ASCL2 induces an immune excluded microenvironment by activating cancer-associated fibroblasts in microsatellite stable colorectal cancer.

Proficient mismatch repair or microsatellite stable (pMMR/MSS) colorectal cancers (CRCs) are vastly outnumbered by deficient mismatch repair or microsatellite instability-high (dMMR/MSI-H) tumors and lack a response to immune checkpoint inhibitors (ICIs). In this study, we reported two distinct expression patterns of ASCL2 in pMMR/MSS and dMMR/MSI-H CRCs. ASCL2 is overexpressed in pMMR/MSS CRCs and maintains a stemness phenotype, accompanied by a lower density of tumor-infiltrating lymphocytes (TILs) than those in dMMR/MSI CRCs. In addition, coadministration of anti-PD-L1 antibodies facilitated T cell infiltration and provoked strong antitumor immunity and tumor regression in the MC38/shASCL2 mouse CRC model. Furthermore, overexpression of ASCL2 was associated with increased TGFB levels, which stimulate local Cancer-associated fibroblasts (CAFs) activation, inducing an immune-excluded microenvironment. Consistently, mice with deletion of Ascl2 specifically in the intestine (Villin-Cre+, Ascl2 flox/flox, named Ascl2 CKO) revealed fewer activated CAFs and higher proportions of infiltrating CD8+ T cells; We further intercrossed Ascl2 CKO with ApcMin/+ model suggesting that Ascl2-deficient expression in intestinal represented an immune infiltrating environment associated with a good prognosis. Together, our findings indicated ASCL2 induces an immune excluded microenvironment by activating CAFs through transcriptionally activating TGFB, and targeting ASCL2 combined with ICIs could present a therapeutic opportunity for MSS CRCs.

Overview of ICARUS-A Curated, Open Access, Online Repository for Atmospheric Simulation Chamber Data.

Atmospheric simulation chambers continue to be indispensable tools for research in the atmospheric sciences. Insights from chamber studies are integrated into atmospheric chemical transport models, which are used for science-informed policy decisions. However, a centralized data management and access infrastructure for their scientific products had not been available in the United States and many parts of the world. ICARUS (Integrated Chamber Atmospheric data Repository for Unified Science) is an open access, searchable, web-based infrastructure for storing, sharing, discovering, and utilizing atmospheric chamber data [https://icarus.ucdavis.edu]. ICARUS has two parts: a data intake portal and a search and discovery portal. Data in ICARUS are curated, uniform, interactive, indexed on popular search engines, mirrored by other repositories, version-tracked, vocabulary-controlled, and citable. ICARUS hosts both legacy data and new data in compliance with open access data mandates. Targeted data discovery is available based on key experimental parameters, including organic reactants and mixtures that are managed using the PubChem chemical database, oxidant information, nitrogen oxide (NOx) content, alkylperoxy radical (RO2) fate, seed particle information, environmental conditions, and reaction categories. A discipline-specific repository such as ICARUS with high amounts of metadata works to support the evaluation and revision of atmospheric model mechanisms, intercomparison of data and models, and the development of new model frameworks that can have more predictive power in the current and future atmosphere. The open accessibility and interactive nature of ICARUS data may also be useful for teaching, data mining, and training machine learning models.

Effectiveness of Xiaoyao capsule on sleep disorders and mood disturbance in patients in recovery from coronavirus disease 2019: a randomized controlled trial.

OBJECTIVE: To study the efficacy of Xiaoyao capsule in improving the clinical symptoms of sleep and mood disorders during recovery from coronavirus disease 2019 (COVID-19). METHODS: The study cohort comprised 200 patients with sleep and mood disorders during recovery from COVID-19. Patients were randomized into the control group and the experimental group in a 1:1 ratio by blocked randomization. The patients received either Xiaoyao capsule (experimental group) or a placebo Xiaoyao capsule (control group) for 2 weeks. The improvements in the Traditional Chinese Medicine (TCM) syndrome scales, total effective rates, and disappearance rates of irritability, anxiety, and poor sleep were compared between the two groups. RESULTS: The TCM syndrome pattern scales, total effective rates, and disappearance rates of irritability, anxiety, and poor sleep did not significantly differ between the experimental group versus the control group in the full analysis set and the per protocol set after 1 and 2 weeks of treatment ( > 0.05). CONCLUSIONS: Xiaoyao capsule do not significantly improve the clinical symptoms of sleep and mood disorders in patients in recovery from COVID-19.

Classic mechanisms and experimental models for the anti-inflammatory effect of traditional Chinese medicine.

Inflammation is a common disease involved in the pathogenesis, complications, and sequelae of a large number of related diseases, and therefore considerable research has been directed toward developing anti-inflammatory drugs for the prevention and treatment of these diseases. Traditional Chinese medicine (TCM) has been used to treat inflammatory and related diseases since ancient times. According to the review of abundant modern scientific researches, it is suggested that TCM exhibit anti-inflammatory effects at different levels, and via multiple pathways with various targets, and recently a series of in vitro and in vivo anti-inflammatory models have been developed for anti-inflammation research in TCM. Currently, the reported classic mechanisms of TCM and experimental models of its anti-inflammatory effects provide reference points and guidance for further research and development of TCM. Importantly, the research clearly confirms that TCM is now and will continue to be an effective form of treatment for many types of inflammation and inflammation-related diseases.

Tumor Tropic Delivery of Hyaluronic Acid-Poly (D,L-lactide-co-glycolide) Polymeric Micelles Using Mesenchymal Stem Cells for Glioma Therapy.

Tumor penetration and the accumulation of nanomedicines are crucial challenges in solid tumor therapy. By taking advantage of the MSC tumor-tropic property, we developed a mesenchymal stem cell (MSC)-based drug delivery system in which paclitaxel (PTX)-encapsulating hyaluronic acid-poly (D,L-lactide-co-glycolide) polymeric micelles (PTX/HA-PLGA micelles) were loaded for glioma therapy. The results indicated that CD44 overexpressed on the surface of both MSCs and tumor cells not only improved PTX/HA-PLGA micelle loading in MSCs, but also promoted the drug transfer between MSCs and adjacent cancer cells. It was hypothesized that CD44-mediated transcytosis played a crucial role and allowed deep glioma penetration depending on sequential intra-intercellular delivery via endocytosis-exocytosis. MSC-micelles were able to infiltrate from normal brain parenchyma towards contralateral tumors and led to the eradication of glioma. The survival of orthotopic glioma-bearing rats was significantly extended. In conclusion, the MSC-based delivery of HA-PLGA micelles is a potential strategy for tumor-targeting drug delivery.

Variability in Aromatic Aerosol Yields under Very Low NOx Conditions at Different HO2/RO2 Regimes.

Current chemical transport models generally use a constant secondary organic aerosol (SOA) yield to represent SOA formation from aromatic compounds under low NOx conditions. However, a wide range of SOA yields (10 to 42%) from m-xylene under low NOx conditions is observed in this study. The chamber HO2/RO2 ratio is identified as a key factor explaining SOA yield variability: higher SOA yields are observed for runs with a higher HO2/RO2 ratio. The RO2 + RO2 pathway, which can be increasingly significant under low NOx and HO2/RO2 conditions, shows a lower SOA-forming potential compared to the RO2 + HO2 pathway. While the traditional low-NOx chamber experiments are commonly used to represent the RO2 + HO2 pathway, this study finds that the impacts of the RO2 + RO2 pathway cannot be ignored under certain conditions. We provide guidance on how to best control for these two pathways in conducting chamber experiments to best obtain SOA yield curves and quantify the contributions from each pathway. On the global scale, the chemical transport model GEOS-Chem is used to identify regions characterized by lower surface HO2/RO2 ratios, suggesting that the RO2 + RO2 pathway is more likely to prove significant to overall SOA yields in those regions. Current models generally do not consider the RO2 + RO2 impacts on aromatic SOA formation, but preliminary sensitivity tests with updated SOA yield parameters based on such a pathway suggest that without this consideration, some types of SOA may be overestimated in regions with lower HO2/RO2 ratios.

Developing highly efficient and electric-field-sensitive fiber-waveguide evanescent couplers.

The slab-coupled optical fiber sensor (SCOS) is an innovative electric field detector with an ultrawide measuring range and a millimeter-level package size. The core sensing part of the SCOS is a fiber-waveguide evanescent coupler (FWEC) that directly determines the device's main performance specifications. This paper presents an investigation of the spectrum characteristics of FWECs with various structural and curing parameters. Methods for fabricating an FWEC with higher resonant depth, narrower free spectral range, and sharper spectrum slope are determined based on the experimental results. Z-cut lithium-niobate FWEC and Z-cut lithium-tantalate FWEC of about ${{1}} \times {0.5} \times {0.3}\;{\rm{mm}}^3$ are fabricated on this basis. Excellent coupling characteristics are achieved in both, according to the relevant spectra. Electric field tests indicate that the peak wavelengths shift linearly with the external AC field amplitude by 0.11 nm/(kV/cm) and 0.24 nm/(kV/cm), respectively. Three optimization methods are proposed to enhance performance: optimizing material selection, adding an antenna structure, and adjusting the calibration method. The results of this work may provide workable guidance for developing miniature, all-dielectric electric field sensors.

[An updated phytochemical and pharmacological progress on Syringa pinnatifolia].

Syringa pinnatifolia is an endemic species of Syringa in Oleaceae family in China, mainly distributed in Helan Mountain, which is located between Inner Mongolia and Ningxia. Its peeled roots, stems and thick twigs have been used as Mongolian folk medicine, called "Shan-chen-xiang" in Chinese, for the treatment of coronary heart diseases, angina pectoris and other cardiopulmonary diseases. Modern researches showed that S. pinnatifolia mainly contains lignans, sesquiterpenoids, and volatile oils, and displays anti-myocardial ischemia, sedation, analgesia, antibacterial and other effects. In the past five years, many groups have made new progress on the study of chemical constituents and pharmacological activities of S. pinnatifolia. On the basis of the previous review by our group, this paper summarizes the advances which is beneficial to the development, research and clinical application of S. pinnatifolia, particularly Shan-chen-xiang.

Protective Effects of Chromium Picolinate Against Diabetic-Induced Renal Dysfunction and Renal Fibrosis in Streptozotocin-Induced Diabetic Rats.

Diabetic nephropathy (DN) is one of the most important complications of diabetes， and the leading cause of end-stage renal disease (ESRD). While Chromium picolinate (CrPic) supplementation has been found to be effective in treating diabetes, its effects on diabetic-induced nephropathy have not been studied. Therefore, in this study, CrPic (1 mg kg -1 d -1) was administered to a DN rat model by oral gavage for eight weeks to investigate its effects. The results show that CrPic supplementation caused a decrease in levels of blood glucose, serum insulin, blood urea nitrogen (BUN), serum creatinine, and urinary albumin in DN rats. It also reversed renal pathological changes, including renal glomerular sclerosis and interstitial fibrosis. In addition, the oxidative defense system in the kidneys of DN rats was found to be improved; the biological activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) increased; and the content of malondialdehyde (MDA) lowered. Immunohistochemical results reveal that the expression levels of renal transforming growth factor-ß1 (TGF-ß1), Smad 2, and Smad 3 decreased significantly in the kidneys of rats in the CrPic-treated group. CrPic administration was thus found to ameliorate diabetic nephropathy in SD rats via an antioxidative stress mechanism, as well the ability to inhibit TGF-ß1/Smad2/3 expression. This study suggests that CrPic could be a potential renal-protective nutrient against diabetic nephropathy.

CD200Fc Improves Neurological Function by Protecting the Blood-brain Barrier after Intracerebral Hemorrhage.

CD200 is widely distributed in the central nervous system and plays an essential role in the immune response in neurological diseases. However, little is currently known about the effects of CD200 signaling on the blood-brain barrier (BBB) function after intracerebral hemorrhage (ICH). In this study, the role of CD200 during ICH in an autologous blood induced mouse ICH model was investigated. Following ICH, critical protein expression, BBB permeability, and neurological function were measured with or without CD200Fc administration. Our results showed that both the expression of CD200 and CD200R1 decreased after ICH and administration of CD200Fc attenuated BBB leakage and improved neurological functions. In conclusion, our work demonstrated that CD200Fc might be a potential treatment option for ICH by protecting the BBB and improving functional outcomes.

Thrombin disrupts vascular endothelial-cadherin and leads to hydrocephalus via protease-activated receptors-1 pathway.

AIMS: Previous studies indicated that intraventricular injection of thrombin would induce hydrocephalus. But how thrombin works in this process remains unclear. Since cadherin plays a critical role in hydrocephalus, we aimed to explore the mechanisms of how thrombin acted on choroid plexus vascular endothelium and how thrombin interacted with vascular endothelial-cadherin (VE-cadherin) during hydrocephalus. METHODS: There were two parts in this study. Firstly, rats received an injection of saline or thrombin into the right lateral ventricle. Magnetic resonance imaging was applied to measure the lateral ventricle volumes. Albumin leakage and Evans blue content were assessed to test the blood-brain barrier function. Immunofluorescence and Western blot were applied to detect the location and the expression of VE-cadherin. Secondly, we observed the roles of protease-activated receptors-1 (PAR1) inhibitor (SCH79797), Src inhibitor (PP2), p21-activated kinase-1 (PAK1) inhibitor (IPA3) in the thrombin-induced hydrocephalus, and their effects on the regulation of VE-cadherin. RESULTS: Our study demonstrated that intraventricular injection of thrombin caused significant downregulation of VE-cadherin in choroid plexus and dilation of ventricles. In addition, the inhibition of PAR1/p-Src/p-PAK1 pathway reversed the decrease of VE-cadherin and attenuated thrombin-induced hydrocephalus. CONCLUSIONS: Our results suggested that the thrombin-induced hydrocephalus was associated with the inhibition of VE-cadherin via the PAR1/p-Src/p-PAK1 pathway.

Probing the Structural and Electronic Properties of Dirhenium Halide Clusters: A Density Functional Theory Study.

Dirhenium halide dianions received considerable attention in past decades due to the unusual metal-metal quadruple bond. The systematic structural evolution of dirhenium halide clusters has not been sufficiently studied and hence is not well-understood. In this work, we report an in-depth investigation on the structures and electronic properties of doubly charged dirhenium halide clusters Re2X82- (X = F, Cl, Br, I). Our computational efforts rely on the well-tested unbiased CALYPSO (Crystal structure AnaLYsis by Particle Swarm Optimization) method combined with density functional theory calculations. We find that all ground-state Re2X82- clusters have cube-like structures of D4h symmetry with two Re atoms encapsulated in halogen framework. The reasonable agreement between the simulated and experimental photoelectron spectrum of the Re2Cl82- cluster supports strongly the reliability of our computational strategy. The chemical bonding analysis reveals that the δ bond is the pivotal factor for the ground-state Re2X82- (X = F, Cl, Br, I) clusters to maintain D4h symmetric cube-like structures, and the enhanced stability of Re2Cl82- is mainly attributed to the chemical bonding of 5d orbital of Re atoms and 3p orbital of Cl atoms.

Structural Stability and Evolution of Medium-Sized Tantalum-Doped Boron Clusters: A Half-Sandwich-Structured TaB12- Cluster.

Transition-metal (TM)-doped boron clusters have received considerable attention in recent years, in part, because of their remarkable size-dependent structural and electronic properties. However, the structures of medium-sized boron clusters doped with TM atoms are still not well-known because of the much increased complexity of the potential surface as well as the rapid increase in the number of low-energy isomers, which are the challenges in cluster structural searches. Here, by means of an unbiased structure search, we systematically investigated the structural evolution of medium-sized tantalum-doped boron clusters, TaBn0/- (n = 10-20). The results revealed that TaBn0/- (n = 10-15) clusters adopt half-sandwich molecular geometries, with the notable exception of TaB10-, while for n = 16-18 and 19-20, the lowest-energy clusters are characterized by drum-type geometries and tubular molecules with two B atoms on the top, respectively. Good agreement between the calculated and experimental photoelectron spectra strongly support the validity of our global minimum structures. Molecular orbital and adaptive natural density partitioning analyses indicate that the enhanced stability of half-sandwich TaB12- is due to the strong interaction of the Ta atom (5d orbitals) with surrounding B atoms (2p orbitals) and σ B-B bonds in the B12 moiety.

CD44, Sonic Hedgehog, and Gli1 Expression Are Prognostic Biomarkers in Gastric Cancer Patients after Radical Resection.

Aim. CD44 and Sonic Hedgehog (Shh) signaling are important for gastric cancer (GC). However, the clinical impact, survival, and recurrence outcome of CD44, Shh, and Gli1 expressions in GC patients following radical resection have not been elucidated. Patients and Methods. CD44, Shh, and Gli1 protein levels were quantified by immunohistochemistry (IHC). The association between CD44, Shh, and Gli1 expression and clinicopathological features or prognosis of GC patients was determined. The biomarker risk score was calculated by the IHC staining score of CD44, Shh, and Gli1 protein. Results. The IHC positive staining of CD44, Shh, and Gli1 proteins was correlated with larger tumour size, worse gross type and histological type, and advanced TNM stage, which also predicted shorter overall survival (OS) and disease-free survival (DFS) after radical resection. Multivariate analysis indicated the Gli1 protein and Gli1, CD44 proteins were predictive biomarkers for OS and DFS, respectively. If biomarker risk score was taken into analysis, it was the independent prognostic factor for OS and DFS. Conclusions. CD44 and Shh signaling are important biomarkers for tumour aggressiveness, survival, and recurrence in GC.

Gastric Mucinous Cancer Histology: Clinicopathological Characteristics and Prognostic Value.

MC tended toward worse tumor biological behavior and long-term survival outcome compared to WMDC. Moreover, MC also showed worse clinicopathological features and survival outcome in some selected patients. For these reasons, MC should be deemed as a special histological type of gastric cancer with worse clinicopathological features and survival outcome.

Prognostic value of three different lymph node staging systems in the survival of patients with gastric cancer following D2 lymphadenectomy.

The log odds of positive lymph nodes (LODDS) was defined as the log of the ratio between the number of positive lymph nodes and the number of negative lymph nodes, which is a novel and promising nodal staging system for gastric cancer. Here, we aimed to compare the prognostic effect of pN, lymph node ratio (LNR) and LODDS. The association between overall survival and pN, LNR and LODDS was retrospectively analysed. The discriminatory ability and monotonicity of gradients (linear trend χ (2) score), homogeneity ability (likelihood ratio test) and prognostic stratification ability (Akaike information criterion [AIC] and receiver operating characteristic [ROC] curve) were compared among three lymph node staging systems. The pN, LNR and LODDS were all identified as independent prognostic factors for gastric cancer patients in the multivariate analysis. LODDS showed the best prognostic performance (linear trend χ (2) score 266.743, likelihood ratio χ (2) test score 427.771, AIC value 5670.226, area under the curve (AUC) 0.793), followed by LNR and pN. In patients with different levels of retrieved lymph nodes (≤10, 11-14, 15-25 and >25), LODDS was the most powerful for prognostic prediction and discrimination of the heterogeneity among the subgroups. Significant differences in survival were observed among patients in different LODDS subgroups after being classified according to the pN and LNR classifications. LODDS appears to be a more powerful system for predicting the overall survival of gastric cancer patients, as compared to LNR and pN, and may serve as an alternative nodal staging system for gastric cancer.

Endoplasmic reticulum stress is involved in the connection between inflammation and autophagy in type 2 diabetes.

Type 2 diabetes is a chronic inflammatory disease. A number of studies have clearly demonstrated that cytokines such as interleukin 1ß (IL1ß) contribute to pancreatic inflammation, leading to impaired glucose homeostasis and diabetic disease. There are findings which suggest that islet ß-cells can secrete cytokines and cause inflammatory responses. In this process, thioredoxin-interacting protein (TXNIP) is induced by endoplasmic reticulum (ER) stress, which further demonstrates a potential role for ER stress in innate immunity via activation of the NOD-like receptor (NLRP) 3/caspase1 inflammasome and in diabetes pathogenesis via the release of cytokines. Recent developments have also revealed a crucial role for the autophagy pathway during ER stress and inflammation. Autophagy is an intracellular catabolic system that not only plays a crucial role in maintaining the normal islet architecture and intracellular insulin content but also represents a form of programmed cell death. In this review, we focus on the roles of autophagy, inflammation, and ER stress in type 2 diabetes but, above all, on the connections among these factors.

Autophagy, a novel target for chemotherapeutic intervention of thyroid cancer.

PURPOSE: Thyroid cancers with unsatisfactory curative effect nowadays are the most common malignant tumors of the endocrine system. Apoptosis evasion, a hallmark of cancer, has driven the search of stimulating novel cell death way in cancer therapy. This review aims to explore the relationship between autophagy and thyroid cancer, especially the chemotherapy agents which are based on autophagy in treating thyroid cancers. METHODS: A computerized literature search of MEDLINE was performed using the following search terms: autophagy and thyroid cancer. RESULTS: Recent studies have found that several chemotherapeutic agents and knockdown of specific microRNA may contribute to autophagic tumor cell death in most thyroid cancer types. CONCLUSIONS: Stimulating autophagy may be an effective alternative treatment to most types of thyroid cancer.

Decolorization of anthraquinone dye Reactive Blue 19 by the combination of persulfate and zero-valent iron.

Decolorization of anthraquinone dye Reactive Blue 19 (RB19) with sulfate radicals generated in situ from persulfate and zero-valent iron (ZVI) was investigated. The effects of initial solution pH, initial concentration of RB19, ZVI and persulfate, reaction temperature and common dissolved anions were studied. 100% color removal efficiency and 54% TOC removal efficiency were achieved in 45 min with an initial RB19 concentration of 0.1 mM under typical conditions (pH 7.0, 0.8 g L(-1) ZVI, 10 mM persulfate and 30 C). The decolorization efficiency of RB19 increased with higher iron dosage, higher initial persulfate concentration, and higher reaction temperature. It is also an acid driven process. The decolorization process followed pseudo-first order kinetics and the activation energy was 98.1 kJ mol-1. RB19 decolorization was inhibited by common dissolved anions such as CL-, NO3-, H2PO4- and HCO3- since they reacted with sulfate radicals that retarded the oxidation process. The experiment demonstrated that the combination of persulfate and ZVI was a promising technology for the decolorization of dye wastewater.

Effective degradation of para-chloronitrobenzene through a sequential treatment using zero-valent iron reduction and Fenton oxidation.

In this study, zero-valent iron (ZVI) was used to pretreat para-chloronitrobenzene (p-CNB), and the major product was para-chloroaniline (p-CAN). By adding H(2)O(2) directly, further p-CAN degradation can be attributed to Fenton oxidation because ferrous ions (Fe(2+)) released during the ZVI corrosion could be used as an activator for H(2)O(2) decomposition. In the reduction process, the reduction efficiency of p-CNB as well as Fe(2+) concentration increased with increasing iron dosage and decreasing solution pH. Under the optimal conditions, 25 mg L(-1) of p-CNB could be transformed in 3 h when initial solution pH was 3.0 and ZVI dosage was 2.0 g L(-1). A sufficient amount of Fe(2+) (50.4 mg L(-1)) was obtained after the above reaction to activate H(2)O(2). In the Fenton process, the oxidization of p-CAN was also more effective in acidic conditions and it increased with increasing H(2)O(2) concentration. The control experiments showed that the sequential treatment was more effective than Fenton oxidation alone in treating p-CNB wastewater since the removal rate of total organic carbon (TOC) was improved by about 34%. It suggested that the amino function group is more susceptible to oxidative radical attack than the nitro function group. Therefore, sequential treatment using zero-valent iron reduction followed by Fenton oxidation is a promising method for p-CNB degradation.