Integrative bioinformatics approach yields a novel gene expression risk model for prognosis and progression prediction in prostate cancer.

Prostate cancer (PCa), a prevalent malignancy among elderly males, exhibits a notable rate of advancement, even when subjected to conventional androgen deprivation therapy or chemotherapy. An effective progression prediction model would prove invaluable in identifying patients with a higher progression risk. Using bioinformatics strategies, we integrated diverse data sets of PCa to construct a novel risk model predicated on gene expression and progression-free survival (PFS). The accuracy of the model was assessed through validation using an independent data set. Eight genes were discerned as independent prognostic factors and included in the prediction model. Patients assigned to the high-risk cohort demonstrated a diminished PFS, and the areas under the curve of our model in the validation set for 1-year, 3-year, and 5-year PFS were 0.9325, 0.9041 and 0.9070, respectively. Additionally, through the application of single-cell RNA sequencing to two castration-related prostate cancer (CRPC) samples and two hormone-related prostate cancer (HSPC) samples, we discovered that luminal cells within CRPC exhibited an elevated risk score. Subsequent molecular biology experiments corroborated our findings, illustrating heightened SYK expression levels within tumour tissues and its contribution to cancer cell migration. We found that the knockdown of SYK could inhibit migration in PCa cells. Our progression-related risk model demonstrated the potential prognostic value of SYK and indicated its potential as a target for future diagnosis and treatment strategies in PCa management.

Clinical assessment of momelotinib drug-drug interactions via CYP3A metabolism and transporters.

Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), time to reach Cmax, and half-life. The increase in momelotinib (23% Cmax, 14% AUC) or M21 (30% Cmax, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% Cmax, 57% AUC) and minimal change in M21 was observed with single-dose rifampin. A moderate decrease in momelotinib (29% Cmax, 46% AUC) and increase in M21 (31% Cmax, 15% AUC) were observed with multiple-dose rifampin compared with single-dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple-dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (Cmax no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% Cmax, 16% AUC decreases) or 1'-hydroxymidazolam (14% Cmax, 16% AUC decreases) but increased rosuvastatin Cmax by 220% and AUC by 170%. Safety findings were mild in this short-term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.

Highly sensitive and simultaneous detection of ascorbic acid, dopamine, and uric acid using Pt@g-C3N4/N-CNTs nanocomposites.

The detection of ascorbic acid (AA), dopamine (DA), and uric acid (UA) is crucial for understanding and managing various illnesses. In this research, Pt@g-C3N4 nanoparticles were synthesized via hydrothermal method and combined with N-doped carbon nanotubes (N-CNTs). The Pt@g-C3N4/N-CNTs-modified glassy carbon (GC) electrode was fabricated as an electrochemical sensor for the determination of AA, DA, and UA. The linear response range of AA, DA, and UA in the optimal condition was 100-3,000 µM, 1-100 µM, and 2-215 µM boasting a low detection limit (S/N = 3) of 29.44 µM (AA), 0.21 µM (UA), and 2.99 µM (DA), respectively. Additionally, the recoveries of AA, DA, and UA in serum sample were 100.4%-106.7%. These results corroborate the feasibility of the proposed method for the simultaneous, sensitive, and reliable detection of AA, DA, and UA. Our Pt@g-C3N4/N-CNTs/GC electrode can provide a potential strategy for disease diagnosis and health monitoring in clinical settings.

Recombinant Human Collagen Type III Improves Hypertrophic Scarring by Regulating the Ratio of Type I/III Collagen.

Hypertrophic scar development is a complication associated with wound healing, impacting local appearance and function. The type I/III collagen ratio affects the extent of hypertrophic scarring; a reduced ratio can ameliorate this. In this study, recombinant human collagen type III was developed. Liquid chromatography-tandem mass spectrometry was used to determine its amino acid sequence and confirm its high level of homology with natural human type III collagen. Recombinant human collagen type III displayed no cytotoxicity and did not confer skin irritation and sensitization. Immunofluorescence and western blot analyses of histidine following incubation with fibroblasts suggested cell entry of recombinant human collagen type III. Furthermore, recombinant human collagen type III promoted the synthesis of the natural type III collagen in fibroblasts, resulting in a more obvious increase of type III collagen content in fibroblasts than that of type I collagen, and then decreased the ratio of type I/III collagen. The results of 5-ethynyl-2'-deoxyuridine staining assay suggested enhanced fibroblast proliferation. Following local injection of recombinant human collagen type III, rabbit ear scarring was significantly reduced after 60 days. Vancouver Scar Scale evaluation showed that all index scores were significantly reduced. Western blotting and Picro-Sirius red staining showed that the natural type III collagen increase in scar tissue was greater than that of type I collagen, decreasing the type I/III ratio. In summary, recombinant human collagen type III can be taken up by fibroblasts and promote natural collagen synthesis-especially that of type III-thereby reducing the type I/III ratio and improving hypertrophic scarring.

Bidirectional relationship between late-onset epilepsy (LOE) and dementia: A systematic review and meta-analysis of cohort studies.

OBJECTIVE: To explore the bidirectional relationship of late-onset epilepsy (LOE) with dementia and Alzheimer's disease (AD). METHODS: Using the common electronic databases, including PubMed, Cochrane Library databases and EMBASE, we systematically reviewed published cohort studies that assessed the risk of LOE in individuals comorbid with dementia or AD, and those with dementia or AD comorbid with LOE that had been published up to 31 March 2023. The data extraction process was carried out independently by two authors. The summary adjusted relative ratio (aRR) was calculated by employing Rev Man 5.3 for the inclusion of studies. To investigate the origins of heterogeneity, we conducted both subgroup and sensitivity analyses. In the presence of heterogeneity, a random-effects model was employed. To evaluate potential publication bias, we utilized the funnel plot and conducted Begg's and Egger's tests. RESULTS: We included 20 eligible studies in the final analysis after a rigorous screening process. Pooled results indicated that LOE was association with an increased risk of all-cause dementia (aRR: 1.34, 95% confidence interval [CI]: 1.13-1.59) and AD (aRR: 2.49, 95% CI: 1.16-5.32). In addition, the pooled effect size for LOE associated with baseline AD and all-cause dementia were 3.51 (95% CI: 3.47-3.56) and 2.53 (95% CI: 2.39-2.67), respectively. Both sensitivity and subgroup analyses showed that these positive correlations persisted. According to the results of the Egger's and Begg's tests, as well as visual inspection of funnel plots, none of the studies appeared to be biased by publication. CONCLUSION: The findings suggested that LOE is a potential risk factor for dementia and AD, and vice versa, dementia and AD are both potential risk indicators for LOE. Since there is substantial heterogeneity among the cohorts analyzed and more cohort studies should be conducted to confirm the correlations found in the current study.

TCP transcription factor StAST1 represses potato tuberization by regulating tuberigen complex activity.

Potato (Solanum tuberosum L.) is cultivated worldwide for its underground tubers, which provide an important part of human nutrition and serve as a model system for belowground storage organ formation. Similar to flowering, stolon-expressed FLOWERING LOCUS T-like (FT-like) protein SELF-PRUNING 6A (StSP6A) plays an instrumental role in tuberization by binding to the bZIP transcription factors StABI5-like 1 (StABL1) and StFD-like 1 (StFDL1), causing transcriptional reprogramming at the stolon subapical apices. However, the molecular mechanism regulating the widely conserved FT-bZIP interactions remains largely unexplored. Here, we identified a TCP transcription factor StAST1 (StABL1 and StSP6A-associated TCP protein 1) binding to both StSP6A and StABL1. StAST1 is specifically expressed in the vascular tissue of leaves and developing stolons. Silencing of StAST1 leads to accelerated tuberization and a shortened life cycle. Molecular dissection reveals that the interaction of StAST1 with StSP6A and StABL1 attenuates the formation of the alternative tuberigen activation complex (aTAC). We also observed StAST1 directly activates the expression of potato GA 20-oxidase gene (StGA20ox1) to regulate GA responses. These results demonstrate StAST1 functions as a tuberization repressor by regulating plant hormone levels; our findings also suggest a mechanism by which the widely conserved FT-FD genetic module is fine-tuned.

Mitochondrial-Targeting Nanotrapper Captured Copper Ions to Alleviate Tumor Hypoxia for Amplified Photoimmunotherapy in Breast Cancer.

Hypoxia is a pervasive feature of solid tumors, which significantly limits the therapeutic effect of photodynamic therapy (PDT) and further influences the immunotherapy efficiency in breast cancer. However, the transient alleviation of tumor hypoxia fails to address the underlying issue of increased oxygen consumption, resulting from the rapid proliferation of tumor cells. At present, studies have found that the reduction of the oxygen consumption rate (OCR) by cytochrome C oxidase (COX) inhibition that induced oxidative phosphorylation (OXHPOS) suppression was able to solve the proposed problem. Herein, we developed a specific mitochondrial-targeting nanotrapper (I@MSN-Im-PEG), which exhibited good copper chelating ability to inhibit COX for reducing the OCR. The results proved that the nanotrapper significantly alleviated the hypoxic tumor microenvironment by copper chelation in mitochondria and enhanced the PDT effect in vitro and in vivo. Meanwhile, the nanotrapper improved photoimmunotherapy through both enhancing PDT-induced immunogenetic cell death (ICD) effects and reversing Treg-mediated immune suppression on 4T1 tumor-bearing mice. The mitochondrial-targeting nanotrapper provided a novel and efficacious strategy to enhance the PDT effect and amplify photoimmunotherapy in breast cancer.

Lycium barbarian seed oil activates Nrf2/ARE pathway to reduce oxidative damage in testis of subacute aging rats / 中国药理学通报

Aim To explore the effects of Lycium berry seed oil on Nrf2/ARE pathway and oxidative damage in testis of subacute aging rats. Methods Fifty out of 60 male SD rats, aged 8 weeks, were subcutaneously injected with 125 mg • kg"D-galactosidase in the neck for 8 weeks to establish a subacute senescent rat model. The presence of senescent cells was observed using P-galactosidase ((3-gal), while testicular morphology was examined using HE staining. Serum levels of testosterone (testosterone, T), follicle-stimulating hormone ( follicle stimulating hormone, FSH ) , luteinizing hormone ( luteinizing hormone, LH ) , superoxide dis-mutase ( superoxide dismutase, SOD ) , glutathione ( glutathione, GSH) and malondialdehyde ( malondial-dehyde, MDA) were measured through ELISA, and the expressions of factors related to aging, oxidative damage, and the Nrf2/ARE pathway were assessed via immunohistochemical analysis and Western blotting. Results After successfully identifying the model, the morphology of the testis was improved and the intervention of Lycium seed oil led to a down-regulation in the expression of [3-gal and -yH2AX. The serum levels of SOD, GSH, T, and FSH increased while MDA and LH decreased (P 0. 05) . Additionally, there was an up-regulated expression of Nrf2, GCLC, NQOl, and SOD2 proteins in testicular tissue ( P 0. 05 ) and nuclear expression of Nrf2 in sertoli cells. Conclusion Lycium barbarum seed oil may reduce oxidative damage in testes of subacute senescent rats by activating the Nrf2/ARE signaling pathway.

Effect of multi-target transcranial direct current stimulation on performance of working memory-postural control dual-task in healthy adults / 中国康复理论与实践

ObjectiveTo investigate the effect of multi-target transcranial direct current stimulation (tDCS) and single-target tDCS on the performance of working memory-postural control dual-task in healthy adults, and to compare the regulatory effect of the two stimulation protocols. MethodsFrom November, 2020 to February, 2021, 19 healthy adults in Shanghai University of Sport were recruited and randomly accepted multi-target tDCS, single-target tDCS and sham stimulation with at least one week interval between any two stimulation protocols. The target areas of multi-target tDCS included left dorsal lateral prefrontal cortex (L-DLPFC) and bilateral primary motor cortex (M1), and single-tDCS only applied to L-DLPFC. Before and after stimulation, participants completed walking and standing balance tests under single task and dual-task conditions with the second task being a N-back task. The dual-task postural control performance, dual-task cost (DTC) and working memory performance were observed before and after stimulation. ResultsSignificant differences were observed among three stimulation protocols in the changes of stride variability (F = 3.792, P = 0.029), DTC of stride variability (F = 3.412, P = 0.040) and velocity of center of pressure (Vcop) (F = 3.815, P = 0.029). The stride variability (P = 0.047) and Vcop (P = 0.015) were significantly lower and the decrease in DTC of stride variability tended to be significant (P = 0.073) following multi-target tDCS, as compared to sham stimulation. Single-target tDCS significantly decreased the changes of stride variability (P = 0.011), DTC of stride variability (P = 0.014) and Vcop (P = 0.025), as compared to sham stimulation. Compared with single target tDCS, multi-target tDCS reduced the changes of the dual-task cost of the area of center of pressure (P = 0.035). Moreover, no significant difference was observed among the three stimulation protocols in the changes of each measure in the working memory test (P > 0.05). ConclusionBoth multi-target tDCS and single-target tDCS can improve the performance of working memory-postural control dual-task in healthy adults, and compared with single-target tDCS, multi-target tDCS has some advantages in regulating postural control.

Erratum: Author correction to "Cascade two-stage tumor re-oxygenation and immune re-sensitization mediated by self-assembled albumin-sorafenib nanoparticles for enhanced photodynamic immunotherapy" Acta Pharm Sin B (2022) 4204-4223

[This corrects the article DOI: 10.1016/j.apsb.2022.07.023.].

Novel approach for enhancing skin allograft survival by bioadhesive nanoparticles loaded with rapamycin.

Skin graft rejection is a significant challenge in skin allografts for skin defects, particularly in extensive burn injury patients when autografts are insufficient. Enhancing the survival duration of allogeneic skin grafts can improve the success rate of subsequent autologous skin grafting, thereby promoting the therapeutic efficacy for wound healing. Rapamycin (Rapa), a potent immunosuppressant with favorable efficacy in organ transplantation, is limited by its systemic administration-associated toxicity and side effects. Therefore, addressing the short survival time of allogeneic skin grafts and minimizing the toxicity related to systemic application of immunosuppressive agents is an urgent requirement. Here, we present a topical formulation based on bioadhesive poly (lactic acid)-hyperbranched polyglycerol nanoparticles (BNPs) with surface-modified encapsulation of Rapamycin (Rapa/BNPs), applied for local immunosuppression in a murine model of allogeneic skin grafts. Our Rapa/BNPs significantly prolong nanoparticle retention, reduce infiltration of T lymphocytes and macrophages, decrease the level of pro-inflammatory cytokines and ultimately extend skin allograft survival with little systemic toxicity compared to free Rapa or Rapamycin-loaded non-bioadhesive nanoparticles (Rapa/NNPs) administration. In conclusion, Rapa/BNPs effectively deliver local immunosuppression and demonstrate potential for enhancing skin allograft survival while minimizing localized inflammation, thus potentially increasing patient survival rates for various types of skin defects.

Verteporfin-Loaded Bioadhesive Nanoparticles for the Prevention of Hypertrophic Scar.

Hypertrophic scarring (HS) is a common skin injury complication with unmet needs. Verteporfin (VP) should be an ideal HS-targeted therapeutic drug due to its efficient fibrosis and angiogenesis inhibitory abilities. However, its application is restricted by its side effects such as dose-dependent cytotoxicity on normal cells. Herein, the bioadhesive nanoparticles encapsulated VP (VP/BNPs) are successfully developed to attenuate the side effects of VP and enhance its HS inhibition effects by limiting VP releasing slowly and stably in the lesion site but not diffusing easily to normal tissues. VP/BNPs displayed significant inhibition on the proliferation, migration, collagen deposition, and vessel formation of human hypertrophic scar fibroblasts (HSFBs) and dermal vascular endothelial cells (HDVECs). In a rat tail HS model, VP/BNPs treated HS exhibits dramatic scar repression with almost no side effects compared with free VP or VP-loaded non-bioadhesive nanoparticles (VP/NNPs) administration. Further immunofluorescence analysis on scar tissue serial sections validated VP/BNPs effectively inhibited the collagen deposition and angiogenesis by firmly confined in the scar tissue and persistently releasing VP targeted to nucleus Yes-associated protein (nYAP) of HSFBs and HDVECs. These findings collectively suggest that VP/BNPs can be a promising and technically advantageous agent for HS therapies.

Photocurable injectable Janus hydrogel with minimally invasive delivery for all-in-one treatment of gastric perforations and postoperative adhesions.

Background: Surgical sutures for sealing gastric perforations (GP) are associated with severe inflammation and postoperative adhesions. Hydrogel bioadhesives offer a potential alternative for sutureless repair of GP; however, their application in minimally invasive surgery is limited due to their prefabricated patch-form, lacking in situ gelation capability. In this study, we emphasized an all-in-one minimally invasive strategy for sutureless repair of acute GP. Methods: an injectable photocurable Janus hydrogel was synthesized, and their ability to seal GP was performed. A rat GP model was used to verify the wound healing and antiadhesion efficiency of hydrogels, and a rabbit GP model was used to verify their laparoscopic feasibility. A fresh human corpse GP model was further employed to verify the user-friendliness of a minimally invasive deliverable (MID) device. A minipig GP model was utilized to evaluate the all-in-one minimally invasive strategy for the treatment of acute GP. Results: Such injectable Janus hydrogel exhibited asymmetric adhesiveness, where the inner-facing side of the hydrogel displays strong sealing and wound healing abilities for GP, while the outward-facing side prevents postoperative adhesion formation. We further developed a minimally invasive deliverable (MID) device integrating hydrogel-delivery parts and photocrosslinking-gelation parts in a laparoscope system. The precise delivery and rapid fluid-tight sealing process of the injectable Janus hydrogel using the MID device for in situ GP repair were demonstrated in a simulated clinical scenario. The in vivo effectiveness of GP sutureless repair was successfully validated in porcine models, with further exploration of the underlying mechanism. Conclusions: Our findings reveal that the injectable Janus hydrogel offers an all-in-one strategy for sutureless GP repair and concurrent prevention of postoperative adhesion formation by incorporating the MID device in minimally invasive surgery, presenting the significant potential to reduce patient surgical complications.

The changes and causes of asthenopia after ICL implantation.

OBJECTIVE: To detect the presence of asthenopia after implantation of Implantable Collamer Lens (ICL). METHOD: Design: prospective observational case series. Patients with myopia and/or astigmatism who underwent ICL surgeries and completed 3-month follow-up were enrolled. Asthenopia scores, amplitude of accommodation (AA), positive/negative relative accommodation (PRA/NRA), accommodative facility (AF), the ratio of accommodative convergence and accommodation (AC/A), Schirmer test, noninvasive breakup time (NBUT), and HOA were examined before surgeries and at 1 week, 1 month and 3 months postoperatively then statistically analyzed. RESULTS: Symptoms of asthenopia were significantly decreased at 1 week after ICL surgeries than those before surgeries, but increased gradually as time went by, eventually recovered at 3 months postoperatively. AA, AF, AC/A decreased 1 week postoperatively, returned to the baseline at 1 month and were improved at 3 months after surgeries. NBUT at 1 week, 1 month and 3 months after surgeries were significantly decreased and was the lowest at 1 week postoperatively. PRA, NRA, Schiermer values and HOA had no significant change. Correlation analysis showed that the lower AF and NBUT after ICL surgeries, the more severe the asthenopia symptoms. CONCLUSION: The symptoms of asthenopia aggravated transiently after ICL implantation surgeries, but improved gradually with time. AF and NBUT were important factors affecting the changes of asthenopia.

Research on the design of somatosensory interactive games for autistic children based on art therapy.

There is no targeted drug treatment for autistic children. Educational intervention and rehabilitation are the main ways to improve the ability development of autistic children. However, there are great differences in the individual symptoms and abilities. It is an urgent need for educators, practitioners and parents of autistic children to find effective ways to improve their cognitive, social and motor abilities. The author cooperates with the therapist to study and design the somatosensory interaction game for autistic children, which is a formal attempt of art therapy on the treatment tool, with the purpose of studying an effective and safe art intervention method. In order to verify the effect, the author recruited 26 children with mild or moderate autism for a six-week empirical evaluation, and the participants were randomly assigned. Among them, 13 participants participated in the art therapy of the proposed somatosensory game group (the experimental group), and 13 participants participated the traditional picture book group (the control group) that improved the emotion, cognition and skills of children, and the design style was more popular with children. The aesthetic design in the picture book could have an intervention effect on the participants, and its artistic effect could serve as an effective reference for the interface design of the game group. The results showed that the two groups had a significant impact on the participants in different aspects. The game group improved not only in terms of concentration and special ability, but also in terms of physical coordination and activity enhancement, it is inferred that the core factors of game therapy are sub-intervention, interaction and feedback, icon design and color matching system; the picture book group has significant improvement in interpersonal relationship guidance and language learning and communication. The results show that it is necessary to take more comprehensive and richer preliminary research on the development of treatment products for autistic children. Because picture book education requires children's initial concentration, it is found that picture book therapy has high requirements for teachers' classroom control and relatively strict requirements for picture book content, and play therapy can be a good complement to these problems.

Potato tonoplast sugar transporter 1 controls tuber sugar accumulation during postharvest cold storage.

Cold-induced sweetening (CIS), the undesirable sugar accumulation in cold-stored potato (Solanum tuberosum L.) tubers, is a severe postharvest issue in the potato processing industry. Although the process of sucrose hydrolysis by vacuolar invertase during potato CIS is well understood, there is limited knowledge about the transportation of sucrose from the cytosol to the vacuole during postharvest cold storage. Here, we report that among the three potato tonoplast sugar transporters (TSTs), StTST1 exhibits the highest expression in tubers during postharvest cold storage. Subcellular localization analysis demonstrates that StTST1 is a tonoplast-localized protein. StTST1 knockdown decreases reducing sugar accumulation in tubers during low-temperature storage. Compared to wild-type, potato chips produced from StTST1-silenced tubers displayed significantly lower acrylamide levels and lighter color after cold storage. Transcriptome analysis manifests that suppression of StTST1 promotes starch synthesis and inhibits starch degradation in cold-stored tubers. We further establish that the increased sucrose content in the StTST1-silenced tubers might cause a decrease in the ABA content, thereby inhibiting the ABA-signaling pathway. We demonstrate that the down-regulation of ß-amylase StBAM1 in StTST1-silenced tubers might be directly controlled by ABA-responsive element-binding proteins (AREBs). Altogether, we have shown that StTST1 plays a critical role in sugar accumulation and starch metabolism regulation during postharvest cold storage. Thus, our findings provide a new strategy to improve the frying quality of cold-stored tubers and reduce the acrylamide content in potato chips.

Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1.

Gastric cancer stem cells (GCSCs) are self-renewing tumor cells that govern chemoresistance in gastric adenocarcinoma (GAC), whereas their regulatory mechanisms remain elusive. Here, the study aims to elucidate the role of ATOH1 in the maintenance of GCSCs. The preclinical model and GAC sample analysis indicate that ATOH1 deficiency is correlated with poor GAC prognosis and chemoresistance. ScRNA-seq reveals that ATOH1 is downregulated in the pit cells of GAC compared with those in paracarcinoma samples. Lineage tracing reveals that Atoh1 deletion strongly confers pit cell stemness. ATOH1 depletion significantly accelerates cancer stemness and chemoresistance in Tff1-CreERT2; Rosa26Tdtomato and Tff1-CreERT2; Apcfl/fl ; p53fl/fl (TcPP) mouse models and organoids. ATOH1 deficiency downregulates growth arrest-specific protein 1 (GAS1) by suppressing GAS1 promoter transcription. GAS1 forms a complex with RET, which inhibits Tyr1062 phosphorylation, and consequently activates the RET/AKT/mTOR signaling pathway by ATOH1 deficiency. Combining chemotherapy with drugs targeting AKT/mTOR signaling can overcome ATOH1 deficiency-induced chemoresistance. Moreover, it is confirmed that abnormal DNA hypermethylation induces ATOH1 deficiency. Taken together, the results demonstrate that ATOH1 loss promotes cancer stemness through the ATOH1/GAS1/RET/AKT/mTOR signaling pathway in GAC, thus providing a potential therapeutic strategy for AKT/mTOR inhibitors in GAC patients with ATOH1 deficiency.

Differential Immune-Modulating Activities of Cell Walls and Secreted Metabolites from Probiotic Bacillus coagulans JBI-YZ6.3 under Normal versus Inflamed Culture Conditions.

Spore-forming probiotic bacteria, including Bacillus coagulans, are resilient and produce a variety of beneficial metabolites. We evaluated the immune-modulating effects of the novel probiotic strain Bacillus coagulans JBI-YZ6.3, where the germinated spores, metabolite fraction, and cell wall fraction were tested in parallel using human peripheral blood mononuclear cell cultures under both normal and lipopolysaccharide-induced inflamed culture conditions. The expression of CD25 and CD69 activation markers was evaluated via flow cytometry. Supernatants were tested for cytokines, interferons, chemokines, and growth factors using Luminex arrays. The germinated spores were highly immunogenic; both the cell wall and metabolite fractions contributed significantly. Under normal culture conditions, increased levels of immune activation were observed as increased expressions of CD25 and CD69 relative to natural killer cells, suggesting an increased ability to attack virus-infected target cells. On monocytes, a complex effect was observed, where the expression of CD25 increased under normal conditions but decreased under inflamed conditions. This, in combination with increased interleukin-10 (IL-10) and decreased monocyte chemoattractant protein-1 (MCP-1) production under inflamed conditions, points to anti-inflammatory effects. The production of the stem cell-related growth factor granulocyte colony-stimulating Factor (G-CSF) was enhanced. Further research is warranted to characterize the composition of the postbiotic metabolite fraction and document the characteristics of immunomodulating agents secreted by this probiotic strain.

Rapid increase in immune surveillance and expression of NKT and γδT cell activation markers after consuming a nutraceutical supplement containing Aloe vera gel, extracts of Poria cocos and rosemary. A randomized placebo-controlled cross-over trial.

GOAL: To evaluate the acute impact of a nutraceutical blend on immune surveillance. STUDY DESIGN: A randomized, double-blind, placebo-controlled, cross-over trial was conducted in 11 healthy subjects. Blood samples were taken immediately before and at 1, 2, and 3 hours after consuming placebo or 500 mg of UP360, which is a blend of botanicals from Aloe vera, Poria cocos, and rosemary (APR extract). Immunophenotyping and flow cytometry quantified numbers of monocytes, NK cells, NKT cells, CD8+ cytotoxic T cells, γδT cells, and total T cells, and expression of CD25 and CD69 activation markers. Plasma was tested for cytokines, chemokines, growth factors, and enzymatic activity of superoxide dismutase and catalase. RESULTS: Compared to the placebo, consumption of APR extract triggered rapid increases in chemokine levels starting at 1 hour, including IP-10 (P<0.05) and MCP-1 (P<0.1), which peaked at 2 hours (P<0.01) and 3 hours (P<0.05), respectively. The stem cell-mobilizing growth factor G-CSF increased at 2 hours (P<0.05). Increased immune surveillance involved a transient effect for monocytes at 1 hour, followed by NKT cells, CD8+ cytotoxic T cells, and γδT cells at 2-3 hours. Increased immune cell alertness was seen at 1 hour by increased CD25 expression on monocytes (P<0.01), NKT cells (P<0.01), and T cells (P<0.05). NKT cells showed upregulation of CD69 at 2 hours (P<0.01). Increased enzymatic activity was seen at 2 hours for the antioxidant enzymes superoxide dismutase (P<0.05) and catalase (P<0.01). CONCLUSION: Consumption of APR extract triggered acute changes to chemokine levels. In addition, immune alertness was increased via the expression of activation markers on multiple types of innate immune cells, followed by increased immune surveillance and antioxidant protection. This suggests a beneficial enhancement of natural immune surveillance, likely via a combination of gut-mediated cytokine release and vagus nerve communication, in combination with cellular protection from oxidative stress.

[COL4A5 genotypes and clinical characteristics of children with Alport syndrome]. / 儿童Alport综合征COL4A5åŸºå› åž‹åŠä¸´åºŠç‰¹ç‚¹åˆ†æž.

OBJECTIVES: To investigate the genotypes of the pathogenic gene COL4A5 and the characteristics of clinical phenotypes in children with Alport syndrome (AS). METHODS: A retrospective analysis was performed for the genetic testing results and clinical data of 19 AS children with COL4A5 gene mutations. RESULTS: Among the 19 children with AS caused by COL4A5 gene mutations, 1 (5%) carried a new mutation of the COL4A5 gene, i.e., c.3372A>G(p.P1124=) and presented with AS coexisting with IgA vasculitis nephritis; 3 children (16%) had large fragment deletion of the COL4A5 gene, among whom 2 children (case 7 had a new mutation site of loss51-53) had gross hematuria and albuminuria at the onset, and 1 child (case 13 had a new mutation site of loss3-53) only had microscopic hematuria, while the other 15 children (79%) had common clinical phenotypes of AS, among whom 7 carried new mutations of the COL4A5 gene. Among all 19 children, 3 children (16%) who carried COL4A5 gene mutations also had COL4A4 gene mutations, and 1 child (5%) had COL4A3 gene mutations. Among these children with double gene mutations, 2 had gross hematuria and proteinuria at the onset. CONCLUSIONS: This study expands the genotype and phenotype spectrums of the pathogenic gene COL4A5 for AS. Children with large fragment deletion of the COL4A5 gene or double gene mutations of COL4A5 with COL4A3 or COL4A4 tend to have more serious clinical manifestations.