Comparative Analysis of Ketamine and Fentanyl Combined with Dexmedetomidine for Lumbar Anesthesia in Proximal Femur Fractures Among the Elderly.

Objective: This study aimed to compare the effects of ketamine and fentanyl combined with dexmedetomidine in lumbar anesthesia for proximal femur fractures among elderly patients. Design: This study employed a prospective, randomized controlled trial (RCT) design. Settings: The study was conducted at Beijing Jishuitan Hospital. Participants: A total of 100 elderly patients with proximal femur fractures who underwent lumbar anesthesia between January 2022 and January 2023. Intervention: Participants were divided into two groups: the ketamine group (n=49) and the fentanyl group (n=51). The ketamine group received ketamine combined with dexmedetomidine, while the fentanyl group received fentanyl combined with dexmedetomidine. Outcome Measures: The following outcome measures were assessed and compared between the two groups: (1) hemodynamic indexes; (2) visual analogue scale (VAS) scores; (3) stress reaction indexes; (4) Incidence of adverse effects. These comparisons were made using the random number table method. Results: No significant differences were observed in systolic blood pressure (SBP), transcutaneous oxygen saturation (SPO2), and heart rate (HR) between the two groups at each time point (P > .05). SBP and HR of both groups were lower than baseline (T0) from T1 onwards. Throughout the surgery, SBP and HR exhibited a decreasing trend with operation time, followed by an increase post-operation. SPO2 showed minimal fluctuations during surgery in both groups. Preoperatively, VAS scores were comparable between groups (P > .05). However, at 12h, 24h, and 48h post-surgery, VAS scores were significantly lower in the ketamine group (P < .05). Stress indicator levels were similar preoperatively (P > .05), but postoperatively, serum cortisol (Cor), epinephrine (E), and norepinephrine (NE) levels were lower in the ketamine group (P < .05). Conclusion: Dexmedetomidine combined with ketamine demonstrates safety and efficacy in the elderly. It significantly reduces postoperative pain and stress reactions while decreasing the incidence of adverse reactions.

[Spatiotemporal Trends and Driving Factors of PM2.5-related Health Burden in Gansu Province, China from 2013 to 2020].

To evaluate the spatiotemporal trends and drivers of PM2.5-related health effects in Gansu Province since the implementation of the Air Pollution Prevention and Control Action Plan, the latest global exposure mortality model （GEMM） was adopted to estimate the health burden attributable to PM2.5 in Gansu Province from 2013 to 2020. The factor decomposition method was used to further quantify the main causes of the long-term changes in deaths attributable to PM2.5 pollution. The results showed that from 2013 to 2020, the population-weighted PM2.5 concentration in Gansu Province decreased by 34.57%, and the proportion of people exposed to areas with an annual average PM2.5 concentration exceeding 35 µg·m-3 decreased significantly from 72.89% to 11.61%. Moreover, the number of attributable deaths in Gansu Province declined from 12 826 （95%CI： 7 840-17 408） in 2 013 to 9 814 （95%CI： 6 407-13 036） in 2020, indicating a decrease of 23.48%. Attributable deaths from stroke, chronic obstructive pulmonary disease, lung cancer, and lower respiratory infection declined, whereas deaths from ischemic heart disease increased by 12.11%. Notably, individuals aged 60 years and older accounted for more than 80% of all age-related deaths. The number of deaths attributable to PM2.5 in central and eastern Gansu Province was significantly higher than that in the Hexi region, and most regions showed a downward trend. The contribution of the total population, age structure, baseline mortality rate, and PM2.5 concentration to the change in PM2.5-related deaths was -1.26%, 16.16%, -9.84%, and -28.55%, respectively. Overall, population aging and a decrease in PM2.5 concentration were the main factors contributing to the increase and decrease in PM2.5-related deaths, respectively. The active clean air policies in Gansu Province have reduced the health burden caused by PM2.5 pollution, but with the trend of population aging, a significant reduction in PM2.5 concentration will be needed in the future to avoid more attributable deaths.

MiR-1909-5p targeting GPX4 affects the progression of aortic dissection by modulating nicotine-induced ferroptosis.

OBJECTIVE: Aortic dissection (AD) is a prevalent and acute clinical catastrophe characterized by abrupt manifestation, swift progression, and elevated fatality rates. Despite smoking being a significant risk factor for AD, the precise pathological process remains elusive. This investigation endeavors to explore the mechanisms by which smoking accelerates AD through ferroptosis induction. METHODOLOGY: In this novel study, we detected considerable endothelial cell death by ferroptosis within the aortic inner lining of both human AD patients with a smoking history and murine AD models induced by ß-aminopropionitrile, angiotensin II, and nicotine. Utilizing bioinformatic approaches, we identified microRNAs regulating the expression of the ferroptosis inhibitor Glutathione peroxidase 4 (GPX4). Nicotine's impact on ferroptosis was further assessed in human umbilical vein endothelial cells (HUVECs) through modulation of miR-1909-5p. Additionally, the therapeutic potential of miR-1909-5p antagomir was evaluated in vivo in nicotine-exposed AD mice. FINDINGS: Our results indicate a predominance of ferroptosis over apoptosis, pyroptosis, and necroptosis in the aortas of AD patients who smoke. Nicotine exposure instigated ferroptosis in HUVECs, where the miR-1909-5p/GPX4 axis was implicated. Modulation of miR-1909-5p in these cells revealed its regulatory role over GPX4 levels and subsequent endothelial ferroptosis. In vivo, miR-1909-5p suppression reduced ferroptosis and mitigated AD progression in the murine model. CONCLUSIONS: Our data underscore the involvement of the miR-1909-5p/GPX4 axis in the pathogenesis of nicotine-induced endothelial ferroptosis in AD.

Investigation of the application of Enhanced Recovery After Surgery (ERAS) in elderly patients undergoing surgery for kidney stones.

OBJECTIVE: To investigate the efficacy and application of Enhanced Recovery After Surgery (ERAS) in elderly patients undergoing surgery for kidney stones. METHODS: Clinical data of 104 elderly patients who underwent kidney stone surgery at West China Hospital, Sichuan University from January 2020 to December 2022 were retrospectively analyzed in this study. The patients were divided into two groups according to different nursing plans. Among them, 52 patients in the control group received conventional nursing, and 52 patients in the study group received ERAS mode nursing. Postoperative recovery, anxiety, complications, stress response and quality of life were compared between the two groups. RESULTS: The time to recovery of postoperative rehabilitation indices in the research group was significantly shorter compared to the control group (P < 0.05). The research group also exhibited a significantly lower incidence of complications such as hematuria, abdominal pain, vomiting, chills, fever, and hypotension (all P < 0.05). Before the initiation of nursing care, there were no significant differences in the State Anxiety Inventory (SAI) and Trait Anxiety Inventory (TAI) scores between the two groups (both P > 0.05). However, after nursing care, the research group exhibited lower SAI and TAI scores compared to the control group (all P < 0.05). Similarly, there was no significant difference in the General Quality of Life Inventory-74 (GQOLI-74) scores in any dimension between the two groups before nursing care (P > 0.05), but the research group showcased higher scores in every dimension after nursing care (P < 0.05). The levels of Heme Oxygenase-1 (HO-1), Endothelin-1 (ET-1), Adrenocorticotropic Hormone (ACTH), and Cortisol (Cor) were significantly lower in the research group after nursing care (all P < 0.05). The acknowledgment and approval scores of nursing care in the research group were higher than those in the control group (P < 0.05). CONCLUSION: The application of ERAS in elderly patients with kidney stones undergoing transurethral ureteral holmium laser lithotripsy is efficacious in mitigating stress reactions, enhancing quality of life and reducing perioperative anxiety, minimizing the incidence of complications, and promoting overall patient recovery.

Super-enhancer-driven IRF2BP2 enhances ALK activity and promotes neuroblastoma cell proliferation.

BACKGROUND: Super-enhancers (SEs) typically govern the expression of critical oncogenes and play a fundamental role in the initiation and progression of cancer. Focusing on genes that are abnormally regulated by SE in cancer may be a new strategy for understanding pathogenesis. In the context of this investigation, we have identified a previously unreported SE-driven gene IRF2BP2 in neuroblastoma (NB). METHODS: The expression and prognostic value of IRF2BP2 were detected in public databases and clinical samples. The effect of IRF2BP2 on NB cell growth and apoptosis was evaluated through in vivo and in vitro functional loss experiments. The molecular mechanism of IRF2BP2 was investigated by the study of chromatin regulatory regions and transcriptome sequencing. RESULTS: The sustained high expression of IRF2BP2 results from the activation of a novel SE established by NB master transcription factors MYCN, MEIS2 and HAND2, and they form a new complex that regulates the gene network associated with the proliferation of NB cell populations. We also observed a significant enrichment of the AP-1 family at the binding sites of IRF2BP2. Remarkably, within NB cells, AP-1 plays a pivotal role in shaping the chromatin accessibility landscape, thereby exposing the binding site for IRF2BP2. This orchestrated action enables AP-1 and IRF2BP2 to collaboratively stimulate the expression of the NB susceptibility gene ALK, thereby upholding the highly proliferative phenotype characteristic of NB. CONCLUSION: Our findings indicate that SE-driven IRF2BP2 can bind to AP-1 to maintain the survival of tumor cells via regulating chromatin accessibility of NB susceptibility gene ALK.

The hospitalization burden of inflammatory bowel disease in a southwestern highland region of China: a territory-wide study from 2015 to 2020.

Background: Yunnan, a southwest highland and newly industrialized region of China, has an unknown hospitalization burden of inflammatory bowel disease (IBD). The study was conducted to explore territorial hospitalization burden of IBD. Methods: The formatted medical records of patients with IBD were collected from a territory-wide database in Yunnan Province, China, from 2015 to 2020. General characteristics of the study population were reported using descriptive statistics. To evaluate the length of stay, hospitalization costs, surgery, complications, and trends in patients with inflammatory bowel disease. The logistic regression analysis was established to explore the factors affecting the hospitalization costs. Results: A total of 12,174 records from 8192 patients were included. The annual hospitalization cost of IBD in Yunnan Province increased significantly from 2015 to 2020. From 2015 to 2020, the regional hospitalization burden of IBD increased, but it represented a decline in cost per hospitalization (r = -0.024, P = 0.008) and the length of stay (r = -0.098, P < 0.001). Surgery rates for hospitalized patients with Crohn's disease (CD) did not decrease (r = -0.002, P = 0.932), and even increased for patients with ulcerative colitis (UC) (r = 0.03, P = 0.002). The costs per hospitalization were $ 827.49 (540.11-1295.50) for UC and $ 1057.03 (644.26-1888.78) for CD. Among the identifiable cost items during the period, drug costs accounted for the highest proportion, accounting for 33% and 37.30% in patients with UC and CD, respectively. Surgical intervention [OR 4.87 (3.75-6.31), P < 0.001], comorbidities [OR 1.72 (1.52-1.94), P < 0.001], complications [OR 1.53 (1.32-1.78), P < 0.001], and endoscopy [OR 2.06 (1.86-2.28), P < 0.001] were predictor of high hospitalization costs. Conclusion: The increasing burden of IBD is noteworthy a newly industrialized region of China. Interventions targeting surgery, complications, and comorbidities may be effective means of controlling the increasing hospitalization costs of IBD in the regions.

Inhibition of the rapamycin-insensitive mTORC1 /4E-BP1 axis attenuates TGF-ß1-induced fibrotic response in human Tenon's fibroblasts.

Subconjunctival fibrosis is the major cause of failure in both conventional and modern minimally invasive glaucoma surgeries (MIGSs) with subconjunctival filtration. The search for safe and effective anti-fibrotic agents is critical for improving long-term surgical outcomes. In this study, we investigated the effect of inhibiting the rapamycin-insensitive mTORC1/4E-BP1 axis on the transforming growth factor-beta 1(TGF-ß1)-induced fibrotic responses in human Tenon's fibroblasts (HTFs), as well as in a rat model of glaucoma filtration surgery (GFS). Primary cultured HTFs were treated with 3 ng/mL TGF-ß1 for 24 h, followed by treatment with 10 µM CZ415 for additional 24 h. Rapamycin (10 µM) was utilized as a control for mTORC1/4E-BP1 signaling insensitivity. The expression levels of fibrosis-associated molecules were measured using quantitative real-time PCR, Western blotting, and immunofluorescence analysis. Cell migration was assessed through the scratch wound assay. Additionally, a rat model of GFS was employed to evaluate the anti-fibrotic effect of CZ415 in vivo. Our findings indicated that both rapamycin and CZ415 treatment significantly reduced the TGF-ß1-induced cell proliferation, migration, and the expression of pro-fibrotic factors in HTFs. CZ415 also more effectively inhibited TGF-ß1-mediated collagen synthesis in HTFs compared to rapamycin. Activation of mTORC1/4E-BP signaling following TGF-ß1 exposure was highly suppressed by CZ415 but was only modestly inhibited by rapamycin. Furthermore, CZ415 was found to decrease subconjunctival collagen deposition in rats post GFS. Our results suggest that rapamycin-insensitive mTORC1/4E-BP1 signaling plays a critical role in TGF-ß1-driven collagen synthesis in HTFs. This study demonstrated that inhibition of the mTORC1/4E-BP1 axis offers superior anti-fibrotic efficacy compared to rapamycin and represents a promising target for improving the success rate of both traditional and modern GFSs.

Multiple exposure pathways and health risk assessment of PAHs in Lanzhou city, a semi-arid region in northwest China.

In the sparse studies for multiple pathway exposure, attention has predominantly been directed towards developed regions, thereby overlooking the exposure level and health outcome for the inhabitants of the semi-arid regions in northwest China. However, cities within these regions grapple with myriad challenges, encompassing insufficient sanitation infrastructure and outdated heating. In this study, we analyzed the characteristics and sources of polycyclic aromatic hydrocarbons (PAHs) pollution in PM2.5, water, diet, and dust during different periods in Lanzhou, and estimated corresponding carcinogenic health risk through inhalation, ingestion, and dermal absorption. Our observations revealed the concentrations of PAHs in PM2.5, food, soil, and water are 200.11 ng m-3, 8.67 mg kg-1, 3.91 mg kg-1, and 14.5 ng L-1, respectively, indicating that the Lanzhou area was seriously polluted. Lifetime incremental cancer risk (ILCR) showed a heightened cancer risk to men compared to women, to the younger than the elderly, and during heating period as opposed to non-heating period. Notably, the inhalation was the primary route of PAHs exposure and the risk of exposure by inhalation cannot be ignored. The total environmental exposure assessment of PAHs can achieve accurate prevention and control of PAHs environmental exposure according to local conditions and targets.

Blocking senescence and tolerogenic function of dendritic cells induced by γδ Treg cells enhances tumor-specific immunity for cancer immunotherapy.

BACKGROUND: Regulatory T (Treg) cells are a key component in maintaining the suppressive tumor microenvironment and immune suppression in different types of cancers. A precise understanding of the molecular mechanisms used by Treg cells for immune suppression is critical for the development of effective strategies for cancer immunotherapy. METHODS: Senescence development and tolerogenic functions of dendritic cells (DCs) induced by breast cancer tumor-derived γδ Treg cells were fully characterized using real-time PCR, flow cytometry, western blot, and functional assays. Loss-of-function strategies with pharmacological inhibitor and/or neutralizing antibody were used to identify the potential molecule(s) and pathway(s) involved in DC senescence and dysfunction induced by Treg cells. Impaired tumor antigen HER2-specific recognition and immune response of senescent DCs induced by γδ Treg cells were explored in vitro and in vivo in humanized mouse models. In addition, the DC-based HER2 tumor vaccine immunotherapy in breast cancer models was performed to explore the enhanced antitumor immunity via prevention of DC senescence through blockages of STAT3 and programmed death-ligand 1 (PD-L1) signaling. RESULTS: We showed that tumor-derived γδ Treg cells promote the development of senescence in DCs with tolerogenic functions in breast cancer. Senescent DCs induced by γδ Treg cells suppress Th1 and Th17 cell differentiation but promote the development of Treg cells. In addition, we demonstrated that PD-L1 and STAT3 signaling pathways are critical and involved in senescence induction in DCs mediated by tumor-derived γδ Treg cells. Importantly, our complementary in vivo studies further demonstrated that blockages of PD-L1 and/or STAT3 signaling can prevent γδ Treg-induced senescence and reverse tolerogenic functions in DCs, resulting in enhanced HER2 tumor-specific immune responses and immunotherapy efficacy in human breast cancer models. CONCLUSIONS: These studies not only dissect the suppressive mechanism mediated by tumor-derived γδ Treg cells on DCs in the tumor microenvironment but also provide novel strategies to prevent senescence and dysfunction in DCs and enhance antitumor efficacy mediated by tumor-specific T cells for cancer immunotherapy.

SRT1720 inhibits bladder cancer cell progression by impairing autophagic flux.

Bladder cancer (BC) is the most common cancer of the urinary tract, with poor survival, high recurrence rates, and lacking of targeted drugs. In this study, we constructed a library to screen compounds inhibiting bladder cancer cells growth. Among them, SRT1720 was identified to inhibit bladder cancer cell proliferation in vitro and in vivo. SRT1720 treatment also suppressed bladder cancer cells migration, invasion and induced apoptosis. Mechanism studies shown that SRT1720 promoted autophagosomes accumulation by inducing early-stage autophagy but disturbed the late-stage of autophagy by blocking fusion of autophagosomes and lysosomes. SRT1720 appears to induce autophagy related proteins expression and alter autophagy-related proteins acetylation to impede the autophagy flux. LAMP2, an important lysosomal associated membrane protein, may mediate SRT1720-inhibited autophagy flux as SRT1720 treatment significantly deacetylated LAMP2 which may influence its activity. Taken together, our results demonstrated that SRT1720 mediated apoptosis and autophagy flux inhibition may be a novel therapeutic strategy for bladder cancer treatment.

Raltitrexed induces apoptosis through activating ROS-mediated ER stress by impeding HSPA8 expression in prostate cancer cells.

Prostate cancer is the most common malignant tumor in males, which frequently develops into castration-resistant prostate cancer (CRPC). CRPC metastasis is the main reason for its high mortality rate. At present, it lacks effective treatment for patients with CRPC. Raltitrexed (RTX) has been shown to be effective in the treatment of colorectal cancer. However, the effect of RTX on prostate cancer and the underlying mechanism remain unknown. In the current study, we found that RTX could dose-dependently inhibit proliferation, migration, colony formation and induce apoptosis in DU145 and PC-3 cells. RTX also increased ROS generation in prostate cancer cells. Pretreatment with N-acetyl-L-cysteine (NAC) significantly prevented RTX-induced cell apoptosis and endoplasmic reticulum (ER) stress signaling activation in prostate cancer cells. Additionally, we found RTX-induced ROS generation and ER stress activation depended on the expression of heat shock protein family A member 8 (HSPA8). Over-expression of HSPA8 could alleviate RTX-induced cell apoptosis, ROS generation and ER stress signaling activation. Finally, our study also showed that RTX attenuated the tumor growth of prostate cancer in the DU145 xenograft model and significantly downregulated HSPA8 expression and activated ER stress signaling pathway in tumor tissues. Our study is the first to reveal that RTX induces prostate cancer cells apoptosis through inhibiting the expression of HSPA8 and further inducing ROS-mediated ER stress pathway action. This study suggests that RTX may be a novel promising candidate drug for prostate cancer therapy.

ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia.

BACKGROUND: In recent years, the development of adjunctive therapeutic hyperthermia for cancer therapy has received considerable attention. However, the mechanisms underlying hyperthermia resistance are still poorly understood. In this study, we investigated the roles of cold­inducible RNA binding protein (Cirbp) in regulating hyperthermia resistance and underlying mechanisms in nasopharyngeal carcinoma (NPC). METHODS: CCK-8 assay, colony formation assay, tumor sphere formation assay, qRT-PCR, Western blot were employed to examine the effects of hyperthermia (HT), HT + oridonin(Ori) or HT + radiotherapy (RT) on the proliferation and stemness of NPC cells. RNA sequencing was applied to gain differentially expressed genes upon hyperthermia. Gain-of-function and loss-of-function experiments were used to evaluate the effects of RNAi-mediated Cirbp silencing or Cirbp overexpression on the sensitivity or resistance of NPC cells and cancer stem-like cells to hyperthermia by CCK-8 assay, colony formation assay, tumorsphere formation assay and apoptosis assay, and in subcutaneous xenograft animal model. miRNA transient transfection and luciferase reporter assay were used to demonstrate that Cirbp is a direct target of miR-377-3p. The phosphorylation levels of key members in ATM-Chk2 and ATR-Chk1 pathways were detected by Western blot. RESULTS: Our results firstly revealed that hyperthermia significantly attenuated the stemness of NPC cells, while combination treatment of hyperthermia and oridonin dramatically increased the killing effect on NPC cells and cancer stem cell (CSC)­like population. Moreover, hyperthermia substantially improved the sensitivity of radiation­resistant NPC cells and CSC­like cells to radiotherapy. Hyperthermia noticeably suppressed Cirbp expression in NPC cells and xenograft tumor tissues. Furthermore, Cirbp inhibition remarkably boosted anti­tumor­killing activity of hyperthermia against NPC cells and CSC­like cells, whereas ectopic expression of Cirbp compromised tumor­killing effect of hyperthermia on these cells, indicating that Cirbp overexpression induces hyperthermia resistance. ThermomiR-377-3p improved the sensitivity of NPC cells and CSC­like cells to hyperthermia in vitro by directly suppressing Cirbp expression. More importantly, our results displayed the significantly boosted sensitization of tumor xenografts to hyperthermia by Cirbp silencing in vivo, but ectopic expression of Cirbp almost completely counteracted hyperthermia-mediated tumor cell-killing effect against tumor xenografts in vivo. Mechanistically, Cirbp silencing-induced inhibition of DNA damage repair by inactivating ATM-Chk2 and ATR-Chk1 pathways, decrease in stemness and increase in cell death contributed to hyperthermic sensitization; conversely, Cirbp overexpression-induced promotion of DNA damage repair, increase in stemness and decrease in cell apoptosis contributed to hyperthermia resistance. CONCLUSION: Taken together, these findings reveal a previously unrecognized role for Cirbp in positively regulating hyperthermia resistance and suggest that thermomiR-377-3p and its target gene Cirbp represent promising targets for therapeutic hyperthermia.

Sanguinarine chloride induces ferroptosis by regulating ROS/BACH1/HMOX1 signaling pathway in prostate cancer.

BACKGROUND: Sanguinarine chloride (S.C) is a benzophenanthrine alkaloid derived from the root of sanguinaria canadensis and other poppy-fumaria species. Studies have reported that S.C exhibits antioxidant, anti-inflammatory, proapoptotic, and growth inhibitory effects, which contribute to its anti-cancer properties. Recent studies suggested that the antitumor effect of S.C through inducing ferroptosis in some cancers. Nevertheless, the precise mechanism underlying the regulation of ferroptosis by S.C remains poorly understood. METHODS: A small molecule library was constructed based on FDA and CFDA approved small molecular drugs. CCK-8 assay was applied to evaluate the effects of the small molecule compound on tumor cell viability. Prostate cancer cells were treated with S.C and then the cell viability and migration ability were assessed using CCK8, colony formation and wound healing assay. Reactive oxygen species (ROS) and iron accumulation were quantified through flow cytometry analysis. The levels of malondialdehyde (MDA) and total glutathione (GSH) were measured using commercially available kits. RNA-seq analysis was performed to identify differentially expressed genes (DEGs) among the treatment groups. Western blotting and qPCR were utilized to investigate the expression of relevant proteins and genes. In vivo experiments employed a xenograft mice model to evaluate the anti-cancer efficacy of S.C. RESULTS: Our study demonstrated that S.C effectively inhibited the viability of various prostate cancer cells. Notably, S.C exhibited the ability to enhance the cytotoxicity of docetaxel in DU145 cells. We found that S.C-induced cell death partially relied on the induction of ferroptosis, which was mediated through up-regulation of HMOX1 protein. Additionally, our investigation revealed that S.C treatment decreased the stability of BACH1 protein, which contributed to HMOX1expression. We further identified that S.C-induced ROS caused BACH1 instability by suppressing USP47expression. Moreover, In DU145 xenograft model, we found S.C significantly inhibited prostate cancer growth, highlighting its potential as a therapeutic strategy. Collectively, these findings provide evidence that S.C could induce regulated cell death (RCD) in prostate cancer cells and effectively inhibit tumor growth via triggering ferroptosis. This study provides evidence that S.C effectively suppresses tumor progression and induces ferroptosis in prostate cancer cells by targeting ROS/USP47/BACH1/HMOX1 axis. CONCLUSION: This study provides evidence that S.C effectively suppresses tumor progression and induces ferroptosis in prostate cancer cells by targeting the ROS/USP47/BACH1/HMOX1 axis. These findings offer novel insights into the underlying mechanism by which S.C inhibits the progression of prostate cancer. Furthermore, leveraging the potential of S.C in targeting ferroptosis may present a new therapeutic opportunity for prostate cancer. This study found that S.C induces ferroptosis by targeting the ROS/USP47/BACH1/HMOX1 axis in prostate cancer cells.

A Temporary Intraoperative Fixation Method for the Absorbable Plates Fixation of Condylar Fracture by Retromandibular Transparotid Approach.

The authors describe a temporary intraoperative fixation method for the absorbable plates' fixation of subcondylar fracture by retromandibular transparotid approach. First, the fracture was temporarily fixed with a 4-hole titanium microplate across the fracture line in the center of the lateral surface of the condyle to maintain the reduction of the fracture. Then, two 4-hole absorbable mini-plates were fixed on the posterior and anterior border of the condylar neck. Finally, the 4-hole titanium microplate and screws were removed before the wound closure. In the absorbable plates' fixation of subcondylar fracture by transparotid approach, the method of temporary intraoperative fixation using a 4-hole titanium microplate offsets the limited exposure of the operative field, smooths the operation, and offers the reliability and validity of the absorbable plates' fixation.

Hepatocyte TIPE2 is a fasting-induced Raf-1 inactivator that drives hepatic gluconeogenesis to maintain glucose homeostasis.

BACKGROUND: The liver regulates metabolic balance during fasting-feeding cycle. Hepatic adaptation to fasting is precisely modulated on multiple levels. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a negative regulator of immunity that reduces several liver pathologies, but its physiological roles in hepatic metabolism are largely unknown. METHODS: TIPE2 expression was examined in mouse liver during fasting-feeding cycle. TIPE2-knockout mice, liver-specific TIPE2-knockout mice, liver-specific TIPE2-overexpressed mice were examined for fasting blood glucose and pyruvate tolerance test. Primary hepatocytes or liver tissues from these mice were evaluated for glucose production, lipid accumulation, gene expression and regulatory pathways. TIPE2 interaction with Raf-1 and TIPE2 transcription regulated by PPAR-α were examined using gene overexpression or knockdown, co-immunoprecipitation, western blot, luciferase reporter assay and DNA-protein binding assay. RESULTS: TIPE2 expression was upregulated in fasted mouse liver and starved hepatocytes, which was positively correlated with gluconeogenic genes. Liver-specific TIPE2 deficiency impaired blood glucose homeostasis and gluconeogenic capacity in mice upon fasting, while liver-specific TIPE2 overexpression elevated fasting blood glucose and hepatic gluconeogenesis in mice. In primary hepatocytes upon starvation, TIPE2 interacted with Raf-1 to accelerate its ubiquitination and degradation, resulting in ERK deactivation and FOXO1 maintenance to sustain gluconeogenesis. During prolonged fasting, hepatic TIPE2 deficiency caused aberrant activation of ERK-mTORC1 axis that increased hepatic lipid accumulation via lipogenesis. In hepatocytes upon starvation, PPAR-α bound with TIPE2 promoter and triggered its transcriptional expression. CONCLUSIONS: Hepatocyte TIPE2 is a PPAR-α-induced Raf-1 inactivator that sustains hepatic gluconeogenesis and prevents excessive hepatic lipid accumulation, playing beneficial roles in hepatocyte adaptation to fasting.

CAB39 promotes cisplatin resistance in bladder cancer via the LKB1-AMPK-LC3 pathway.

Systemic therapy for muscle-invasive bladder cancer (BC) remains dominated by cisplatin-based chemotherapy. However, resistance to cisplatin therapy greatly limits long-term survival. Resistance to cisplatin-based chemotherapy still needs to be addressed. In this study, we established three cisplatin-resistant BC cell lines by multiple cisplatin pulse treatments. Interestingly, after exposure to cisplatin, all cisplatin-resistant cell lines showed lower reactive oxygen species (ROS) levels than the corresponding parental cell lines. Using proteomic analysis, we identified 35 proteins that were upregulated in cisplatin-resistant BC cells. By knocking down eleven of these genes, we found that after CAB39 knockdown, BC cisplatin-resistant cells were more sensitive to cisplatin. Overexpression of CAB39 had the opposite effect. Then, the knockdown of six genes downstream of CAB39 revealed that CAB39 promoted cisplatin resistance in BC through LKB1. Moreover, a key cause of cisplatin-induced cell death is damage to mitochondria and increased ROS levels. In our study, cisplatin-resistant cells exhibited higher autophagic flux and healthier mitochondrial status after cisplatin exposure. We demonstrated that the CAB39-LKB1-AMPK-LC3 pathway plays a critical role in enhancing autophagy to maintain the health of mitochondria and reduce ROS levels. In addition, the autophagy inhibitor chloroquine (CQ) can significantly enhance the killing effect of cisplatin on BC cells. Compared with gemcitabine plus cisplatin (GC), GC plus CQ significantly reduced tumor burden in vivo. In conclusion, our study shows that CAB39 counteracts the killing of cisplatin by enhancing the autophagy of BC cells to damaged mitochondria and other organelles to alleviate the damage of cells caused by harmful substances such as ROS.

The RNA polymerase II subunit B (RPB2) functions as a growth regulator in human glioblastoma.

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor with a poor prognosis. The growth of GBM cells depends on the core transcriptional apparatus, thus rendering RNA polymerase (RNA pol) complex as a candidate therapeutic target. The RNA pol II subunit B (POLR2B) gene encodes the second largest subunit of the RNA pol II (RPB2); however, its genomic status and function in GBM remain unclear. Certain GBM data sets in cBioPortal were used for investigating the genomic status and expression of POLR2B in GBM. The function of RPB2 was analyzed following knockdown of POLR2B expression by shRNA in GBM cells. The cell counting kit-8 assay and PI staining were used for cell proliferation and cell cycle analysis. A xenograft mouse model was established to analyze the function of RPB2 in vivo. RNA sequencing was performed to analyze the RPB2-regulated genes. GO and GSEA analyses were applied to investigate the RPB2-regulated gene function and associated pathways. In the present study, the genomic alteration and overexpression of the POLR2B gene was described in glioblastoma. The data indicated that knockdown of POLR2B expression suppressed tumor cell growth of glioblastoma in vitro and in vivo. The analysis further demonstrated the identification of the RPB2-regulated gene sets and highlighted the DNA damage-inducible transcript 4 gene as the downstream target of the POLR2B gene. The present study provides evidence indicating that RPB2 functions as a growth regulator in glioblastoma and could be used as a potential therapeutic target for the treatment of this disease.

Understanding the time-activity pattern to improve the measurement of personal exposure: An exploratory and experimental research.

Although ambient fine particulate matter (PM2.5) concentrations and their components are commonly used as proxies for personal exposure monitoring, developing an accurate and cost-effective method to use these proxies for personal exposure measurement continues to pose a significant challenge. Herein, we propose a scenario-based exposure model to precisely estimate personal exposure level of heavy metal(loid)s (HMs) using scenario HMs concentrations and time-activity patterns. Personal exposure levels and ambient pollution levels for PM2.5 and HMs differed significantly with corresponding personal/ambient ratios of approximately 2, and exposure scenarios could narrow the assessment error gap by 26.1-45.4%. Using a scenario-based exposure model, we assessed the associated health risks of a large sample population and identified that the carcinogenic risk of As exceeded 1 × 10-6, while we observed non-carcinogenic risks from As, Cd, Ni, and Mn in personal exposure to PM2.5. We conclude that the scenario-based exposure model is a preferential alternative for monitoring personal exposure compared to ambient concentrations. This method ensures the feasibility of personal exposure monitoring and health risk assessments in large-scale studies.

Neurokinin-1 receptor drives PKCɑ-AURKA/N-Myc signaling to facilitate the neuroendocrine progression of prostate cancer.

The widespread application of antiandrogen therapies has aroused a significant increase in the incidence of NEPC, a lethal form of the disease lacking efficient clinical treatments. Here we identified a cell surface receptor neurokinin-1 (NK1R) as a clinically relevant driver of treatment-related NEPC (tNEPC). NK1R expression increased in prostate cancer patients, particularly higher in metastatic prostate cancer and treatment-related NEPC, implying a relation with the progression from primary luminal adenocarcinoma toward NEPC. High NK1R level was clinically correlated with accelerated tumor recurrence and poor survival. Mechanical studies identified a regulatory element in the NK1R gene transcription ending region that was recognized by AR. AR inhibition enhanced the expression of NK1R, which mediated the PKCα-AURKA/N-Myc pathway in prostate cancer cells. Functional assays demonstrated that activation of NK1R promoted the NE transdifferentiation, cell proliferation, invasion, and enzalutamide resistance in prostate cancer cells. Targeting NK1R abrogated the NE transdifferentiation process and tumorigenicity in vitro and in vivo. These findings collectively characterized the role of NK1R in tNEPC progression and suggested NK1R as a potential therapeutic target.

Hairy gene homolog increases nasopharyngeal carcinoma cell stemness by upregulating Bmi-1.

B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) is overexpressed in various cancer types. We found that Bmi-1 mRNA levels were elevated in nasopharyngeal carcinoma (NPC) cell lines. In immunohistochemical analyses, high Bmi-1 levels were observed in not only 5 of 38 non-cancerous nasopharyngeal squamous epithelial biopsies, but also in 66 of 98 NPC specimens (67.3%). High Bmi-1 levels were detected more frequently in T3-T4, N2-N3 and stage III-IV NPC biopsies than in T1-T2, N0-N1 and stage I-II NPC samples, indicating that Bmi-1 is upregulated in advanced NPC. In 5-8F and SUNE1 NPC cells, stable depletion of Bmi-1 using lentiviral RNA interference greatly suppressed cell proliferation, induced G1-phase cell cycle arrest, reduced cell stemness and suppressed cell migration and invasion. Likewise, knocking down Bmi-1 inhibited NPC cell growth in nude mice. Both chromatin immunoprecipitation and Western blotting assays demonstrated that Hairy gene homolog (HRY) upregulated Bmi-1 by binding to its promoter, thereby increasing the stemness of NPC cells. Immunohistochemistry and quantitative real-time PCR analyses revealed that HRY expression correlated positively with Bmi-1 expression in a cohort of NPC biopsies. These findings suggested that HRY promotes NPC cell stemness by upregulating Bmi-1, and that silencing Bmi-1 can suppress NPC progression.