Tartronic Acid as a Potential Inhibitor of Pathological Calcium Oxalate Crystallization.

Kidney stones are a pervasive disease with notoriously high recurrence rates that require more effective treatment strategies. Herein, tartronic acid is introduced as an efficient inhibitor of calcium oxalate monohydrate (COM) crystallization, which is the most prevalent constituent of human kidney stones. A combination of in situ experimental techniques and simulations are employed to compare the inhibitory effects of tartronic acid with those of its molecular analogs. Tartronic acid exhibits an affinity for binding to rapidly growing apical surfaces of COM crystals, thus setting it apart from other inhibitors such as citric acid, the current preventative treatment for kidney stones. Bulk crystallization and in situ atomic force microscopy (AFM) measurements confirm the mechanism by which tartronic acid interacts with COM crystal surfaces and inhibits growth. These findings are consistent with in vivo studies that reveal the efficacy of tartronic acid is similar to that of citric acid in mouse models of hyperoxaluria regarding their inhibitory effect on stone formation and alleviating stone-related physical harm. In summary, these findings highlight the potential of tartronic acid as a promising alternative to citric acid for the management of calcium oxalate nephropathies, offering a new option for clinical intervention in cases of kidney stones.

Enhanced Therapeutic Potential of Hybrid Exosomes Loaded with Paclitaxel for Cancer Therapy.

The advancement of exosome studies has positioned engineered exosomes as crucial biomaterials for the development of advanced drug delivery systems. This study focuses on developing a hybrid exosome system by fusing mesenchymal stem cells (MSCs) exosomes with folate-targeted liposomes. The aim was to improve the drug loading capacity and target modification of exosome nanocarriers for delivering the first-line chemotherapy drug paclitaxel (PTX) and its effectiveness was assessed through cellular uptake studies to evaluate its ability to deliver drugs to tumor cells in vitro. Additionally, in vivo experiments were conducted using a CT26 tumor-bearing mouse model to assess the therapeutic efficacy of hybrid exosomes loaded with PTX (ELP). Cellular uptake studies demonstrated that ELP exhibited superior drug delivery capabilities to tumor cells in vitro. Moreover, in vivo experiments revealed that ELP significantly suppressed tumor growth in the CT26 tumor-bearing mouse model. Notably, for the first time, we examined the tumor microenvironment following intratumoral administration of ELP. We observed that ELP treatment activated CD4+ and CD8+ T cells, reduced the expression of M2 type tumor-associated macrophages (TAMs), polarized TAMs towards the M1 type, and decreased regulatory T cells (Tregs). Our research highlights the considerable therapeutic efficacy of ELP and its promising potential for future application in cancer therapy. The development of hybrid exosomes presents an innovative approach to enhance drug delivery and modulate the tumor microenvironment, offering exciting prospects for effective cancer treatment strategies.

Clinical experience of professor ZHANG Ren in the staging treatment with characteristic acupuncture techniques for oculomotor paralysis. / å¼ ä»æ•™æŽˆç‰¹è‰²é’ˆæ³•åˆ†æœŸæ²»ç–—åŠ¨çœ¼ç¥žç»éº»ç—¹ä¸´åºŠç»éªŒæ’·è¦.

The paper summarizes the clinical experience of professor ZHANG Ren in the staging treatment with characteristic acupuncture techniques for oculomotor paralysis. According to the symptoms of oculomotor paralysis, the staging treatment is given, in which acupuncture is dominant and the needling techniques are optioned in compliance with the symptoms. In the early, middle and late stages of illness, three different acupuncture therapies are delivered accordingly, i.e. the combination of the point-toward-point needling at the four acupoints located on the forehead and the electroacupuncture with disperse-dense wave, the surrounding needling and the triple needling at the acupoints around the eyeball, as well as the perpendicular needle insertion at the three acupoints within the orbit. Professor ZHANG Ren lays the stress on identifying the etiology and differentiating the symptoms, as well as the early intervention for the disease. For the intractable cases, the comprehensive regimen such as acupoint injection, dermal needling and auricular point sticking is supplemented. During treatment, the spirit harmonization is greatly considered to ensure the effectiveness. On the basis of the staging acupuncture therapy, the acupuncture technique for harmonizing the spirit and regulating qi is combined to obtain the favorable clinical effect on oculomotor paralysis.

Piezo channels in the intestinal tract.

The intestine is the largest mechanosensitive organ in the human body whose epithelial cells, smooth muscle cells, neurons and enteroendocrine cells must sense and respond to various mechanical stimuli such as motility, distension, stretch and shear to regulate physiological processes including digestion, absorption, secretion, motility and immunity. Piezo channels are a newly discovered class of mechanosensitive ion channels consisting of two subtypes, Piezo1 and Piezo2. Piezo channels are widely expressed in the intestine and are involved in physiological and pathological processes. The present review summarizes the current research progress on the expression, function and regulation of Piezo channels in the intestine, with the aim of providing a reference for the future development of therapeutic strategies targeting Piezo channels.

Lipid metabolism in the immune niche of tumor-prone liver microenvironment.

The liver is a common primary site not only for tumorigenesis, but also for cancer metastasis. Advanced cancer patients with liver metastases also show reduced response rates and survival benefits when treated with immune checkpoint inhibitors. Accumulating evidence has highlighted the importance of the liver immune microenvironment in determining tumorigenesis, metastasis-organotropism, and immunotherapy resistance. Various immune cells such as T cells, natural killer and natural killer T cells, macrophages and dendritic cells, and stromal cells including liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and hepatocytes are implicated in contributing to the immune niche of tumor-prone liver microenvironment. In parallel, as the major organ for lipid metabolism, the increased abundance of lipids and their metabolites is linked to processes crucial for nonalcoholic fatty liver disease and related liver cancer development. Furthermore, the proliferation, differentiation, and functions of hepatic immune and stromal cells are also reported to be regulated by lipid metabolism. Therefore, targeting lipid metabolism may hold great potential to reprogram the immunosuppressive liver microenvironment and synergistically enhance the immunotherapy efficacy in the circumstance of liver metastasis. In this review, we describe how the hepatic microenvironment adapts to the lipid metabolic alterations in pathologic conditions like nonalcoholic fatty liver disease. We also illustrate how these immunometabolic alterations promote the development of liver cancers and immunotherapy resistance. Finally, we discuss the current therapeutic options and hypothetic combination immunotherapies for the treatment of advanced liver cancers.

Effect of electroacupuncture at "Neiguan" (PC 6) and "Zusanli" (ST 36) on gastrointestinal hormone in the antral tissue of rats with functional dyspepsia. / 电针"å† å ³""足三里"å¯¹åŠŸèƒ½æ€§æ¶ˆåŒ–ä¸è‰¯å¤§é¼ èƒƒçª¦ç»„ç»‡èƒƒè‚ æ¿€ç´ çš„å½±å“.

OBJECTIVES: To observe the effects of electroacupuncture (EA) at "Neiguan" (PC 6) and "Zusanli"(ST 36) on the gastric emptying rate, the level of serotonin (5-HT) and the protein expression of motilin (MTL), ghrelin, substance P (SP) and vasoactive intestinal peptide (VIP) in the antral tissue of the rats with functional dyspepsia (FD) and explore the effect mechanism of EA in treatment of FD. METHODS: A total of 21 SPF male SD rat pups were randomly divided into a normal group, a model group and an EA group, with 7 rats in each group. In the model group and the EA group, FD model was prepared by the gavage with 0.1% sucrose iodoacetamide solution combined with the modified small platform method. After the successful modeling, EA was applied to "Neiguan" (PC 6) and "Zusanli"(ST 36) in the rats of the EA group, with disperse-dense wave, 20 Hz/100 Hz in frequency, stimulated for 30 min, once daily, for 7 days consecutively. Before and after intervention, the general condition of the rats was observed in each group. After the completion of intervention, the gastric emptying rate was measured, the morphological changes of gastric antral tissue were observed using HE staining, the level of 5-HT was detected with ELISA method, and the protein expression of MTL, ghrelin, SP, and VIP was determined with Western blot method in the antral tissue of rats. RESULTS: In the normal group, the rats were in a good mental state, with lustrous fur, flexible movement and the increase of food intake and body mass. In the model group, the rats were poor in mental state, lack of lustre in fur, preference for the body curled up, reduced activity and response; and a part of rats had loose stool, obviously enlarged gastric body and gastric food retention. In the EA group, the general condition of rats, e.g. the mental state, food intake and activity, were improved, the gastric body got smaller obviously and the gastric food retention was reduced when compared with the model group. The antral structure was intact, the glands were rich and no injury of the gastric mucosa was found, e.g. inflammatory reaction and edema in the rats of each group. Compared with the normal group, the gastric emptying rate was decreased (P<0.01), 5-HT level was increased (P<0.01), the protein expression of MTL and ghrelin was reduced (P<0.01) and that of VIP was elevated (P<0.01) in the rats of the model group. The gastric emptying rate was increased (P<0.01), 5-HT level was decreased (P<0.01), and the protein expression of MTL and ghrelin was elevated (P<0.05, P<0.01) in the rats of the EA group when compared with those in the model group. CONCLUSIONS: Electroacupuncture at "Neiguan" (PC 6) and "Zusanli"(ST 36) may effectively relieve gastric dysfunction, strengthen gastric motility and promote gastric emptying so as to alleviate the symptoms of dyspepsia in FD rats, and its mechanism may be related to the regulation of gastrointestinal hormones in the antral tissue.

[Effect of moxibustion of acupoints for both lung and intestine disorders on lung inflammation and intestinal short-chain fatty acids in asthmatic model rats].

OBJECTIVE: To explore the mechanism of moxibustion in the treatment of asthmatic inflammation from the point of short-chain fatty acids (SCFAs) in rats with asthma. METHODS: A total of 48 SD rats (half male and half female) were randomly divided into 4 groups： normal, model, lung treatment and joint-treatment of lung and intestine (joint-treatment), with 12 rats in each group. The asthma model was made by subcutaneous (bilateral back and inguinal regions) and intraperitoneal injection of mixture solution of ovalbumin and aluminium hydroxide gel (on day 1 and 8) and followed by inhalation of atomized 1% ovalbumin (20 min from day 15, once daily for one week). Moxibustion was applied to bilateral "Feishu" (BL13) for rats of the lung treatment group or bilateral "Feishu" (BL13) and "Tianshu" (ST25) for rats of the joint treatment group. One hour after the intervention, the rats in the later three groups were separately given atomized 1% ovalbumin solution inhalation for 20 min. The treatment was conducted for 30 min, once daily for 14 consecutive days. At the end of the intervention, the percentage of inflammatory cells in blood was detected by biochemical method and histopathological changes of the lung were observed after H.E. staining. The inflammatory cells in the bronchoalveolar lavage fluid (BALF) were counted after Wright-Giemsa staining. The mRNA expressions of interleukin (IL)-4, IL-5, IL-13, IL-17, IL-33, leukotriene (LT), thymic stromal lymphopoietin (TSLP) and prostaglandin D2 (PGD2) were detected by real-time PCR, and the contents of SCFAs in rats' feces were detected by gas chromatography-mass spectrometry. RESULTS: Relevant to the normal group, the model group had an obvious increase in the percentages of neutrophils, lymphocytes and eosinophils in the blood, the percentages of neutrophils and eosinophils in the BALF, and in the expression levels of PGD2, TSLP, LT, IL-4, IL-5, IL-13, IL-17 and IL-33 mRNAs in the lung tissues (P<0.01, P<0.05), and a marked decrease in the contents of acetic acid, propionic acid, isobutyric acid, butyric acid and valeric acid in feces (P<0.05, P<0.01). After the treatment, the percentages of neutrophils and lymphocytes in the peripheral blood, eosinophils in the BALF, and the expression levels of PGD2, TSLP, LT, IL-4, IL-17, IL-33 mRNAs in the lung tissues in both the lung treatment and joint treatment groups, as well as neutrophils of BALF, and expression of IL-5 and IL-13 mRNAs in the joint treatment group were significantly down-regulated (P<0.01, P<0.05), while the contents of acetic acid, propionic acid and valerate in the lung treatment group, and acetic acid, propionic acid, isobutyric acid, butyric acid and valeric acid in the joint treatment group were all strikingly increased (P<0.05, P<0.01). The effect of the joint treatment was superior to that of lung treatment in down-regulating the expressions of LT and IL-5 mRNAs (P<0.05, P<0.01) and up-requlating the content of propionic acid (P<0.05). Results of H.E. staining showed thickened alveolar wall, infiltration of a large number of inflammatory cells and interstitial fibrous tissue hyperplasia around the bronchus and scattered arrangement of cells of the lung tissue in the model group, which was relatively milder in both lung treatment and joint treatment groups, particularly the later. CONCLUSION: Joint treatment of asthma from the lung and intestine can better regulate the contents of intestinal SCFAs and alleviate the inflammatory response of asthmatic model rats, thus, intestinal SCFAs may be involved in the process of moxibustion in improving inflammatory response.

Myeloid-intrinsic cell cycle-related kinase drives immunosuppression to promote tumorigenesis.

Massive expansion of immature and suppressive myeloid cells is a common feature of malignant solid tumors. Over-expression of cyclin-dependent kinase 20, also known as cell cycle-related kinase (CCRK), in hepatocellular carcinoma (HCC) correlates with reduced patient survival and low immunotherapy responsiveness. Beyond tumor-intrinsic oncogenicity, here we demonstrated that CCRK is upregulated in myeloid cells in tumor-bearing mice and in patients with HCC. Intratumoral injection of Ccrk-knockdown myeloid-derived suppressor cells (MDSCs) increased tumor-infiltrating CD8+T cells and suppressed HCC tumorigenicity. Using an indel mutant transgenic model, we showed that Ccrk inactivation in myeloid cells conferred a mature phenotype with elevated IL-12 production, driving Th1 responses and CD8+T cell cytotoxicity to reduce orthotopic tumor growth and prolong survival. Mechanistically, CCRK activates STAT3/E4BP4 signaling in MDSCs to acquire immunosuppressive activity through transcriptional IL-10 induction and IL-12 suppression. Taken together, our findings unravel mechanistic insights into MDSC-mediated immunosuppression and offer a therapeutic kinase-target for cancer immunotherapy.

Cold-Induced Reprogramming of Subcutaneous White Adipose Tissue Assessed by Single-Cell and Single-Nucleus RNA Sequencing.

Adipose browning has demonstrated therapeutic potentials in several diseases. Here, by conducting transcriptomic profiling at the single-cell and single-nucleus resolution, we reconstituted the cellular atlas in mouse inguinal subcutaneous white adipose tissue (iWAT) at thermoneutrality or chronic cold condition. All major nonimmune cells within the iWAT, including adipose stem and progenitor cells (ASPCs), mature adipocytes, endothelial cells, Schwann cells, and smooth muscle cells, were recovered, allowing us to uncover an overall and detailed blueprint for transcriptomes and intercellular cross-talks and the dynamics during white adipose tissue brown remodeling. Our findings also unravel the existence of subpopulations in mature adipocytes, ASPCs, and endothelial cells, as well as new insights on their interconversion and reprogramming in response to cold. The adipocyte subpopulation competent of major histocompatibility complex class II (MHCII) antigen presentation is potentiated. Furthermore, a subcluster of ASPC with CD74 expression was identified as the precursor of this MHCII+ adipocyte. Beige adipocytes are transdifferented from preexisting lipid generating adipocytes, which exhibit developmental trajectory from de novo differentiation of amphiregulin cells (Aregs). Two distinct immune-like endothelial subpopulations are present in iWAT and are responsive to cold. Our data reveal fundamental changes during cold-evoked adipose browning.

Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma.

OBJECTIVE: Therapy-induced tumour microenvironment (TME) remodelling poses a major hurdle for cancer cure. As the majority of patients with hepatocellular carcinoma (HCC) exhibits primary or acquired resistance to antiprogrammed cell death (ligand)-1 (anti-PD-[L]1) therapies, we aimed to investigate the mechanisms underlying tumour adaptation to immune-checkpoint targeting. DESIGN: Two immunotherapy-resistant HCC models were generated by serial orthotopic implantation of HCC cells through anti-PD-L1-treated syngeneic, immunocompetent mice and interrogated by single-cell RNA sequencing (scRNA-seq), genomic and immune profiling. Key signalling pathway was investigated by lentiviral-mediated knockdown and pharmacological inhibition, and further verified by scRNA-seq analysis of HCC tumour biopsies from a phase II trial of pembrolizumab (NCT03419481). RESULTS: Anti-PD-L1-resistant tumours grew >10-fold larger than parental tumours in immunocompetent but not immunocompromised mice without overt genetic changes, which were accompanied by intratumoral accumulation of myeloid-derived suppressor cells (MDSC), cytotoxic to exhausted CD8+ T cell conversion and exclusion. Mechanistically, tumour cell-intrinsic upregulation of peroxisome proliferator-activated receptor-gamma (PPARγ) transcriptionally activated vascular endothelial growth factor-A (VEGF-A) production to drive MDSC expansion and CD8+ T cell dysfunction. A selective PPARγ antagonist triggered an immune suppressive-to-stimulatory TME conversion and resensitised tumours to anti-PD-L1 therapy in orthotopic and spontaneous HCC models. Importantly, 40% (6/15) of patients with HCC resistant to pembrolizumab exhibited tumorous PPARγ induction. Moreover, higher baseline PPARγ expression was associated with poorer survival of anti-PD-(L)1-treated patients in multiple cancer types. CONCLUSION: We uncover an adaptive transcriptional programme by which tumour cells evade immune-checkpoint targeting via PPARγ/VEGF-A-mediated TME immunosuppression, thus providing a strategy for counteracting immunotherapeutic resistance in HCC.

Incidence, Attributable Mortality, and Healthcare and Out-of-Pocket Costs of Clostridioides difficile Infection in US Medicare Advantage Enrollees.

BACKGROUND: US attributable Clostridioides difficile infection (CDI) mortality and cost data are primarily from Medicare fee-for-service populations, and little is known about Medicare Advantage Enrollees (MAEs). This study evaluated CDI incidence among MAEs from 2012 to 2019 and determined attributable mortality and costs by comparing MAEs with and without CDI occurring in 2018. METHODS: This retrospective cohort study assessed CDI incidence and associated mortality and costs for eligible MAEs ≥65 years of age using the de-identified Optum Clinformatics Data Mart database (Optum; Eden Prairie, Minnesota, USA). Outcomes included mortality, healthcare utilization, and costs, which were assessed via a propensity score-matched cohort using 2018 as the index year. Outcome analyses were stratified by infection acquisition and hospitalization status. RESULTS: From 2012 to 2019, overall annual CDI incidence declined from 609 to 442 per 100 000 person-years. Although the incidence of healthcare-associated CDI declined overall (2012, 53.2%; 2019, 47.2%), community-associated CDI increased (2012, 46.8%; 2019, 52.8%). The 1-year attributable mortality was 7.9% (CDI cases, 26.3%; non-CDI controls, 18.4%). At the 2-month follow-up, CDI-associated excess mean total healthcare and out-of-pocket costs were $13 476 and $396, respectively. Total excess mean healthcare costs were greater among hospitalized (healthcare-associated, $28 762; community-associated, $28 330) than nonhospitalized CDI patients ($5704 and $2320, respectively), whereas total excess mean out-of-pocket cost was highest among community-associated hospitalized CDI patients ($970). CONCLUSIONS: CDI represents an important public health burden in the MAE population. Preventive strategies and treatments are needed to improve outcomes and reduce costs for healthcare systems and this growing population of older US adults.

Fibrotic immune microenvironment remodeling mediates superior anti-tumor efficacy of a nano-PD-L1 trap in hepatocellular carcinoma.

The local microenvironment where tumors develop can shape cancer progression and therapeutic outcome. Emerging evidence demonstrate that the efficacy of immune-checkpoint blockade (ICB) is undermined by fibrotic tumor microenvironment (TME). The majority of hepatocellular carcinoma (HCC) develops in liver fibrosis, in which the stromal and immune components may form a barricade against immunotherapy. Here, we report that nanodelivery of a programmed death-ligand 1 (PD-L1) trap gene exerts superior efficacy in treating fibrosis-associated HCC when compared with the conventional monoclonal antibody (mAb). In two fibrosis-associated HCC models induced by carbon tetrachloride and a high-fat, high-carbohydrate diet, the PD-L1 trap induced significantly larger tumor regression than mAb with no evidence of toxicity. Mechanistic studies revealed that PD-L1 trap, but not mAb, consistently reduced the M2 macrophage proportion in the fibrotic liver microenvironment and promoted cytotoxic interferon gamma (IFNγ)+tumor necrosis factor α (TNF-α)+CD8+T cell infiltration to the tumor. Moreover, PD-L1 trap treatment was associated with decreased tumor-infiltrating polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) accumulation, resulting in an inflamed TME with a high cytotoxic CD8+T cell/PMN-MDSC ratio conductive to anti-tumor immune response. Single-cell RNA sequencing analysis of two clinical cohorts demonstrated preferential PD-L1 expression in M2 macrophages in the fibrotic liver, thus supporting the translational potential of nano-PD-L1 trap for fibrotic HCC treatment.

Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients.

OBJECTIVE: Immune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we elucidated the role of a programmed cell death protein 1 (PD-1) isoform, Δ42PD-1, in HCC progression and resistance to nivolumab ICB. DESIGN: We investigated 74 HCC patients in three cohorts, including 41 untreated, 28 treated with nivolumab and 5 treated with pembrolizumab. Peripheral blood mononuclear cells from blood samples and tumour infiltrating lymphocytes from tumour tissues were isolated for immunophenotyping. The functional significance of Δ42PD-1 was explored by single-cell RNA sequencing analysis and validated by functional and mechanistic studies. The immunotherapeutic efficacy of Δ42PD-1 monoclonal antibody was determined in HCC humanised mouse models. RESULTS: We found distinct T cell subsets, which did not express PD-1 but expressed its isoform Δ42PD-1, accounting for up to 71% of cytotoxic T lymphocytes in untreated HCC patients. Δ42PD-1+ T cells were tumour-infiltrating and correlated positively with HCC severity. Moreover, they were more exhausted than PD-1+ T cells by single T cell and functional analysis. HCC patients treated with anti-PD-1 ICB showed effective PD-1 blockade but increased frequencies of Δ42PD-1+ T cells over time especially in patients with progressive disease. Tumour-infiltrated Δ42PD-1+ T cells likely sustained HCC through toll-like receptors-4-signalling for tumourigenesis. Anti-Δ42PD-1 antibody, but not nivolumab, inhibited tumour growth in three murine HCC models. CONCLUSION: Our findings not only revealed a mechanism underlying resistance to PD-1 ICB but also identified anti-Δ42PD-1 antibody for HCC immunotherapy.

Accurate identification of structural variations from cancer samples.

Structural variations (SVs) are commonly found in cancer genomes. They can cause gene amplification, deletion and fusion, among other functional consequences. With an average read length of hundreds of kilobases, nano-channel-based optical DNA mapping is powerful in detecting large SVs. However, existing SV calling methods are not tailored for cancer samples, which have special properties such as mixed cell types and sub-clones. Here we propose the Cancer Optical Mapping for detecting Structural Variations (COMSV) method that is specifically designed for cancer samples. It shows high sensitivity and specificity in benchmark comparisons. Applying to cancer cell lines and patient samples, COMSV identifies hundreds of novel SVs per sample.

[Effect of "joint treatment of lung and intestine" with moxibustion on lung function and airway inflammation in asthmatic rats].

OBJECTIVE: To investigate the role of moxibustion of "Feishu" (BL13)，"Tianshu" (ST25) for asthma by simultaneously treating lung and intestine (i.e., treating both lung and intestine at the same time) in asthmatic rats. METHODS: A total of 48 SD rats were randomly divided into normal, model, lung treatment and joint-treatment of lung and intestine (joint-treatment) groups, with 12 rats in each. The asthma model was established by subcutaneous (bilateral back and inguinal regions) and intraperitoneal injection of mixture solution of albumin and Aluminium Hydroxide gel (on day 1st, and 9th) and followed by inhalation of atomized 1% ovalbumin (on day 15th, 20 min each time, once daily for 1 week). Moxibustion was applied to bilateral BL13 for rats of the lung treatment group or bilateral BL13 and ST25 for rats of the joint-treatment group. One hour after the intervention, the rats in the later three groups were separately given nebulized 1% ovalbumin solution inhalation for 20 min. The treatments were conducted once daily for 14 consecutive days. After intervention, the lung functions including the forced expiratory flow 25% (FEF 25%), maximal mid-expiratory flow (MMEF), dynamic lung compliance (Cdyn), forced expiratory volume/ forced vital capacity (FEV/FVC), peak expiratory flow (PEF), and lung resistance (RL) were measured by using a small animal lung function detector, and pathological changes and collagen deposition in the lung tissues were observed by H.E. and Masson staining, separately. The levels of interleukin (IL)-17, IL-4, IL-13, IL-33, IL-5, leukotriene (LT) and thymic stromal lymphocyte (TSLP) in the lung tissue were measured by ELISA. RESULTS: Compared with the normal group, the FEF 25%, MMEF， Cdyn， FEV/FVC and PEF were significantly decreased (P<0.05, P<0.01)， and the pulmonary RL, collagen deposition, and contents of IL-17, IL-4, IL-13, IL-33, IL-5, TSLP and LT were notably increased (P<0.05, P<0.01) in the model group. After intervention, the MMEF and Cdyn in the lung treatment group, PEF, MMEF, Cdyn, FEV/FVC, FEF 25% in the joint-treatment group, were markedly increased (P<0.05, P<0.01), whereas the collagen deposition, IL-17, IL-4 and TSLP in both the lung treatment and joint-treatment groups, RL, IL-13, IL-33, IL-5 and LT in the joint-treatment group were considerably down-regulated (P<0.05, P<0.01). The effects of the joint treatment were apparently superior to those of lung treatment in down-regulating the contents of TSLP and LT (P<0.05, P<0.01). H.E. staining showed thickened alveolar wall, infiltration of a large number of inflammatory cells in the bronchus of the model group, which was relatively milder in the joint-treatment group. CONCLUSION: "Joint treatment of lung and intestine" with moxibustion is superior to "lung treatment" alone in ameliorating the lung function and mitigating airway inflammation in rats with asthma.

Mapping and Modeling Physicochemical Fields in Solid-State Batteries.

The safety and energy density of solid-state batteries can be, in principle, substantially increased compared with that of conventional lithium-ion batteries. However, the use of solid-state electrolytes instead of liquid electrolytes introduces pronounced complexities to the solid-state system because of the strong coupling between different physicochemical fields. Understanding the evolution of these fields is critical to unlocking the potential of solid-state batteries. This necessitates the development of experimental and theoretical methods to track electrochemical, stress, crack, and thermal fields upon battery cycling. In this Perspective, we survey existing characterization techniques and the current understanding of multiphysics coupling in solid-state batteries. We propose that the development of experimental tools that can map multiple fields concurrently and systematic consideration of material plasticity in theoretical modeling are important for the advancement of this emerging battery technology. This Perspective provides introductory material on solid-state batteries to scientists from a broad physical chemistry community, motivating innovative and interdisciplinary studies in the future.

Intramuscular Inoculation of AS02-Adjuvanted Respiratory Syncytial Virus (RSV) F Subunit Vaccine Shows Better Efficiency and Safety Than Subcutaneous Inoculation in BALB/c Mice.

We previously explored a panel of adjuvants formulated with pre-fusion RSV-F protein and found that AS02 may be a promising candidate adjuvant for developing RSV-F subunit vaccines with improved immunogenicity and desired immune response type. In this study, we performed a head-to-head comparison of the effect of intramuscular injection to that of subcutaneous injection on the immune response and protective efficacy of recombinant RSV-F subunit vaccine with or without adjuvants (Alhydrogel, squalene-based emulsion adjuvants MF59, AS03, and AS02) in BALB/c mice. After inoculations, antigen-specific antibodies, neutralizing antibodies, antibody subtypes, cytokines, and the persistence of immune response were evaluated. Moreover, challenge tests were also performed to illustrate the possible effect of inoculation routes and adjuvant on virus clearance and histochemistry changes in the lungs of mice. The results indicated that intramuscular inoculation is a more effective and antigen dose-sparing route to enhance the immune response, although subcutaneous inoculation induced faster and stronger IgG antibodies after the initial immunization. Furthermore, adjuvant, but not immunization route, is a more critical factor to affect the humoral/cellular immune response and the immune bias. In addition, adjuvant inoculated via the intramuscular route is safer than that via the subcutaneous route, especially for AS02. This study highlights the importance of the adjuvant and immunization routes in the design and clinical transformation of adjuvanted vaccines. Further investigation is needed to illustrate the mechanism underlying the above difference in both efficiency and safety.

Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors.

Despite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy such as anti-PD-L1 antibody in treating cancers, myeloid-derived suppressor cells (MDSCs) that lead to the formation of the protumor immunosuppressive microenvironment are one of the major contributors to ICB resistance. Therefore, inhibition of MDSC accumulation and function is critical for further enhancing the therapeutic efficacy of anti-PD-L1 antibody in a majority of cancer patients. Artemisinin (ART), the most effective antimalarial drug with tumoricidal and immunoregulatory activities, is a potential option for cancer treatment. Although ART is reported to reduce MDSC levels in 4T1 breast tumor model and improve the therapeutic efficacy of anti-PD-L1 antibody in T cell lymphoma-bearing mice, how ART influences MDSC accumulation, function, and molecular pathways as well as MDSC-mediated anti-PD-L1 resistance in melanoma or liver tumors remains unknown. Here, we reported that ART blocks the accumulation and function of MDSCs by polarizing M2-like tumor-promoting phenotype towards M1-like antitumor one. This switch is regulated via PI3K/AKT, mTOR, and MAPK signaling pathways. Targeting MDSCs by ART could significantly reduce tumor growth in various mouse models. More importantly, the ART therapy remarkably enhanced the efficacy of anti-PD-L1 immunotherapy in tumor-bearing mice through promoting antitumor T cell infiltration and proliferation. These findings indicate that ART controls the functional polarization of MDSCs and targeting MDSCs by ART provides a novel therapeutic strategy to enhance anti-PD-L1 cancer immunotherapy.

CASC15 Gene Polymorphisms and Glioma Susceptibility in Chinese Children.

OBJECTIVE: Gliomas are the most common tumors in the central nervous system. The cancer susceptibility candidate 15 (CASC15) gene has been reported to be a susceptibility gene for several types of cancer. No studies have been carried out on the predisposing effect of CASC15 gene single nucleotide polymorphisms (SNPs) on glioma risk. METHODS: In order to determine whether CASC15 gene SNPs are involved in glioma susceptibility, the first association study in a relatively large sample, which consisted of 171 patients and 228 healthy controls recruited from China, was performed. The contribution of SNPs (rs6939340 A>G, rs4712653 T>C and rs9295536 C>A) to the risk of glioma was evaluated by multinomial logistic regression, based on the calculation of the odds ratio (OR) and 95% confidence interval (CI). RESULTS: In the single locus and combined analysis, it was revealed that the genetic risk score had no significant associations between CASC15 gene SNPs and glioma risk. However, in the stratified analysis, a significant decrease in risk of glioma was observed in subjects of <60 months old with the rs4712653 TT genotype, when compared to those with the CC/CT genotype (OR=0.12, 95% CI=0.02-0.91, P=0.041). CONCLUSION: The present study provides referential evidence on the association between the genetic predisposition of the CASC15 gene and glioma risk in Chinese children. However, more well-designed case-control studies and functional experiments are needed to further explore the role of CASC15 gene SNPs.