediated immunomodulation. However, RT alone is insufficient to sustain STING activation in tumors under a safe X-ray dose. Here, we propose a radiosensitization cooperated with cGAS stimulation strategy by engineering a core-shell structured nanosized radiosensitizer-based cGAS-STING agonist, which is constituted with the hafnium oxide (HfO2) core and the manganese oxide (MnO2) shell. HfO2-mediated radiosensitization enhances immunogenic cell death to afford tumor associated antigens and adequate cytosolic dsDNA, while the GSH-degradable MnO2 sustainably releases Mn2+ in tumors to improve the recognition sensitization of cGAS. The synchronization of sustained Mn2+ supply with cumulative cytosolic dsDNA damage synergistically augments the cGAS-STING activation in irradiated tumors, thereby enhancing RT-triggered local and system effects when combined with an immune checkpoint inhibitor. Therefore, the synchronous radiosensitization with sustained STING activation is demonstrated as a potent immunostimulation strategy to optimize cancer radio-immuotherapy.

The Data and Safety Monitoring Board: The Toughest Job in Clinical Trials.

The DSMB: The Toughest Job in Clinical TrialsIn this review article, the authors discuss methods that DSMBs can use to compare the absolute and relative risks of benefits and adverse effects between trial interventions and illustrate how the DSMB can use this approach to evaluate the balance of these competing risks. Two approaches are discussed - the win ratio and the DOOR probability on one treatment relative to another.

The effect of internet use on depressive symptoms in middle-aged and older adults with functional disability: the mediating role of social isolation.

Objective: The popularization of the internet provides the possibility to improve the depressive symptoms (DS) and social isolation of middle-aged and older adults with functional disability. There was a significant correlation between internet use and DS in middle-aged and older adults with functional disability, but the relationship between internet use, social isolation, and DS remains to be confirmed. Methods: Data were obtained from 7,955 middle-aged and older adults aged 45 years and older from the 2018 China Health and Retirement Longitudinal Study (CHARLS). Multiple linear regression models were used to analyze the association between internet use and DS, and the Sobel test was used to explore mediating models. Results: Results showed that internet use was negatively associated with DS among Chinese middle-aged and older adults. Among them, social needs (B = -0.770, p = 0.041), and information reception (B = -1.067, p = 0.007) were significantly related to DS in middle-aged and older adults. Only information reception (B = -3.161, p = 0.031) was significantly related to DS among middle-aged and older adults with functional disability. Social isolation partially mediated the association between internet use and DS in middle-aged and older adults without functional disability, whereas it was fully mediated in middle-aged and older adults with functional disability. Conclusion: This study indicates that when formulating health policies to promote the mental health of Chinese middle-aged and older adults, the use of the internet should not be overlooked.

Modified internal curvilinear distraction device with a pre-embedding guide rail, drive screw, and universal joint for curvilinear lengthening of the mandible: A finite element analysis and animal experiment.

OBJECTIVES: The semiburied design of the traditional internal distractor has a relatively high risk of infection and aesthetic problems. To reduce these potential risks, a modified internal distractor with design of pre-embedding curvilinear rail, drive screw, and universal joint was invented. Its stress distribution characteristics and the effect on curvilinear distraction osteogenesis (DO) in vivo were further tested. MATERIALS AND METHODS: Finite element analysis (FEA) was performed on a model of the human mandible and distraction device to measure the stress distribution during curvilinear DO. Six beagles underwent curvilinear DO and consolidation using the new device. Radiological and histological examinations were performed on the new bone. RESULTS: On FEA, the stress was concentrated in the condyle (128.6 MPa) and curved guide rails (324.8 MPa). Four of the six animals completed the DO period and were consolidated for 12 weeks. Secondary infections were not observed. Radiography showed that a new fan-shaped bone-15.5 ± 5.5 mm in length and 4.6 ± 1.6 mm in height-was formed in the bone gap. Micro-computed tomography and histological examinations of specimens indicated that the structure of the new bone was similar to that of the normal bone. CONCLUSIONS: The modified internal curvilinear distraction device meets the mechanical strength requirement and achieve curvilinear DO in animal experiments.