Hydrogel-Integrated Multimodal Response as a Wearable and Implantable Bidirectional Interface for Biosensor and Therapeutic Electrostimulation.

A hydrogel that fuses long-term biologic integration, multimodal responsiveness, and therapeutic functions has received increasing interest as a wearable and implantable sensor but still faces great challenges as an all-in-one sensor by itself. Multiple bonding with stimuli response in a biocompatible hydrogel lights up the field of soft hydrogel interfaces suitable for both wearable and implantable applications. Given that, we proposed a strategy of combining chemical cross-linking and stimuli-responsive physical interactions to construct a biocompatible multifunctional hydrogel. In this hydrogel system, ureidopyrimidinone/tyramine (Upy/Tyr) difunctionalization of gelatin provides abundant dynamic physical interactions and stable covalent cross-linking; meanwhile, Tyr-doped poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) acts as a conductive filler to establish electrical percolation networks through enzymatic chemical cross-linking. Thus, the hydrogel is characterized with improved conductivity, conformal biointegration features (i.e., high stretchability, rapid self-healing, and excellent tissue adhesion), and multistimuli-responsive conductivity (i.e., temperature and urea). On the basis of these excellent performances, the prepared multifunctional hydrogel enables multimodal wearable sensing integration that can simultaneously track both physicochemical and electrophysiological attributes (i.e., motion, temperature, and urea), providing a more comprehensive monitoring of human health than current wearable monitors. In addition, the electroactive hydrogel here can serve as a bidirectional neural interface for both neural recording and therapeutic electrostimulation, bringing more opportunities for nonsurgical diagnosis and treatment of diseases.

Combination therapy with B7H3-redirected bispecific antibody and Sorafenib elicits enhanced synergistic antitumor efficacy.

Rationale: Current traditional treatment options are frequently ineffective to fight against ovarian cancer due to late diagnosis and high recurrence. Therefore, there is a vital need for the development of novel therapeutic agents. B7H3, an immune checkpoint protein, is highly expressed in various cancers, representing it a promising target for cancer immunotherapy. Although targeting B7H3 by bispecific T cell-engaging antibodies (BiTE) has achieved successes in hematological malignancies during recent years, attempts to use them for the treatment of solid cancers are less favorable, in part due to the heterogeneity of tumors. Sorafenib is an unselective inhibitor of multiple kinases currently being tested in clinical trials for several tumors, including ovarian cancer which showed limited activity and inevitable side effect for ovarian cancer treatment. However, it is able to enhance antitumor immune response, which indicates sorafenib may improve the efficiency of immunotherapy. Methods: We evaluated the expression of B7H3 in ovarian cancer using online database and validated its expression of tumor tissues by immunohistochemistry staining. Then, B7H3 expression and the effects of sorafenib on ovarian cancer cell lines were determined by flow cytometry. In addition, 2D and 3D ovarian cancer models were established to test the combined therapeutic effect in vitro. Finally, the efficiency of B7H3×CD3 BiTE alone and its combination with sorafenib were evaluated both in vitro and in vivo. Results: Our data showed that B7H3 was highly expressed in ovarian cancer compared with normal samples. Treatment with sorafenib inhibited ovarian cancer cell proliferation and induced a noticeable upregulation of B7H3 expression level. Further study suggested that B7H3×CD3 BiTE was effective in mediating T cell killing to cancer cells. Combined treatment of sorafenib and B7H3×CD3 BiTE had synergistic anti-tumor effects in ovarian cancer models. Conclusions: Overall, our study indicates that combination therapy with sorafenib and B7H3×CD3 BiTE may be a new therapeutic option for the further study of preclinical treatment of OC.

Effect of levothyroxine on pregnancy outcomes in women with thyroid autoimmunity: a systematic review with meta-analysis of randomized controlled trials.

OBJECTIVE: To investigate whether levothyroxine is associated with improved live birth and other benefits in women with thyroid autoimmunity. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Women positive for thyroid peroxidase antibody. INTERVENTION(S): MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched without any language restrictions. Pooled effect sizes were calculated using random-effects models. MAIN OUTCOME MEASURE(S): The primary outcome was the incidence of live birth, miscarriage, preterm birth, clinical pregnancy, ectopic pregnancy, neonatal admission, and birth weight. The summary measures were reported as relative risk (RR) with 95% confidence interval. RESULT(S): Levothyroxine supplementation was not associated with an increased rate of live birth or a decreased risk of miscarriage. Results were similar in subgroup analyses of live birth by age, baseline thyrotropin, baseline thyroid peroxidase antibody, body mass index, and use of assisted conception. For live birth, the effect estimate lay within the futility boundary for RR of 20% and 15%, but at a 10% RR, the effect estimate lay between the futility boundary and the inferior boundary. CONCLUSION(S): High- to moderate-quality evidence demonstrated that the use of levothyroxine was not associated with improvements in clinical pregnancy outcomes among women positive for thyroid peroxidase antibody. REGISTRATION NUMBER: PROSPERO CRD42019132976.

Identification and Comparison of Tannins in Gall of Rhus chinensis Mill. and Gall of Quercus infectoria Oliv. by High-Performance Liquid Chromatography-Electrospray Mass Spectrometry.

Gall of Rhus chinensis Mill. (Chinese galls) and gall of Quercus infectoria Oliv. (Turkish galls) have similar applications and chemical compositions, and their extracts have been widely used for industrial production and for medicinal applications. In this study, high-performance liquid chromatography-electrospray mass spectrometry (HPLC-ESI-MS/MS) methods were established for profiling the components of Chinese galls and Turkish galls. Compounds representing 96.56 and 99.15% of the total peak area of Chinese galls and Turkish galls were identified. The results identified that the ellagic acid, galloyl-HHDP-glucose and pedunculagin act as the identifying markers for the comparison of Chinese galls and Turkish galls in HPLC-ESI-MS/MS. The peak area of tetragalloyl-glucoside, heptagalloyl-glucoside and pentagalloyl-glucoside can be used to distinguish these two phytomedicines. This work provides a reference for the study of the chemical composition of Chinese galls and Turkish galls, which not only introduce a simple and reliable method to prevent the adulteration or misuse of Chinese galls and Turkish galls but also lay the foundations for clarifying the material basis of their similar pharmacological action.

Hollow Microcapsules with Ulcerative Colitis Therapeutic Effects Made of Multifunctional Turkish Galls Extraction.

Ulcerative colitis (UC) has been listed as one of the refractory diseases of modern society by the World Health Organization. Our previous studies found that Turkish galls Gallotannins (TGTs) have a significant effect on anti-UC. Here, TGTs were extracted using a simple method and TGTs-FeIII microcapsules were prepared by a self-assembly technique. Microcapsules were characterized by liquid chromatography-mass spectrometry, scanning electron microscopy, and so forth. The results verified that hollow spheres of TGTs-FeIII microcapsules were successfully prepared. It is interesting that microcapsules were more likely to accumulate on the inflammatory surface from ex vivo and in vivo adhesion experiments, and effectively alleviate UC symptoms. This study will provide valuable insight into the development of safe and efficient drug delivery system platforms for further biomedical usages.

Three types of gut bacteria collaborating to improve Kui Jie'an enema treat DSS-induced colitis in mice.

A rising amount of evidences show that gut microbiota is an important factor in mediating the growth of ulcerative colitis (UC), the major product of colon bacteria fermentation butyrate as mediator have effects on the mucosal immune system by expanding regulatory T cells (Treg) in the colon. Turkish galls, an insect gall parasitized on the tree branches of Quercus infectoria Oliv., exhibiting the promising prospect in treating the remedy of UC by regulating the bacteria, whereas its mechanism remains unclear. Here, this work found that three types of gut bacteria collaborating to improve DSS-induced UC in mice after Turkish galls intervention, including putative SCFAs-producing bacteria (PCPB), anti-inflammatory bacteria and harmful bacteria. The Helicobacter, Bilophila, Acinetobacter and Odoribacter, which belong to the harmful bacteria were dramatically increased in UC group, whereas the harmful bacteria were reduced after treatment with Turkish galls. The Allobaculum, Bacteriodes, Blautia, Butyricimonas, belonging to PCPB, were significantly increased after Turkish galls and butyrate intervention, and we also observed that the concentration of butyrate increased with the grows of PCPB. The Bifidobacterium, Lactococcus, which belong to the anti-inflammatory bacteria, were also significantly increased after Turkish galls intervention. Meanwhile, rectal administration of Turkish galls and butyrate could increase mucosa inflammation and diarrhea. The expression of cytokines in the colon was improved by butyrate and Turkish galls treatment group. The percentage of Treg out of CD4+ population was evaluated by flow cytometry after Turkish galls and butyrate intervention. The results suggested that Turkish galls alleviated UC by modulating three types of the gut microbiota, and butyrate may be used to relieve inflammatory. This study may help us to understand the mechanism of Turkish galls in treating UC from the perspective of intestinal flora and also offered a mechanism reference for UC treatment using an insect gall in rich of polyphenolic compounds.

Screening for active constituents in Turkish galls against ulcerative colitis by mass spectrometry guided preparative chromatography strategy: in silico, in vitro and in vivo study.

Turkish galls have been reported to exhibit remedial effects in ulcerative colitis (UC). However, the active constituents of Turkish galls for the treatment of UC remain unclear. The objective of this study was to screen for anti-inflammatory active constituents and clarify their associated molecular mechanisms. Therefore, systems pharmacology was developed to predict the relationship between constituents and the corresponding targets as well as pathways. In addition, mass spectrometry-guided preparative chromatography technique was used for preparing constituents to evaluate the anti-inflammatory activities and the therapeutic efficacy against UC. In silico, active constituents exhibited a remedial effect on UC possibly by regulating multiple pathways and attacking multiple targets, of which those involved mainly in the NF-κB pathway were selected for verification. In vitro, 5 categories of constituents were screened as active constituents by comparing the cytotoxicity and detecting the level of the pro-inflammatory factors of 9 category constituents. In vivo, dextran sulfate sodium (DSS)-induced UC was significantly ameliorated in active constituents-fed mice. The results indicated that the active fraction comprising methyl gallate, digallic acid, di-O-galloyl-ß-d-glucose, and tri-O-galloyl-ß-d-glucose primarily contributed to the treatment of UC. Moreover, active fraction could also inhibit the phosphorylation level of IKKß, thus inhibiting the downstream NF-κB signaling pathway. The approach developed in this study not only clarifies the anti-inflammation effect of Turkish galls but also provides a beneficial reference for the discovery of the base material and functional mechanism of this herbal medicine.

Uric Acid Produces an Inflammatory Response through Activation of NF-κB in the Hypothalamus: Implications for the Pathogenesis of Metabolic Disorders.

Epidemiological studies have shown that an elevated uric acid (UA) level predicts the development of metabolic syndrome and diabetes; however, there is no direct evidence of this, and the underlying mechanism remains unclear. Here, we showed that a high-UA diet triggered the expression of pro-inflammatory cytokines, activated the NF-κB pathway, and increased gliosis in the hypothalamus. Intracerebroventricular injection of UA induced hypothalamic inflammation and reactive gliosis, whereas these effects were markedly ameliorated by the inhibition of NF-κB. Moreover, magnetic resonance imaging confirmed that hyperuricemia in rodents and humans was associated with gliosis in the mediobasal hypothalamus. Importantly, the rats administered UA exhibited dyslipidemia and glucose intolerance, which were probably mediated by hypothalamic inflammation and hypothalamic neuroendocrine alterations. These results suggest that UA can cause hypothalamic inflammation via NF-κB signaling. Our findings provide a potential therapeutic strategy for UA-induced metabolic disorders.

Gamma knife surgery for pineal region tumors: an alternative strategy for negative pathology / Cirurgia com gamma knife como tratamento experimental para tumores da região da pineal: uma estratégia alternativa quando os dados anatomopatológicos são negativos

Objective : Pineal region tumors (PRTs) are uncommon, and treatments vary among neoplasm types. The authors report their experience with gamma knife surgery (GKS) as an initial treatment in a series of PRT patients with unclear pathological diagnoses. Method : Seventeen PRT patients with negative pathology who underwent GKS were retrospectively studied. Nine patients had further whole-brain and spinal cord radiotherapy and chemotherapy 6–9 months after GKS. Results : Sixteen of 17 cases were followed up over a mean of 33.3 months. The total response rate was 75%, and the control rate was 81.3%. No obvious neurological deficits or complications were attributable to GKS. Conclusion : The findings indicate that GKS may be an alternative strategy in selected PRT patients who have negative pathological diagnoses, and that good outcomes and quality of life can be obtained with few complications. .

Tumores da região da pineal (TRP) são pouco frequentes e as propostas de tratamento são bastante variadas. Os autores relatam sua experiência em cirurgias com uso gamma knife (CGK) como tratamento experimental inicial em séries de TRP que não têm diagnóstico anatomopatológico ou nos quais o diagnóstico não ficou claro. Foram estudados retrospectivamente 17 pacientes com TRP nestas condições e que foram submetidos a CGK. Destes, 9 pacientes foram submetidos posteriormente a radioterapia de todo o encéfalo e medula espinhal entre 6 e 9 meses depois da CGK. Dezesseis dos 17 pacientes foram acompanhados por um período médio de 33,3 meses. A taxa total de resposta nos pacientes foi de 75% e a taxa dos controles, 81,3%. Não houve nenhum déficit neurológico evidente que pudesse ser atribuído à CGK. A CGK como tratamento experimental pode ser uma estratégia alternativa no grupo específico de pacientes com TRP em que não há diagnóstico anatomopatológico, podendo ser obtida uma boa qualidade de vida com poucas complicações para esse grupo de pacientes.

All-trans retinoic acid inhibits craniopharyngioma cell growth: study on an explant cell model.

The ratio between FABP5 and CRABPII determines cellular response to physiological level of retinoic acid; tumor cells undergo proliferation with high level of FABP5 and apoptosis with high level of CRABPII. We intended to study FABP5 and CRABPII expression in craniopharyngiomas, to establish craniopharyngioma cell model using explants method, and to study the effect of pharmacological dose of retinoic acid on craniopharyngioma cells. Expression of FABP5 and CRABPII in craniopharyngioma tissue from 20 patients was studied using immunohistochemistry. Primary craniopharyngioma cell cultures were established using tissue explants method. Craniopharyngioma cells were treated using various concentrations of all-trans retinoic acid, and cell growth curve, apoptosis, expression of FABP5, CRABPII and NF-κB were assayed in different groups. FABP5/CRABPII ratio was significantly higher in adamatinomatous group than that in papillary group. Cell cultures were established in 19 cases (95 %). Pharmacological level retinoic acid inhibited cell growth and induced cellular apoptosis in dose dependent manner, and apoptosis rate cells treated with 30 µM retinoic acid for 24 h was 43 %. Also, retinoic acid increased CRABPII, and decreased FABP5 and NF-κB expression in craniopharyngioma cells. High FABP5/CRABPII ratio is observed in adamatinomatous craniopharyngioma. Retinoic acid at pharmacological level induced craniopharyngioma cell apoptosis via increasing FABP5/CRABPII ratio and inhibiting NF-κB signaling pathway. Our study demonstrated that all-trans retinoic acid might be a candidate for craniopharyngioma adjuvant chemotherapy in future.