Establishment and application of a root wounding-immersion method for efficient virus-induced gene silencing in plants.

In the post-genomic era, virus-induced gene silencing (VIGS) has played an important role in research on reverse genetics in plants. Commonly used Agrobacterium-mediated VIGS inoculation methods include stem scratching, leaf infiltration, use of agrodrench, and air-brush spraying. In this study, we developed a root wounding-immersion method in which 1/3 of the plant root (length) was cut and immersed in a tobacco rattle virus (TRV)1:TRV2 mixed solution for 30 min. We optimized the procedure in Nicotiana benthamiana and successfully silenced N. benthamiana, tomato (Solanum lycopersicum), pepper (Capsicum annuum L.), eggplant (Solanum melongena), and Arabidopsis thaliana phytoene desaturase (PDS), and we observed the movement of green fluorescent protein (GFP) from the roots to the stem and leaves. The silencing rate of PDS in N. benthamiana and tomato was 95-100%. In addition, we successfully silenced two disease-resistance genes, SITL5 and SITL6, to decrease disease resistance in tomatoes (CLN2037E). The root wounding-immersion method can be used to inoculate large batches of plants in a short time and with high efficiency, and fresh bacterial infusions can be reused several times. The most important aspect of the root wounding-immersion method is its application to plant species susceptible to root inoculation, as well as its ability to inoculate seedlings from early growth stages. This method offers a means to conduct large-scale functional genome screening in plants.

Ventriculoperitoneal shunting obstruction: a multicentre clinical audit for cerebrospinal fluid parameters and its prediction role.

BACKGROUND: Shunt obstruction is a type of ventriculoperitoneal shunt (VPS) failure. Whether changes in cerebrospinal fluid (CSF) parameters can influence shunt outcomes or not is debatable. METHODS: In this study, we retrospectively included adult hydrocephalus patients who received VPS from 6 general hospitals in different provinces of China from November 2013 to September 2021. The inclusion criteria: Patients with hydrocephalus of all etiologies underwent shunt surgery from 6 general hospitals in different provinces of China were included in the study. The exclusion criteria: 1.Patients under the age of 18; 2.Patients who had previous shunt surgery; 3. Shunt failure from other factors; 4.Patients died from other causes; 5. Patients with incomplete data. The CSF of shunt patients had been analyzed at the time of shunt insertion. The CSF samples were collected and analyzed when the shunt was implanted. The relationship between CSF parameters and the incidence rate of shunt obstruction in one year was analyzed. RESULTS: A total of 717 eligible patients from 6 hospitals were included, of whom 59(8.23%) experienced obstruction. Multivariate logistic regression analysis identified that protein level(odds ratio [OR] 1.161, 95% CI 1.005 ~ 1.341, p = 0.043), decreased glucose level(< 2.5 mmol/L)(odds ratio 3.784, 95% confidence interval 1.872 ~ 7.652, p = 0.001) and protein level increase(> 0.45 g/L) (odds ratio 3.653, 95% confidence interval 1.931 ~ 6.910, p = 0.001)were independent risk factors of shunt obstruction. CONCLUSION: This study suggested that increased protein level (> 0.45 g/L) and decreased glucose level (< 2.5 mmol/L) in CSF indicated an increased risk of shunt obstruction in a patient with hydrocephalus. Thus, shunt surgery should be more carefully considered when the CSF glucose and protein were abnormal.

Preoperative peripheral inflammatory markers are predictors of postoperative central diabetes insipidus in craniopharyngioma patients: a retrospective study.

BACKGROUND: Postoperative central diabetes insipidus (CDI) is commonly observed in craniopharyngioma (CP) patients, and the inflammatory response plays an important role in CPs. We aimed to evaluate the predictive value of preoperative peripheral inflammatory markers and their combinations regarding CDI occurrence in CPs. METHODS: The clinical data including preoperative peripheral inflammatory markers of 208 CP patients who underwent surgical treatment were retrospectively collected and analyzed. The preoperative peripheral white blood cells (WBC), neutrophils, lymphocytes, monocytes, platelet (PLT), neutrophil-to-lymphocyte ratio (NLR), derived-NLR (dNLR), monocyte-to-lymphocyte ratio (MLR) and PLT-to-lymphocyte ratio (PLR) were assessed in total 208 CP patients and different age and surgical approach CP patient subgroups. Their predictive values were evaluated by the receiver operator characteristic curve analysis. RESULTS: Preoperative peripheral WBC, neutrophils, NLR, dNLR, MLR, and PLR were positively correlated and lymphocyte was negatively associated with postoperative CDI occurrence in CP patients, especially when WBC ≥ 6.66 × 109/L or lymphocyte ≤ 1.86 × 109/L. Meanwhile, multiple logistic regression analysis showed that WBC > 6.39 × 109/L in the > 18 yrs age patients, WBC > 6.88 × 109/L or lymphocytes ≤ 1.85 × 109/L in the transcranial approach patients were closely associated with the elevated incidence of postoperative CDI. Furthermore, the area under the curve obtained from the receiver operator characteristic curve analysis showed that the best predictors of inflammatory markers were the NLR in total CP patients, the MLR in the ≤ 18 yrs age group and the transsphenoidal group, the NLR in the > 18 yrs age group and the dNLR in the transcranial group. Notably, the combination index NLR + dNLR demonstrated the most valuable predictor in all groups. CONCLUSIONS: Preoperative peripheral inflammatory markers, especially WBC, lymphocytes and NLR + dNLR, are promising predictors of postoperative CDI in CPs.

Inducing ubiquitination and degradation of TrxR1 protein by LW-216 promotes apoptosis in non-small cell lung cancer via triggering ROS production.

Thioredoxin reductases are frequently overexpressed in various solid tumors as a protective mechanism against heightened oxidative stress. Inhibitors of this system, such as Auranofin, are effective in eradicating cancer cells. However, the clinical significance of thioredoxin reductase 1 (TrxR1) in lung cancer, as well as the potential for its antagonist as a treatment option, necessitated further experimental validation. In this study, we observed significant upregulation of TrxR1 specifically in non-small cell lung cancer (NSCLC), rather than small cell lung cancer. Moreover, TrxR1 expression exhibited associations with survival rate, tumor volume, and histological classification. We developed a novel TrxR1 inhibitor named LW-216 and assessed its antitumor efficacy in NSCLC. Our results revealed that LW-216 is effectively bound with intracellular TrxR1 at sites R371 and G442, facilitating TrxR1 ubiquitination and suppressing TrxR1 expression, while not affecting TrxR2 expression. Treatment of LW-216-induced DNA damage and cell apoptosis in NSCLC cells through the generation of reactive oxygen species (ROS). Importantly, supplementation with N-acetylcysteine (NAC) or ectopic TrxR1 expression reversed LW-216-induced apoptosis. Furthermore, LW-216 displayed potent tumor growth inhibition in NSCLC cell-implanted mice, reducing TrxR1 expression in xenografts. Remarkably, LW-216 exhibited superior antitumor activity compared to Auranofin in vivo. Collectively, our research provides compelling evidence supporting the potential of targeting TrxR1 by LW-216 as a promising therapeutic strategy for NSCLC.

Recent advances in the application of gasotransmitters in spinal cord injury.

Spinal Cord Injury (SCI) is a condition characterized by complete or incomplete motor and sensory impairment, as well as dysfunction of the autonomic nervous system, caused by factors such as trauma, tumors, or inflammation. Current treatment methods primarily include traditional approaches like spinal canal decompression and internal fixation surgery, steroid pulse therapy, as well as newer techniques such as stem cell transplantation and brain-spinal cord interfaces. However, the above methods have limited efficacy in promoting axonal and neuronal regeneration. The challenge in medical research today lies in promoting spinal cord neuron regeneration and regulating the disrupted microenvironment of the spinal cord. Studies have shown that gas molecular therapy is increasingly used in medical research, with gasotransmitters such as hydrogen sulfide, nitric oxide, carbon monoxide, oxygen, and hydrogen exhibiting neuroprotective effects in central nervous system diseases. The gas molecular protect against neuronal death and reshape the microenvironment of spinal cord injuries by regulating oxidative, inflammatory and apoptotic processes. At present, gas therapy mainly relies on inhalation for systemic administration, which cannot effectively enrich and release gas in the spinal cord injury area, making it difficult to achieve the expected effects. With the rapid development of nanotechnology, the use of nanocarriers to achieve targeted enrichment and precise control release of gas at Sites of injury has become one of the emerging research directions in SCI. It has shown promising therapeutic effects in preclinical studies and is expected to bring new hope and opportunities for the treatment of SCI. In this review, we will briefly outline the therapeutic effects and research progress of gasotransmitters and nanogas in the treatment of SCI.

[Construction and Optimization of CD19 Chimeric Antigen Receptor T Cells Derived from C57BL/6J Mice].

OBJECTIVE: To explore the stimulation conditions, optimal culture time and infection time of C57BL/6J mice CD3+ T cells in vitro, so as to improve the infection efficiency of CD19 chimeric antigen receptor T cells (mCD19 CAR-T). METHODS: Purified C57BL/6J mice CD3+ T cells were cultured in anti-CD3/CD28 coated, anti-CD3 coated+soluble anti-CD28 and anti-CD3 coated, respectively. The cells were stimulated in above three conditions for 12 h and 24 h, following with 24 h, 48 h and 72 h incubation and then the number of cell clones was recorded. C57BL/6J mice CD3+ T cells were stimulated for 12 h, 24 h, and 36 h under the above three conditions, then interleukin (IL)-2 (100 U/ml) was added. The number of cell clones was recorded under microscope at 24 h, 48 h, and 72 h of culture. After 24 h of stimulation, CD3+ T cells derived from C57BL/6J mice were infected with retrovirus for 48 h to establish mCD19 CAR-T cells, and the percentage of GFP+ CAR-T cells was detected by flow cytometry. RESULTS: The infection efficiency of mCD19 CAR-T cells derived from C57BL/6J mice was only 5.23% under the optimized conditions of mCD19 CAR-T cells derived from BALB/c mice. The number of clones of C57BL/6J mice CD3+ T cells was the highest in anti-CD3 coated+soluble anti-CD28 group after stimulated for 24 h and followed cultured for 48 h. After 24 hours of stimulation under the above conditions and 48 hours of culture with IL-2, the number of T cell proliferating clones in the anti-CD3 coated+soluble anti-CD28 group was significantly increased compared with the same group without IL-2, and the infection efficiency of CAR-T cells in this group reached 17.63%±4.17%. CONCLUSION: The optimal conditions for constructing CAR-T cells from C57BL/6J mice CD3+ T cells are different from those of BABL/c mice. T cells stimulated by anti-CD3 coated+soluble anti-CD28+IL-2 can obtain mCD19 CAR-T cells with the highest efficiency after retrovirus infection.

Risk factors for inadequate bowel preparation before colonoscopy: A meta-analysis.

OBJECTIVE: This meta-analysis aimed to comprehensively explore the risk factors for inadequate bowel preparation (IBP). METHODS: We searched the Embase, PubMed, Web of Science, and The Cochrane Library databases up to August 24, 2023, to identify observational studies and randomized controlled trials (RCTs) that examined risk factors for IBP. A random effects model was used to pool the adjusted odds ratios and 95% confidence intervals. RESULTS: A total of 125 studies (91 observational studies, 34 RCTs) were included. Meta-analyses of observational studies revealed that three preparation-related factors, namely, characteristics of last stool (solid or brown liquid), incomplete preparation intake, and incorrect diet restriction, were strong predictors of IBP. The other factors were moderately correlated with IBP incidence, including demographic variables (age, body mass index, male sex, Medicaid insurance, and current smoking), comorbidities (diabetes, liver cirrhosis, psychiatric disease, Parkinson's disease, previous IBP, poor mobility, inpatient, and Bristol stool form 1/2), medications (tricyclic antidepressants, opioids, antidepressants, narcotics, antipsychotics, and calcium channel blockers), and preparation-related factors (preparation-to-colonoscopy interval not within 3 to 5/6 h, nonsplit preparation, and preparation instructions not followed). No colonoscopy indications were found to be related to IBP. Meta-analyses of RCTs showed that education, constipation, stroke/dementia, and discomfort during preparation were also moderately associated with IBP. Most of the other findings were consistent with the pooled results of observational studies. However, primarily due to imprecision and inconsistency, the certainty of evidence for most factors was very low to moderate. CONCLUSIONS: We summarized five categories of risk factors for IBP. Compared to demographic variables, comorbidities, medications, and colonoscopy indications, preparation-related elements were more strongly associated with IBP. These findings may help clinicians identify high-risk individuals and provide guidance for IBP prevention.

Interaction of immune cells with renal cancer development: Mendelian randomization (MR) study.

BACKGROUND: Renal cell carcinoma (RCC) is a prevalent and extensively immune-infiltrated malignancy of the urinary system. Immune cells play a crucial role in both the progression and therapeutic interventions targeting RCC. Nevertheless, the interplay between RCC and immune cells remains understudied, lacking substantial evidence supporting their causal relationship. METHODS: For the purpose of investigating the causal connection between RCC and immune cell characteristics, a two-way two-sample Mendelian randomization (MR) analysis was carried out in this study. The aim was to determine whether specific immune cell traits have a causal impact on the risk of RCC. In order to achieve this, publicly accessible genetic data was utilized to examine and establish the potential relationship between 731 immune cell characteristics and the likelihood of developing RCC. Additionally, various techniques were applied to verify the reliability, variability, and presence of horizontal pleiotropy in the outcomes. RESULTS: We found a bidirectional causal relationship between RCC and immune cells according to the MR analysis results. It should be noted that CD4-CD8-T cells (OR = 1.61, 95%CI = 1.02-2.55, P = 4.07 × 10-2) pose a risk for RCC, whereas BAFF-R (OR = 0.69, 95%CI = 0.53-0.89, P = 5.74 × 10-3) and CD19 (OR = 0.59, 95%CI = 1.02-2.55, P = 4.07 × 10-2) on B cells act as protective factors. Furthermore, the presence of RCC reduces the levels of B cells (OR = 1.05, 95%CI = 1.01-1.09, P = 1.19 × 10-2) and CD8 + T cells (OR = 1.04, 95%CI = 1.00-1.08, P = 2.83 × 10-2). CONCLUSIONS: Our research illustrates the intricate correlation between immune cells and RCC, presenting novel insights for the prospective safeguarding against RCC risk and the exploration of fresh therapeutic targets.

A Novel Approach for Glioblastoma Treatment by Combining Apoptosis Inducers (TMZ, MTX, and Cytarabine) with E.V.A. (Eltanexor, Venetoclax, and A1210477) Inhibiting XPO1, Bcl-2, and Mcl-1.

Adjuvant treatment for Glioblastoma Grade 4 with Temozolomide (TMZ) inevitably fails due to therapeutic resistance, necessitating new approaches. Apoptosis induction in GB cells is inefficient, due to an excess of anti-apoptotic XPO1/Bcl-2-family proteins. We assessed TMZ, Methotrexate (MTX), and Cytarabine (Ara-C) (apoptosis inducers) combined with XPO1/Bcl-2/Mcl-1-inhibitors (apoptosis rescue) in GB cell lines and primary GB stem-like cells (GSCs). Using CellTiter-Glo® and Caspase-3 activity assays, we generated dose-response curves and analyzed the gene and protein regulation of anti-apoptotic proteins via PCR and Western blots. Optimal drug combinations were examined for their impact on the cell cycle and apoptosis induction via FACS analysis, paralleled by the assessment of potential toxicity in healthy mouse brain slices. Ara-C and MTX proved to be 150- to 10,000-fold more potent in inducing apoptosis than TMZ. In response to inhibitors Eltanexor (XPO1; E), Venetoclax (Bcl-2; V), and A1210477 (Mcl-1; A), genes encoding for the corresponding proteins were upregulated in a compensatory manner. TMZ, MTX, and Ara-C combined with E, V, and A evidenced highly lethal effects when combined. As no significant cell death induction in mouse brain slices was observed, we conclude that this drug combination is effective in vitro and expected to have low side effects in vivo.

B-Myb deficiency boosts bortezomib-induced immunogenic cell death in colorectal cancer.

B-Myb has received considerable attention for its critical tumorigenic function of supporting DNA repair. However, its modulatory effects on chemotherapy and immunotherapy have rarely been reported in colorectal cancer. Bortezomib (BTZ) is a novel compound with chemotherapeutic and immunotherapeutic effects, but it fails to work in colorectal cancer with high B-Myb expression. The present study was designed to investigate whether B-Myb deletion in colorectal cancer could potentiate the immune efficacy of BTZ against colorectal cancer and to clarify the underlying mechanism. Stable B-Myb knockdown was induced in colorectal cancer cells, which increased apoptosis of the cancer cells relative to the control group in vitro and in vivo. We found that BTZ exhibited more favourable efficacy in B-Myb-defective colorectal cancer cells and tumor-bearing mice. BTZ treatment led to differential expression of genes enriched in the p53 signaling pathway promoted more powerful downstream DNA damage, and arrested cell cycle in B-Myb-defective colorectal cancer. In contrast, recovery of B-Myb in B-Myb-defective colorectal cancer cells abated BTZ-related DNA damage, cell cycle arrest, and anticancer efficacy. Moreover, BTZ promoted DNA damage-associated enhancement of immunogenicity, as indicated by potentiated expression of HMGB1 and HSP90 in B-Myb-defective cells, thereby driving M1 polarization of macrophages. Collectively, B-Myb deletion in colorectal cancer facilitates the immunogenic death of cancer cells, thereby further promoting the immune efficacy of BTZ by amplifying DNA damage. The present work provides an effective molecular target for colorectal cancer immunotherapy with BTZ.

Comparison of three concentrations of ropivacaine in posterior quadratus lumborum block: A randomized clinical trial.

Background: A conclusive evidence regarding the optimal concentration and volume of local anesthetic for quadratus lumborum block is lacking. Methods: In this single-center, prospective, randomized, controlled study, 60 patients scheduled for laparoscopic colorectal surgery were randomly assigned to 3 different combinations of volume and concentration of ropivacaine (3 mg/kg) - Group 0.25%, Group 0.375% and Group 0.5%. All subjects received ultrasound-guided posterior quadratus lumborum block prior to the induction. The primary outcome was the complete sensory block rate of surgical site measured at 30 min after quadratus lumborum block, after extubation, at 12, 24, and 48 h after operation. Secondary outcomes were the changes in hemodynamic parameters before and after incision (ΔSBP, ΔDBP and ΔHR), postoperative pain score, the sufentanil consumption after surgery, length of stay and adverse reactions. Results: The sensory block rate of surgical site at 5 time points differed significantly among the three groups (P < 0.001). Both Group 0.375% (P < 0.001) and Group 0.5% (P < 0.001) had a higher sensory block rate than Group 0.25%, but no significant difference was observed between the former two. Group 0.375% and Group 0.5% had lower postoperative pain scores, lower sufentanil consumption after surgery and shorter length of stay. No statistical difference was observed in ΔSBP, ΔDBP, ΔHR and the incidence of adverse reactions. Conclusions: 0.375% and 0.5% ropivacaine in posterior quadratus lumborum block provide better sensory block of surgical site when compared to 0.25% in laparoscopic colorectal surgery. Trial registration number: Chinese Clinical Trials Registry (ChiCTR2100043949).

Silent uterine rupture in the term pregnancy: Three case reports.

RATIONALE: Uterine rupture is extremely hazardous to both mothers and infants. Diagnosing silent uterine rupture in pregnant women without uterine contractions is challenging due to the presence of nonspecific symptoms, signs, and laboratory indicators. Therefore, it is crucial to identify the elevated risks associated with silent uterine rupture. PATIENT CONCERNS: on admission, case 1 was at 37 gestational weeks, having undergo laparoscopic transabdominal cerclage 8 months prior to the in vitro fertilization embryo transfer procedure, case 2 was at 38 4/7 gestational weeks with a history of 5 previous artificial abortion and 2 previous vaginal deliveries, case 3 was at 37 6/7 gestational weeks with a history of laparoscopic myomectomy. DIAGNOSES: The diagnosis of silent uterine rupture was based on clinical findings from cesarean delivery or laparoscopic exploration. INTERVENTIONS: Case 1 underwent emergent cesarean delivery, revealing a 0.25 cm × 0.25 cm narrow concave area above the Ring Ties with active and bright amniotic fluid flowing from the tear. Case 2 underwent vaginal delivery, and on the 12th postpartum day, ultrasound imaging and magnetic resonance imaging revealed a 5.8 cm × 3.3 cm × 2.3 cm lesion on the lower left posterior wall of the uterus, and 15th postpartum day, laparoscopic exploration confirmed the presence of an old rupture of uterus. Case 3 underwent elective cesarean delivery, revealing a 3.0 cm × 2.0 cm uterine rupture without active bleeding at the bottom of the uterus. OUTCOMES: The volumes of antenatal bleeding for the 3 patients were approximately 500 mL, 320 mL, and 400 mL, respectively. After silent uterine ruptures were detected, the uterine tear was routinely repaired. No maternal or neonatal complications were reported. LESSONS: Obstetricians should give particular consideration to the risk factors for silent uterine rupture, including a history of uterine surgery, such as laparoscopic transabdominal cerclage, laparoscopic myomectomy, and induced abortion.

Targeting the adenosine signaling pathway in macrophages for cancer immunotherapy.

One of the ways in which macrophages support tumorigenic growth is by producing adenosine, which acts to dampen antitumor immune responses and is generated by both tumor and immune cells in the tumor microenvironment (TME). Two cell surface expressed molecules, CD73 and CD39, boost catalytic adenosine triphosphate, leading to further increased adenosine synthesis, under hypoxic circumstances in the TME. There are four receptors (A1, A2A, A2B, and A3) expressed on macrophages that allow adenosine to perform its immunomodulatory effect. Researchers have shown that adenosine signaling is a key factor in tumor progression and an attractive therapeutic target for treating cancer. Several antagonistic adenosine-targeting biological therapies that decrease the suppressive action of tumor-associated macrophages have been produced and explored to transform this result from basic research into a therapeutic advantage. Here, we'll review the newest findings from studies of pharmacological compounds that target adenosine receptors, and their potential therapeutic value based on blocking the suppressive action of macrophages in tumors.

Penehyclidine for Prevention of Postoperative Nausea and Vomiting in Patients Undergoing Gynecological Laparoscopic Surgery Under Combined Intravenous and Inhalation Anesthesia: A Randomized, Double-Blind, Placebo-Controlled Trial.

Purpose: We designed this study to investigate the effect of intravenous use of penehyclidine on postoperative nausea and vomiting (PONV) after gynecological laparoscopic surgery. Patients and Methods: Ninety-two Women Patients (Aged ≥ 18) Scheduled for Elective Gynecologic Laparoscopy Were Enrolled in the Current Study. Patients Were Equally Randomized Assigned Into Penehyclidine group (PHC group: received a bolus of penehyclidine 10 µg/kg during the induction of anesthesia, then followed by a continuous infusion of 10 µg/kg penehyclidine at a fixed rate of 2.0 mL/h in postoperative intravenous analgesia pump over 48h, 0.5 mg upper limit respectively) or Control group (received 0.9% saline in replace of penehyclidine at the same time points). The primary outcome measure was the incidence of postoperative nausea and vomiting in the postanesthesia care unit and ward area. Quality of Recovery-15 (QoR-15) scores and general comfort questionnaire (GCQ) scores were assessed on postoperative day (POD) 1, 2. Results: Patients between two groups had comparable baseline characteristics. Compared with the Control group, the incidence and severity of PONV, postoperative nausea (PON), and postoperative vomiting (POV) were significantly lower in the PHC group at 2h (PONV: P = 0.002, P = 0.004, respectively; PON: P = 0.018, P = 0.038, respectively; POV: P = 0.011, P = 0.072, respectively), 24h (PONV: P = 0.003, P = 0.001, respectively; PON: P = 0.010, P = 0.032, respectively; POV: P = 0.006, P = 0.044, respectively), and 48h (PONV: P = 0.003, P = 0.002, respectively; PON: P = 0.007, P = 0.019, respectively; POV: P = 0.002, P = 0.013, respectively) after surgery. The QoR-15 and GCQ scores of the PHC group were significantly higher than those of the Control group at POD 1, 2 (P < 0.001; P < 0.001, respectively). Conclusion: Our findings suggest that perioperative intravenous application of penehyclidine can effectively prevent postoperative nausea and vomiting in gynecological laparoscopic surgery patients and improve postoperative recovery.

AtPCa-Net: anatomical-aware prostate cancer detection network on multi-parametric MRI.

Multi-parametric MRI (mpMRI) is widely used for prostate cancer (PCa) diagnosis. Deep learning models show good performance in detecting PCa on mpMRI, but domain-specific PCa-related anatomical information is sometimes overlooked and not fully explored even by state-of-the-art deep learning models, causing potential suboptimal performances in PCa detection. Symmetric-related anatomical information is commonly used when distinguishing PCa lesions from other visually similar but benign prostate tissue. In addition, different combinations of mpMRI findings are used for evaluating the aggressiveness of PCa for abnormal findings allocated in different prostate zones. In this study, we investigate these domain-specific anatomical properties in PCa diagnosis and how we can adopt them into the deep learning framework to improve the model's detection performance. We propose an anatomical-aware PCa detection Network (AtPCa-Net) for PCa detection on mpMRI. Experiments show that the AtPCa-Net can better utilize the anatomical-related information, and the proposed anatomical-aware designs help improve the overall model performance on both PCa detection and patient-level classification.

Bifenthrin induces changes in clinical poisoning symptoms, oxidative stress, DNA damage, histological characteristics, and transcriptome in Chinese giant salamander (Andrias davidianus) larvae.

Bifenthrin (BF) is a broad-spectrum insecticide that has gained widespread use due to its high effectiveness. However, there is limited research on the potential toxic effects of bifenthrin pollution on amphibians. This study aimed to investigate the 50 % lethal concentration (LC50) and safety concentration of Chinese giant salamanders (CGS) exposed to BF (at 0, 6.25,12.5,25 and 50 µg/L BF) for 96 h. Subsequently, CGS were exposed to BF (at 0, 0.04, and 4 µg/L BF) for one week to investigate its toxic effects. Clinical poisoning symptoms, liver pathology, oxidative stress factors, DNA damage, and transcriptome differences were observed and analyzed. The results indicate that exposure to BF at 4 µg/L significantly decreased the adenosine-triphosphate (ATP), superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) contents in the brain, liver, and kidney of CGS. Additionally, the study found that the malondialdehyde (MDA), reactive oxygen species (ROS), and 8-hydroxydeoxyguanosine (8-OHdG) contents were increased. The liver tissue exhibited significant inflammatory reactions and structural malformations. RNA-seq analysis of the liver showed that BF caused abnormal antioxidant indices of CGS. This affected molecular function genes such as catalytic activity, ATP-dependent activity, metabolic processes, signaling and immune system processes, behavior, and detoxification, which were significantly upregulated, resulting in the differential genes significantly enriched in the calcium signaling pathway, PPARα signaling pathway and NF-kB signaling pathway. The results suggest that BF induces the abnormal production of free radicals, which overwhelms the body's self-defense system, leading to varying degrees of oxidative stress. This can result in oxidative damage, DNA damage, abnormal lipid metabolism, autoimmune diseases, clinical poisoning symptoms, and tissue inflammation. This work provides a theoretical basis for the rational application of bifenthrin and environmental risk assessment, as well as scientific guidance for the conservation of amphibian populations.

Expression of overall survival-EMT-immune cell infiltration genes predict the prognosis of glioma.

This study investigates the crucial role of immune- and epithelial-mesenchymal transition (EMT)-associated genes and non-coding RNAs in glioma development and diagnosis, given the challenging 5-year survival rates associated with this prevalent CNS malignant tumor. Clinical and RNA data from glioma patients were meticulously gathered from CGGA databases, and EMT-related genes were sourced from dbEMT2.0, while immune-related genes were obtained from MSigDB. Employing consensus clustering, novel molecular subgroups were identified. Subsequent analyses, including ESTIMATE, TIMER, and MCP counter, provided insights into the tumor microenvironment (TIME) and immune status. Functional studies, embracing GO, KEGG, GSVA, and GSEA analyses, unraveled the underlying mechanisms governing these molecular subgroups. Utilizing the LASSO algorithm and multivariate Cox regression, a prognostic risk model was crafted. The study unveiled two distinct molecular subgroups with significantly disparate survival outcomes. A more favorable prognosis was linked to low immune scores, high tumor purity, and an abundance of immune infiltrating cells with differential expression of non-coding RNAs, including miRNAs. Functional analyses illuminated enrichment of immune- and EMT-associated pathways in differentially expressed genes and non-coding RNAs between these subgroups. GSVA and GSEA analyses hinted at abnormal EMT status potentially contributing to glioma-associated immune disorders. The risk model, centered on OS-EMT-ICI genes, exhibited promise in accurately predicting survival in glioma. Additionally, a nomogram integrating the risk model with clinical characteristics demonstrated notable accuracy in prognostic predictions for glioma patients. In conclusion, OS-EMT-ICI gene and non-coding RNA expression emerges as a valuable indicator intricately linked to immune microenvironment dysregulation, offering a robust tool for precise prognosis prediction in glioma patients within the OBMRC framework.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Promote the Recovery of Spinal Cord Injury and Inhibit Ferroptosis by Inactivating IL-17 Pathway.

Mesenchymal stem cell (MSC)-derived exosomes are considered as alternative to cell therapy in various diseases. This study aimed to understand the effect of bone marrow MSC-derived exosomes (BMMSC-exos) on spinal cord injury (SCI) and to unveil its regulatory mechanism on ferroptosis. Exosomes were isolated from BMMSCs and the uptake of BMMSCs-exos by PC12 cells was determined using PKH67 staining. The effect of BMMSC-exos on SCI in rats was studied by evaluating pathological changes of spinal cord tissues, inflammatory cytokines, and ferroptosis-related proteins. Transcriptome sequencing was used to discover the differential expressed genes (DEGs) between SCI rats and BMMSC-exos-treated rats followed by functional enrichment analyses. The effect of BMMSC-exos on ferroptosis and interleukin 17 (IL-17) pathway was evaluated in SCI rats and oxygen-glucose deprivation (OGD)-treated PC12 cells. The results showed that particles extracted from BMMSCs were exosomes that could be taken up by PC12 cells. BMMSC-exos treatment ameliorated injuries of spinal cord, suppressed the accumulation of Fe2+, malondialdehyde (MDA), and reactive oxygen species (ROS), with the elevated glutathione (GSH). Also, BMMSC-exos downregulated the expression of acyl-CoA synthetase long chain family member 4 (ACSL4) and upregulated glutathione peroxidase 4 (GPX4) and cysteine/glutamate antiporter xCT. A total of 110 DEGs were discovered and they were mainly enriched in IL-17 signaling pathway. Further in vitro and in vivo experiments showed that BMMSC-exos inactivated IL-17 pathway. BMMSC-exos promote the recovery of SCI and inhibit ferroptosis by inhibiting the IL-17 pathway, which provides BMMSC-exos as an alternative to the management of SCI.

SPI1 exacerbates iron accumulation and promotes osteoclast formation through inhibiting the expression of Hepcidin.

BACKGROUND: Osteoporosis (OP) can be caused by an overactive osteoclastic function. Anti-osteoporosis considerable therapeutic effects in tissue repair and regeneration because bone resorption is a unique osteoclast function. In this study, we mainly explored the underlying mechanisms of osteoclasts' effects on osteoporosis. METHODS: RAW264.7 cells were used and induced toward osteoclast and iron accumulation by M-CSF and RANKL administration. We investigated Hepcidin and divalent metal transporter 1 (DMT1) on iron accumulation and osteoclast formation in an ovariectomy (OVX)-induced osteoporosis. Osteoporosis was induced in mice by OVX, and treated with Hepcidin (10, 20, 40, 80 mg/kg, respectively) and overexpression of DMT1 by tail vein injection. Hepcidin, SPI1, and DMT1 were detected by immunohistochemical staining, western blot and RT-PCR. The bioinformatics assays, luciferase assays, and Chromatin Immunoprecipitation (ChIP) verified that Hepcidin was a direct SPI1 transcriptional target. Iron accumulation was detected by laser scanning confocal microscopy, Perl's iron staining and iron content assay. The formation of osteoclasts was assessed using tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: We found that RAW264.7 cells differentiated into osteoclasts when exposed to M-CSF and RANKL, which increased the protein levels of osteoclastogenesis-related genes, including c-Fos, MMP9, and Acp5. We also observed higher concentration of iron accumulation when M-CSF and RANKL were administered. However, Hepcidin inhibited the osteoclast differentiation cells and decreased intracellular iron concentration primary osteoclasts derived from RAW264.7. Spi-1 proto-oncogene (SPI1) transcriptionally repressed the expression of Hepcidin, increased DMT1, facilitated the differentiation and iron accumulation of mouse osteoclasts. Overexpression of SPI1 significantly declined luciferase activity of HAMP promoter and increased the enrichment of HAMP promoter. Furthermore, our results showed that Hepcidin inhibited osteoclast differentiation and iron accumulation in mouse osteoclasts and OVX mice. CONCLUSION: Therefore, the study revealed that SPI1 could inhibit Hepcidin expression contribute to iron accumulation and osteoclast formation via DMT1 signaling activation in mouse with OVX.