RNAi screens identify HES4 as a regulator of redox balance supporting pyrimidine synthesis and tumor growth.

NADH/NAD+ redox balance is pivotal for cellular metabolism. Systematic identification of NAD(H) redox regulators, although currently lacking, would help uncover unknown effectors critically implicated in the coordination of growth metabolism. In this study, we performed a genome-scale RNA interference (RNAi) screen to globally survey the genes involved in redox modulation and identified the HES family bHLH transcription factor HES4 as a negative regulator of NADH/NAD+ ratio. Functionally, HES4 is shown to be crucial for maintaining mitochondrial electron transport chain (ETC) activity and pyrimidine synthesis. More specifically, HES4 directly represses transcription of SLC44A2 and SDS, thereby inhibiting mitochondrial choline oxidation and cytosolic serine deamination, respectively, which, in turn, ensures coenzyme Q reduction capacity for DHODH-mediated UMP synthesis and serine-derived dTMP production. Accordingly, inhibition of choline oxidation preserves mitochondrial serine catabolism and ETC-coupled redox balance. Furthermore, HES4 protein stability is enhanced under EGFR activation, and increased HES4 levels facilitate EGFR-driven tumor growth and predict poor prognosis of lung adenocarcinoma. These findings illustrate an unidentified mechanism, underlying pyrimidine biosynthesis in the intersection between serine and choline catabolism, and underscore the physiological importance of HES4 in tumor metabolism.

Self-assembling peptide hydrogel scaffold integrating stem cell-derived exosomes for infected bone defects.

Infected bone defect (IBD) is a great challenge in orthopedics, which involves in bone loss and infection. Here, a self-assembling hydrogel scaffold (named AMP-RAD/EXO), integrating antimicrobial peptides(AMPs), RADA16 and BMSCs exosomes with an innovative strategy, is developed and applied in IBD treatment for sustained antimicrobial ability, accelerating osteoblasts proliferation and promoting bone regeneration. AMPs present an excellent ability to inhibit infection, RADA16 is a self-assembling peptide hydrogel for AMPs delivery, and BMSCs exosomes can promote the bone regeneration. The prepared AMP-RAD/EXO exhibited a polyporous 3D structure for imbibition of BMSCs exosomes and migration of osteoblasts. In vitro studies indicate AMP-RAD/EXO can inhibit the growth of Staphylococcus aureus, accelerate the proliferation and migration of BMSCs. More importantly, in vivo results also prove that AMP-RAD/EXO exhibit an excellent effect on IBD treatment. Thus, the prepared AMP-RAD/EXO provides a multifunctional scaffold concept for bone tissue engineering technology.

Application of Perioperative Pain Management in the Perioperative Nursing of Labia Minora Plasty and its Effect on the Rehabilitation of Patients.

Objective: The objective of this study is to investigate effective pain management strategies for women undergoing labiaplasty surgery. By focusing on pain relief, patient rehabilitation, and satisfaction improvement, we aim to enhance the overall patient experience and outcomes of this common gynecological plastic surgery. Methods: A total of 126 individuals diagnosed with labia minora hypertrophy and who underwent plastic surgery on their labia minora within the period of July 2020 to July 2023 were chosen as the participants for this study. They were divided into an observation group and a comparison group, each consisting of 63 cases, based on the different nursing methods. The comparison group was treated with routine perioperative nursing after labia minora surgery, and the observation group was treated with perioperative pain nursing management based on the comparison group. Postoperative pain score, comfort score, incision healing time, first urination time, night Pittsburgh Sleep Quality Index (PSQI) score, complications, and satisfaction were compared between the two groups. All data were established in an Excel database, and statistical analysis was performed using SPSS26.0. Statistical methods used include descriptive analysis, t tests, and Chi-square tests. Results: The mean incision healing time of the observation group was 3.90±0.61 days, and that of the control group was 3.62±0.64 days. The mean incision healing time of the observation group was significantly different from that of the control group (P < .05). VRS scores and PSQI scores were significantly lower in both groups 1 week aftercare compared with 1 day before care, indicating improvements in pain and sleep quality. The improvement degree of VRS score and PSQI score in the observation group was significantly different (P < .05). The number of incision infections, hematoma, flap necrosis, skin scar, delayed healing, and total complication rate were 3 in the observation group and 11 in the comparison group, indicating that the complication rate in the observation group was significantly lower than that in the comparison group. The comparison difference was statistically significant (P < .05). Through the Chi-square test, the nursing satisfaction and perineal aesthetic effect satisfaction of the observation group were significantly higher than those of the comparison group, and the difference was statistically significant (P < .05). Conclusions: The implementation of perioperative pain nursing management has been shown to effectively alleviate pain in patients diagnosed with labia minora hypertrophy. This approach not only enhances treatment comfort but also significantly reduces the occurrence of postoperative complications. Additionally, it accelerates the healing process of incisions, improves the quality of incision healing, and enhances patient satisfaction with both the aesthetic outcome of the perineal area and the quality of nursing care provided.

Targeting the macrophage immunocheckpoint: a novel insight into solid tumor immunotherapy.

Tumor immunotherapy, which targets immune checkpoints, presents a promising strategy for the treatment of various cancer types. However, current clinical data indicate challenges in its application to solid tumors. Recent studies have revealed a significant correlation between the degree of immune response in immunotherapy and the tumor microenvironment, particularly with regard to tumor-infiltrating immune cells. Among these immune cells, macrophages, a critical component, are playing an increasingly vital role in tumor immunotherapy. This review focuses on elucidating the role of macrophages within solid tumors and provides an overview of the progress in immunotherapy approaches centered around modulating macrophage responses through various immune factors. Video Abstract.

Dual blockade of CD47 and CD24 signaling using a novel bispecific antibody fusion protein enhances macrophage immunotherapy.

CD47 and its receptor signal regulatory protein α (SIRPα) act as a dominant antiphagocytic, "don't eat me" signal. Recent studies reveal CD24 as a novel target for cancer immunotherapy by macrophages in ovarian cancer and breast cancer. However, whether simultaneous blockade of CD47 and CD24 by a bispecific antibody may result in a potential synergy is still unclear. In the present study, we for the first time designed and developed a bispecific antibody fusion protein, PPAB001 for cotargeting CD47 and CD24. Data demonstrate that simultaneous blockade of CD47/SIRPα and CD24/Siglec-10 signaling by PPAB001 potently promoted macrophage phagocytosis of tumor cells. Compared to single CD47 or CD24 targeting agents, PPAB001 was more effective in inhibiting tumor growth in both mouse 4T-1 syngeneic and human SK-OV-3 xenogeneic tumor models. Mechanistically, we found that PPAB001 therapy markedly increased the proportion of tumor-infiltrating macrophages and upregulated interleukin-6 and tumor necrosis factor-α levels that were representative macrophage inflammatory cytokines. Notably, an increased ratio of M1/M2 in tumor-infiltrating macrophages in the mice treated with PPAB001 suggested that the dual blockade may promote the transition of macrophages from M2 to M1. Taken together, our data supported the development of PPAB001 as a novel immunotherapeutic in the treatment of CD47 and CD24 double-positive cancers.

Mangiferin alleviates renal inflammatory injury in spontaneously hypertensive rats by inhibiting MCP-1/CCR2 signaling pathway.

Objective: Hypertension is a low-grade inflammation state of the disease and was easily complicated by kidneys' inflammatory response. Mangiferin (MGF), a pharmacologically active compound in various plants including Mangifera indica, has a strong anti-inflammatory activity. However, the effects of MGF on renal inflammatory injury in spontaneously hypertensive rats (SHRs) remain unclear. The purpose of this study was to investigate the protective effects and mechanisms of MGF on renal inflammatory injury in SHRs. Methods: MGF was used in SHRs at the doses of 10, 20, 40 mg/kg/d for 8 weeks consecutively. The blood and urine were collected for assessment of renal function. Renal tissues were collected for histological, immunohistochemistry, ELISA, Western blot and real time reverse transcription PCR (RT-PCR) analysis. Results: The results showed that the levels of interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and recombinant chemokine C-C-Motif receptor 2 (CCR2) were increased in SHRs, meanwhile, the level of IL-10 was decreased in SHR. Treatment of MGF inhibited the expression of IL-6, TNF-α, MCP-1 and CCR2, and promoted the expression of IL-10. Furthermore, the content of blood urea nitrogen (BUN) and serum uric acid (SUA) was significantly increased in the model group, and treatment of MGF had no obvious effects on these parameters at all dose levels. Conclusion: Our study proved that the kidneys of SHRs had significant inflammatory injury, and MGF had the protective effects on renal inflammatory injury in SHRs; The protective mechanism may be mediated partly by the MCP-1/CCR2 signaling pathway. Thus, it is a potential new drug for the treatment of hypertension.

Identification and verification of three autophagy-related genes as potential biomarkers for the diagnosis of psoriasis.

Psoriasis vulgaris is the most common form of the four clinical types. However, early diagnosis of psoriasis vulgaris is difficult due to the lack of effective biomarkers. The aim of this study was to screen potential biomarkers for the diagnosis of psoriasis. In our study, we downloaded the original data from GSE30999 and GSE41664, and the autophagy-related genes list from human autophagy database to identify differentially expressed autophagy-related genes (DERAGs) by R software. Then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for DERAGs. DERAGs were validated by the other four databases (GSE13355, GSE14905, GSE6710, and GSE55201) to screen biomarkers with high diagnostic value for the early diagnosis of psoriasis vulgaris. Finally, DERAGs were verified in our clinical blood samples by ELISA. A total of 12 DERAGs were identified between 123 paired non-lesional and lesional skin samples from patients with psoriasis vulgaris. GO and KEGG enrichment analysis indicated the TORC2 complex was more enriched and the NOD-like receptor signaling pathway was mostly enriched. Three autophagy-related genes (BIRC5, NAMPT and BCL2) were identified through bioinformatics analysis and verified by ELISA in clinical blood samples. And these genes showed high diagnostic value for the early diagnosis of psoriasis vulgaris. We identified three autophagy-related genes (BIRC5, NAMPT and BCL2) with high diagnostic value for the early diagnosis of psoriasis vulgaris through bioinformatics analysis and clinical samples. Therefore, we proposed that BIRC5, NAMPT and BCL2 may be as potential biomarkers for the early diagnosis of psoriasis vulgaris. In addition, BIRC5, NAMPT and BCL2 may affect the development of psoriasis by regulating autophagy.

Predicting diabetic kidney disease for type 2 diabetes mellitus by machine learning in the real world: a multicenter retrospective study.

Objective: Diabetic kidney disease (DKD) has been reported as a main microvascular complication of diabetes mellitus. Although renal biopsy is capable of distinguishing DKD from Non Diabetic kidney disease(NDKD), no gold standard has been validated to assess the development of DKD.This study aimed to build an auxiliary diagnosis model for type 2 Diabetic kidney disease (T2DKD) based on machine learning algorithms. Methods: Clinical data on 3624 individuals with type 2 diabetes (T2DM) was gathered from January 1, 2019 to December 31, 2019 using a multi-center retrospective database. The data fell into a training set and a validation set at random at a ratio of 8:2. To identify critical clinical variables, the absolute shrinkage and selection operator with the lowest number was employed. Fifteen machine learning models were built to support the diagnosis of T2DKD, and the optimal model was selected in accordance with the area under the receiver operating characteristic curve (AUC) and accuracy. The model was improved with the use of Bayesian Optimization methods. The Shapley Additive explanations (SHAP) approach was used to illustrate prediction findings. Results: DKD was diagnosed in 1856 (51.2 percent) of the 3624 individuals within the final cohort. As revealed by the SHAP findings, the Categorical Boosting (CatBoost) model achieved the optimal performance 1in the prediction of the risk of T2DKD, with an AUC of 0.86 based on the top 38 characteristics. The SHAP findings suggested that a simplified CatBoost model with an AUC of 0.84 was built in accordance with the top 12 characteristics. The more basic model features consisted of systolic blood pressure (SBP), creatinine (CREA), length of stay (LOS), thrombin time (TT), Age, prothrombin time (PT), platelet large cell ratio (P-LCR), albumin (ALB), glucose (GLU), fibrinogen (FIB-C), red blood cell distribution width-standard deviation (RDW-SD), as well as hemoglobin A1C(HbA1C). Conclusion: A machine learning-based model for the prediction of the risk of developing T2DKD was built, and its effectiveness was verified. The CatBoost model can contribute to the diagnosis of T2DKD. Clinicians could gain more insights into the outcomes if the ML model is made interpretable.

The negative effect of G1958A polymorphism on MTHFD1 protein stability and HCC growth.

PURPOSE: Methylenetetrahydrofolate dehydrogenase (MTHFD1), a key enzyme on the folate pathway, has been implicated in the tumor development of distinct types of cancers. The single nucleotide polymorphism (SNP) of 1958G > A mutation in the coding region of MTHFD1 (arginine 653 is mutated into glutamine) has been detected in a significant proportion of clinical samples of hepatocellular carcinoma (HCC). METHODS : Hepatoma cell lines, 97H and Hep3B were used. The expression of MTHFD1 and SNP mutation protein was determined by immunoblotting analysis. The protein ubiquitination of MTHFD1 was detected by immunoprecipitation analysis. The post-translational modification sites and interacting proteins of MTHFD1 in the presence of G1958A SNP were identified by mass spectrometry. Metabolic flux analysis was used to detect the synthesis of relevant metabolites sourced from serine isotope. RESULTS: The present study showed G1958A SNP of MTHFD1, encoding MTHFD1 R653Q, was associated with the attenuated protein stability caused by ubiquitination-mediated protein degradation. Mechanistically, MTHFD1 R653Q displayed an enhanced binding to the E3 ligase TRIM21, which was responsible for the augmented ubiquitination, and MTHFD1 K504 was identified to be the primary ubiquitination site. The subsequent metabolite analysis revealed MTHFD1 R653Q resulted in the repressed flux of serine-derived methyl group into metabolite precursors for purine synthesis, and the compromised purine synthesis was demonstrated to be responsible for the impeded growth capability in MTHFD1 R653Q-expressing cells. Moreover, the suppressive effect of MTHFD1 R653Q expression in tumorigenesis was verified by xenograft analysis, and the relationship between MTHFD1 G1958A SNP and its protein levels was revealed in clinical human liver cancer specimens. CONCLUSION: Our results uncovered an unidentified mechanism underlying of the impact of G1958A SNP on MTHFD1 protein stability and tumor metabolism in HCC. which provides a molecular basis for the according clinical management when considering MTHFD1 as a therapeutic target.

Clinical study on the treatment of primary trigeminal neuralgia by robot-assisted percutaneous balloon compression.

Background: C-arm-guided percutaneous puncture balloon compression alone has risk factors of puncture failure, complications, and poor prognosis. Robot-assisted PBC can effectively increase the one-time puncture success rate and improve the safety of the procedure. However, evidence on the superiority of robot-assisted PBC over C-arm-guided PBC alone remains relatively limited. Methods: Retrospective analysis The clinical data of 60 patients with trigeminal neuralgia aged 60 years or older in the Department of Neurosurgery of the Fourth Hospital of Harbin Medical University from January 2021 to October 2021. There were 29 males and 31 females, and the patients' ages ranged from 60 to 79 years, with an average of 71.63 ± 5.12 years. Two groups were divided according to the surgical method, the C-arm guidance-only group (30 cases, n = 30) and the robot-assisted group (30 cases, n = 30). The success rate of first puncture, total operation time, number of "pear-shaped" balloons, number of C-arm x-ray scans, and immediate postoperative relief rate were recorded in both groups, and follow-up was performed to evaluate the postoperative results and complications. The overall evaluation of postoperative results and complications was performed. Results: Intraoperative balloon compression was successfully completed in all 60 patients, and the first puncture success rate was higher in the robot-assisted group than in the simple C-arm group, with a significant difference between the two groups (P < 0.001). In terms of intraoperative balloon morphology, the number of "pear-shaped" balloons was higher in the PBC than in the C-arm-only PBC group, with a significant difference between the two groups (P < 0.005). The degree of immediate postoperative remission in the robotic group was 0 VAS score, which was not statistically significant in both groups (P > 0.05). By the final follow-up, the mean VAS score of the robot-assisted group was lower than that of the simple C-arm group, and both were statistically significant (P < 0.05); complications of masticatory muscle weakness or abnormal facial sensation occurred in both groups after surgery, but the number of cases in the robot-assisted group was less than that of the simple C-arm group. Conclusion: Robot-assisted PBC is better than PBC with a C-arm x-ray machine in terms of first puncture success rate, number of intraoperative balloon "pear-shaped" cases, number of C-arm x-ray scans and short-term efficacy.

A novel synthetic chalcone derivative, 2,4,6-trimethoxy-4'-nitrochalcone (Ch-19), exerted anti-tumor effects through stimulating ROS accumulation and inducing apoptosis in esophageal cancer cells.

Esophageal cancer has always been associated with poor prognosis and a low five-year survival rate. Chalcone, a flavonoid family member, has shown anti-tumor property in several types of cancer. However, few studies reported the potency and mechanisms of action of synthetic Chalcone derivatives against esophageal squamous cell carcinoma. In this study, we designed and synthesized a series of novel chalcone analogs and Ch-19 was selected for its superior anti-tumor potency. Results indicated that Ch-19 shows a dose- and time-dependent anti-tumor activity in both KYSE-450 and Eca-109 esophageal cancer cells. Moreover, treatment of Ch-19 resulted in the regression of KYSE-450 tumor xenografts in nude mice. Furthermore, we investigated the potential mechanism involved in the effective anti-tumor effects of Ch-19. As a result, we observed that Ch-19 treatment promoted ROS accumulation and caused G2/M phase arrest in both Eca-109 and KYSE-450 cancer cell lines, thereby resulting in cell apoptosis. Taken together, our study provided a novel synthetic chalcone derivative as a potential anti-tumor therapeutic candidate for treating esophageal cancer.

Necroptosis Contributes to LPS-Induced Activation of the Hypothalamic-Pituitary-Adrenal Axis in a Piglet Model.

Stressors cause activation of the hypothalamic-pituitary-adrenal (HPA) axis and a systemic inflammatory response. As a newly proposed cell death manner in recent years, necroptosis occurs in a variety of tissue damage and inflammation. However, the role of necroptosis in HPA axis activation remains to be elucidated. The aim of this study was to investigate the occurrence of necroptosis and its role in HPA activation in a porcine stress model induced by Escherichia coli lipopolysaccharide (LPS). Several typical stress behaviors like fever, anorexia, shivering and vomiting were observed in piglets after LPS injection. HPA axis was activated as shown by increased plasma cortisol concentration and mRNA expression of pituitary corticotropin-releasing hormone receptor 1 (CRHR1) and adrenal steroidogenic acute regulatory protein (StAR). The mRNA expression of tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 in the hypothalamus, pituitary gland and adrenal gland was elevated by LPS, accompanied by the activation of necroptosis indicated by higher mRNA expression of necroptosis signals including receptor-interacting protein kinase (RIP) 1, RIP3, and phosphorylated mixed-lineage kinase domain-like protein (MLKL). Furthermore, necrostatin-1 (Nec-1), an inhibitor of necroptosis, inhibited necroptosis indicated by decreased mRNA levels of RIP1, RIP3, MLKL, and phosphoglycerate mutase family member 5 (PGAM5) in the hypothalamus, pituitary gland and adrenal gland. Nec-1 also decreased the mRNA expression of TNF-α and IL-ß and inhibited the activation of the HPA axis indicated by lower plasma cortisol concentration and mRNA expression of adrenal type 2 melanocortin receptor (MC2R) and StAR. These findings suggest that necroptosis is present and contributes to HPA axis activation induced by LPS. These findings provide a potential possibility for necroptosis as an intervention target for alleviating HPA axis activation and stress responses.

The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers.

The dual tyrosine kinase (EGFR/HER2) inhibitor lapatinib is currently used to clinically treat HER2-positive breast cancer. However, a majority of patients do not respond to lapatinib therapy within 6 months. Therefore, potentiating the anti-tumor effect of lapatinib by combination treatment has a great potential to overcome the obstacle. Herein, we aim to investigate the anti-tumor activity of lapatinib in combination with brusatol and explore the potential mechanism involved in the combinatorial treatment. Our findings revealed that the Nrf2 inhibitor brusatol potently enhanced the anti-tumor effect of lapatinib against SK-BR-3, SK-OV-3 and AU565 cancer cells in a synergistic manner. Furthermore, we found that lapatinib plus brusatol more effectively decreased Nrf2 level and induced ROS generation in both SK-BR-3 and SK-OV-3 cells. Moreover, we also observed a significant reduction on the phosphorylation of HER2, EGFR, AKT and ERK1/2 in SK-BR-3 and SK-OV-3 cells when treated with lapatinib plus brusatol compared to either agent alone. More importantly, brusatol significantly augmented the anti-tumor effects of lapatinib in the SK-OV-3 xenograft model. In summary, these data provide a potential rationale for the combination of brusatol and lapatinib on the treatment of HER2-positive cancers.

Explainable machine learning models for predicting 30-day readmission in pediatric pulmonary hypertension: A multicenter, retrospective study.

Background: Short-term readmission for pediatric pulmonary hypertension (PH) is associated with a substantial social and personal burden. However, tools to predict individualized readmission risk are lacking. This study aimed to develop machine learning models to predict 30-day unplanned readmission in children with PH. Methods: This study collected data on pediatric inpatients with PH from the Chongqing Medical University Medical Data Platform from January 2012 to January 2019. Key clinical variables were selected by the least absolute shrinkage and the selection operator. Prediction models were selected from 15 machine learning algorithms with excellent performance, which was evaluated by area under the operating characteristic curve (AUC). The outcome of the predictive model was interpreted by SHapley Additive exPlanations (SHAP). Results: A total of 5,913 pediatric patients with PH were included in the final cohort. The CatBoost model was selected as the predictive model with the greatest AUC for 0.81 (95% CI: 0.77-0.86), high accuracy for 0.74 (95% CI: 0.72-0.76), sensitivity 0.78 (95% CI: 0.69-0.87), and specificity 0.74 (95% CI: 0.72-0.76). Age, length of stay (LOS), congenital heart surgery, and nonmedical order discharge showed the greatest impact on 30-day readmission in pediatric PH, according to SHAP results. Conclusions: This study developed a CatBoost model to predict the risk of unplanned 30-day readmission in pediatric patients with PH, which showed more significant performance compared with traditional logistic regression. We found that age, LOS, congenital heart surgery, and nonmedical order discharge were important factors for 30-day readmission in pediatric PH.

The Effect of Guselkumab on Work Productivity in Biologic-Naïve Patients with Active Psoriatic Arthritis Through Week 52 of the Phase 3, Randomized, Placebo-Controlled DISCOVER-2 Trial.

INTRODUCTION: The phase 3 DISCOVER-2 trial evaluated the effect of guselkumab on impaired work productivity and nonwork activity in biologic-naïve patients with psoriatic arthritis (PsA). METHODS: Adults with active PsA were randomized (1:1:1) to guselkumab 100 mg every 4 weeks (Q4W), guselkumab 100 mg at weeks 0 and 4 and then every 8 weeks (Q8W), or placebo (with crossover to guselkumab Q4W at week 24). Least squares mean change from baseline in Work Productivity and Activity Impairment Questionnaire for PsA (WPAI-PsA) domains and employment were assessed by treatment group. Multivariate analysis of data from weeks 0 through 24 assessed independent associations between PsA clinical features and WPAI-PsA domains. RESULTS: In total, 738 patients were evaluated (guselkumab Q4W n = 245; guselkumab Q8W n = 248; placebo n = 245). At week 24, improvements (reduced impairment) in presenteeism (Q4W -20.1%, Q8W -19.6%, placebo -10.5%), work productivity (Q4W -20.1%, Q8W -19.2%, placebo -10.6%), and nonwork activity (Q4W -20.5%, Q8W -21.2%, placebo -9.9%) were greater in guselkumab-treated versus placebo-treated patients. At week 52, following placebo crossover at week 24, improvements were similar among groups. Baseline absenteeism was minimal and did not change in any group. By week 52, 23.1-25.9% of guselkumab-treated patients who were unemployed at baseline were employed. All WPAI-PsA domains were positively associated with C-reactive protein level, fatigue, and pain. All domains except absenteeism were positively associated with enthesitis and Psoriasis Area and Severity Index score. Age was negatively associated with presenteeism and work productivity loss, female sex and tender joint count were positively associated with nonwork activity impairment, and dactylitis was positively associated with presenteeism. CONCLUSION: Both guselkumab regimens reduced work productivity loss and nonwork activity impairment in patients with active PsA. Association of work productivity loss and nonwork activity impairment with PsA joint and skin features suggests that improvement in both features is beneficial for optimizing improved work productivity loss and nonwork activity impairment. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03158285.

Vegetable-derived indole enhances the melanoma-treating efficacy of chemotherapeutics.

Food-drug interaction is an important but overlooked issue. For example, little is known concerning whether or not the chemotherapy of cancers is affected by the well-defined dietary chemicals such as 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr1) derived from daily consumed cruciferous vegetables. This work, inspired by the described melanogenesis reduction by certain indoles, presents that LTr1 mitigates the melanogenesis and thus potentiates the in vitro and in vivo anti-melanoma effectiveness of different chemotherapeutic agents including dacarbazine, vemurafenib, and sorafenib. In B16 melanoma cells, LTr1 was shown to inhibit the melanogenesis by acting towards the regulatory (R) subunit of protein kinase A (PRKAR1a) associated with the phosphorylation of cAMP-response element binding protein (CREB). This allows LTr1 to reduce the expression of melanogenesis-related enzymes such as tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and tyrosinase-related protein 2 (TYRP2). Furthermore, LTr1 was addressed to bind to the aryl hydrocarbon receptor (AhR) and up-regulate the expression of CYP1A1 encoding cytochrome P450 1A1, leading to the escalation of reactive oxygen species (ROS) level. The increased ROS generation promotes the cysteine-to-cystine transformation to inhibit the pheomelanogenesis in melanomas. Collectively, the work identifies LTr1 as a new melanogenesis inhibitor that modulates the PKA/CREB/MITF and AhR/CYP1A1/ROS pathways, thereby providing a new option for (re)sensitizing melanomas to chemotherapeutics.

Synthesis and antitumor activity of benzophenone compound.

Seven benzophenone compounds were synthesized in one or two steps, then their antitumor activity was evaluated. The total yields ranged from 9% to 44%. Compounds 3c-5c exhibited obvious antitumor activity. Among them, compounds 3c and 4c exhibited excellent and broad-spectrum antitumor activity. Compound 3c exhibited much stronger inhibitory activities against fourteen cancer cells than cisplatin. In particular, compound 3c exhibited stronger cytotoxicity against hepatocarcinoma SMMC-7721 cells than Taxol, with a half maximal inhibitory concentration (IC50) of approximately 0.111 µM. These results demonstrated that compounds 3c, 4c and 5c were very promising antitumor leads for further structural modification.

Three new polyketide derivatives of the endophytic fungus Aspergillus cristatus 2H1.

Three new polyketide derivatives, 2-ethoxycarbonyl-endocrocin (1), 6-methoxy-2-ethoxycarbonyl-endocrocin (2) and pannorin C (3), along with sixteen known compounds (4-19) were isolated from a plant endophytic fungus Aspergillus cristatus 2H1. Their structures were elucidated by 1D/2D NMR and HR-ESI-MS data analysis. Compound 3 showed weak antibacterial activity against Staphylococcus aureus (MIC 20 µg/ml). Compounds 14 and 15 showed effective cytotoxicity on human melanoma A375 cells (IC50 4.13 µM for 14, 3.39 µM for 15).

Endoplasmic reticulum stress promotes sorafenib resistance via miR-188-5p/hnRNPA2B1-mediated upregulation of PKM2 in hepatocellular carcinoma.

Emerging evidence has shown that endoplasmic reticulum (ER) stress promotes sorafenib resistance in hepatocellular carcinoma (HCC). However, the underlying mechanisms are poorly understood. The purpose of this study was to explore the mechanism by which ER stress promotes sorafenib resistance in HCC. We found that pyruvate kinase isoform M2 (PKM2) was highly expressed in human HCC tissues and co-related with worse clinicopathologic features and overall survival. Activation of ER stress positively correlated with PKM2 expression both in HCC tissue samples and tunicamycin (TM)-induced HCC cell lines. PKM2 knockdown increased sorafenib-induced apoptosis and decreased the ability of colony formation, while upregulation of PKM2 reverses this phenomenon. Furthermore, high-throughput sequencing identified that activation of ER stress significantly downregulated the expression of miR-188-5p in HCC cells. According to bioinformatics analysis and dual-luciferase assays, we further confirmed that hnRNPA2B1 is the target gene of miR-188-5p. Downregulating the expression of hnRNPA2B1 with siRNA could decrease the expression of PKM2 and enhance sorafenib-induced apoptosis in HepG2 cells. Our study demonstrated that ER stress could promote sorafenib resistance through upregulating PKM2 via miR-188-5p/hnRNPA2B1. Therefore, targeting the miR-188-5p/hnRNPA2B1/PKM2 pathway and ER stress may prove instrumental in overcoming sorafenib resistance in HCC treatment.

[Community Distribution of the Rhizospheric and Endophytic Bacteria of Phragmites australis and Their Limiting Factors in Iron Tailings].

The composition of the rhizospheric and endophytic bacteria Phragmites australis in spring and summer around the Qiananling iron tailings reservoir in the Huairou District of Beijing was studied using Illumina high-throughput sequencing technology. Sequencing identified 40 phyla, and Proteobateria and Actinobacteria were the dominant phyla in all samples, accounting for more than 80% of the sequences in all samples. At the genus level, Pseudoarthrobacter was dominant. α-diversity analysis showed that species richness(Sobs, Chao) and species diversity indexes(Shannon, PD) of the rhizosphere soil microorganisms were significantly higher than those of endophytes. The maximum and minimum differences of the Sobs, Chao, Shannon, PD indexes were 1336, 1582.24, 6.48, and 81.18, respectively. ß-diversity analysis indicated that there were significant differences in the community compositions of rhizosphere soil microorganisms and root endophytes, while now notable differences were observed between samples in different seasons. In addition, the dominant strains in each sample(such as Pseudomonas, Arthrobacter, and Streptomyces) were highly resistant to heavy metals. Among the 774 genera, a total of 250 genera coexisted in four types of samples, indicating that the microbial community composition of different samples had some degree of similarity. Correlation analysis between soil physical and chemical properties showed that Ni, Fe, available phosphorus, effective sulphur, and organic matter were significantly related to the microbial communities. Through the prediction of COG function, it was found that the microbial metabolic functions(i.e., energy production and conversion, amino acid transport and metabolism, carbohydrate transport and metabolism, inorganic ion transport, and metabolism) were abundant.