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

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

The Effect of Acupuncture on Brain Iron Deposition and Body Iron Metabolism in Vascular Cognitive Impairment: Protocol for a Randomized Controlled Trial.

BACKGROUND: Vascular cognitive impairment (VCI) persistently impairs cognition and the ability to perform activities of daily living, seriously compromising patients' quality of life. Previous studies have reported that disorders of serum iron metabolism and iron deposition in the brain can lead to inflammation, abnormal protein aggregation and degeneration, and massive neuronal apoptosis in the central nervous system, which in turn leads to a progressive decline in cognitive processes. Our previous clinical studies have found acupuncture to be a safe and effective intervention for treating VCI, but the specific mechanisms require further exploration. OBJECTIVE: The objective of the trial is to evaluate the clinical efficacy of Tongdu Xingshen acupuncture and to investigate whether it can improve VCI by regulating brain iron deposition and body iron metabolism. METHODS: In total, 42 patients with VCI and 21 healthy individuals will participate in this clinical trial. The 42 patients with VCI will be randomized into acupuncture and control groups, while the 21 healthy individuals will be in the healthy control group. Both the control and acupuncture groups will receive conventional medical treatment and cognitive rehabilitation training. In addition, the acupuncture group will receive electroacupuncture treatment with Tongdu Xingshen for 30 minutes each time, 6 times a week for 4 weeks. Meanwhile, the healthy control group will not receive any intervention. All 3 groups will undergo baseline assessments of brain iron deposition, serum iron metabolism, and neuropsychological tests after enrollment. The acupuncture and control groups will be evaluated again at the end of 4 weeks of treatment, as described earlier. By comparing neuropsychological test scores between groups, we will examine the efficacy of Tongdu Xingshen acupuncture in treating VCI. Additionally, we will test the correlations between neuropsychological test scores, brain iron deposition, and body iron metabolism indexes to explore the possible mechanisms of Tongdu Xingshen acupuncture in treating VCI. RESULTS: Participants are currently being recruited. The first participant was enrolled in June 2023, which marked the official start of the experiment. As of the submission of the paper, there were 23 participants. The recruitment process is expected to continue until June 2025, at which point the processing and analysis of data will begin. As of May 15, 2024, up to 30 people have been enrolled in this clinical trial. CONCLUSIONS: This study will provide data on the effects of Tongdu Xingshen acupuncture on cerebral iron deposition as well as somatic iron metabolism in patients with VCI. These results will help to prove whether Tongdu Xingshen acupuncture can improve VCI by regulating brain iron deposition and body iron metabolism, which will provide the clinical and theoretical basis for the wide application of acupuncture therapy in VCI rehabilitation. TRIAL REGISTRATION: China Clinical Registration Agency ChiCTR2300072188; https://tinyurl.com/5fcydtkv. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/56484.

N-Acetylcysteine Alleviates D-Galactose-Induced Injury of Ovarian Granulosa Cells in Female Rabbits by Regulating the PI3K/Akt/mTOR Signaling Pathway.

The ovary plays a crucial role in the reproductive system of female animals. Ovarian problems such as ovarian insufficiency, premature aging, polycystic ovary syndrome, and ovarian cysts may lead to ovulation disorders, abnormal hormone secretion, or luteal dysfunction, thereby increasing the risk of infertility and abortion. Only when the ovarian function and other organs in the reproductive system remain healthy and work normally can female animals be ensured to carry out reproductive activities regularly, improve the pregnancy rate and litter size, promote the healthy development of the fetus, and then improve their economic value. The follicle, as the functional unit of the ovary, is composed of theca cells, granulosa cells (GCs), and oocytes. GCs are the largest cell population and main functional unit in follicles and provide the necessary nutrients for the growth and development of follicles. N-acetylcysteine (NAC) is a prevalent and cell-permeable antioxidant molecule that effectively prevents apoptosis and promotes cellular survival. Over the past few years, its function in boosting reproductive performance in animals at the cellular level has been widely acknowledged. However, its specific role and mechanism in influencing GCs is yet to be fully understood. The objective of this study was to examine the effects of NAC on ovarian damage in female rabbits. For this purpose, D-galactose (D-gal) was first used to establish a model of damaged GCs, with exposure to 1.5 mg/mL of D-gal leading to substantial damage. Subsequently, varying concentrations of NAC were introduced to determine the precise mechanism through which it influences cell damage. Based on the results of the Cell Counting Kit-8 assay, flow cytometry, and Western blotting, it was found that 0.5 mg/mL of NAC could significantly suppress cell apoptosis and promote proliferation. In particular, it decreased the expression levels of Bax, p53, and Caspase-9 genes, while concurrently upregulating the expression of the BCL-2 gene. Moreover, NAC was found to alleviate intracellular oxidative stress, suppress the discharge of mitochondrial Cytochrome c, and boost the enzymatic activities of CAT (Catalase), GSH (Glutathione), and SOD (Superoxide dismutase). RNA sequencing analysis subsequently underscored the critical role of the PI3K/Akt/mTOR pathway in governing proliferation and apoptosis within GCs. These findings demonstrated that NAC could significantly influence gene expression within this pathway, thereby clarifying the exact relationship between the PI3K/Akt/mTOR signaling cascade and the underlying cellular processes controlling proliferation and apoptosis. In conclusion, NAC can reduce the expression of Bax, p53, and Caspase-9 genes, inhibit the apoptosis of GCs, improve cell viability, and resist D-gal-induced oxidative stress by increasing the activity of CAT, GSH, and SOD. The molecular mechanism of NAC in alleviating D-gal-induced ovarian GC injury in female rabbits by regulating the PI3K/Akt/mTOR signaling pathway provides experimental evidence for the effect of NAC on animal reproductive function at the cellular level.

Loss of AR-regulated AFF3 contributes to prostate cancer progression and reduces ferroptosis sensitivity by downregulating ACSL4 based on single-cell sequencing analysis.

Prostate cancer (PCa) is one of the most common cancers affecting the health of men worldwide. Castration-resistant prostate cancer (CRPC), the advanced and refractory phase of prostate cancer, has multiple mechanisms of resistance to androgen deprivation therapy (ADT) such as AR mutations, aberrant androgen synthase, and abnormal expression of AR-related genes. Based on the research of the AR pathway, new drugs for the treatment of CRPC have been developed in clinical practice, such as Abiraterone and enzalutamide. However, many areas in this pathway are still worth exploring. In this study, single-cell sequencing analysis was utilized to scrutinize significant genes in the androgen receptor (AR) pathway related to CRPC. Our analysis of single-cell sequencing combined with bulk-cell sequencing revealed a substantial downregulation of AR-regulated AFF3 in CRPC. Overexpression of AFF3 restricted the proliferation and migration of prostate cancer cells whilst also increasing their sensitivity towards enzalutamide, while knockdown of AFF3 had the opposite effect. To elucidate the mechanism of tumor inhibition by AFF3, we applied GSVA and GSEA to investigate the metabolic pathways related to AFF3 and revealed that AFF3 had an impact on fatty acids metabolism and ferroptosis through the regulation of ACSL4 protein expression. Based on correlation analysis and flow cytometry, we can speculate that AFF3 can impact the sensitivity of the CRPC cell lines to the ferroptosis inducer (RSL3) by regulating ACSL4. Therefore, our findings may provide new insights into the mechanisms of drug resistance in CRPC, and AFF3 may serve as a novel prognostic biomarker in prostate cancer.

Comprehensive repair of the alveolar cleft using cortical and cancellous bone layers: A retrospective study.

To retrospectively review the clinical effect of comprehensive treatment of alveolar cleft (CTAC) using the mandible as the bone source. Patients with alveolar clefts who met the inclusion criteria were subjected to a CTAC protocol that included the following: (1) preoperative orthodontic treatment for creating good soft-tissue conditions; (2) 'area-like grafting' with subperiosteal osteogenic chin bone instead of cartilaginous osteogenic iliac bone; (3) simulation of normal bone anatomy via a sandwich-like bone graft consisting of 'cortical bone + cancellous bone + cortical bone'; and (4) strong internal fixation to ensure initial bone block stability. At 6 months postoperatively, the titanium plate was removed and cone-beam computed tomography was performed to evaluate the surgical results. A total of 54 patients underwent treatment with the CTAC protocol. The average age at the initial operation was 10.3 ± 2.1 years, and the average hospital stay was 2.8 ± 0.6 days. At 6 months postoperatively, 49 patients (90.7%) showed good clinical results. The transplanted bone block formed a 'cortical bone + cancellous bone + cortical bone' structure similar to that of the normal jawbone. A mature bone bridge formed, and the impacted permanent teeth continued to erupt and enter the bone graft area. CTAC is a comprehensive restorative solution for alveolar cleft repair that integrates multiple concepts, including orthodontics, embryology, anatomy, and improvements to surgical methods. The method is easy to perform, causes little surgical trauma, and shows a stable success rate, and is thus worth promoting.

A single-institution retrospective evaluation of noninvasive localization for non-palpable breast microcalcification.

TECHNIQUE: From January 1, 2018, to December 31, 2021, we localized the breast microcalcification of 40 patients before the surgical excision. We measured the distance between the nipple and the center of the calcification on the CC view and the ML view, respectively. The operation proceeded around the intersection between two lines, slightly larger than the diameter of the microcalcification. We also analyze the pathological findings. RESULTS: All 40 patients successfully detected calcification by mammograms preoperatively using the method mentioned above. 38 patients have the microcalcification removal within the one-time operation, while the other two underwent an extended lumpectomy. 20 of 40 calcifications (50 %) were malignant and 12(30 %) were precancerous lesions. In the group of women older than 45 years old, the percentages of malignant and atypical hyperplasias are 56.25 % (18/32) and 31.25 % (10/32) respectively. CONCLUSION: Our non-invasive method of preoperative localization is safe and cost-effective. Furthermore, initial observations suggest that there may be a link between age and malignant microcalcification.

HIF-1α-Induced Mitophagy Regulates the Regenerative Outcomes of Stem Cells in Fat Transplantation.

Hypoxia is a crucial factor with type diversity that plays an important role in stem cell transplantation. However, the effects of hypoxia on adipose-derived stem cells (ADSCs) are largely unclear in the autologous fat transplantation (AFT) model, which shows a special type of "acute-progressively resolving hypoxia." Here, an AFT model in nude mice and a hypoxic culture model for ADSCs were combined to explore the link between hypoxia-inducible factor-1 α subunit (HIF-1α) and mitophagy under hypoxic conditions. The results showed that the activity of ADSCs in the first 7 days after grafting was the key stage for volume retention, and the expression of HIF-1α, light chain 3 beta (LC3B), and Beclin1 in ADSCs increased during this period. We also found that hypoxia for longer than 48 h damaged the differentiation and mitochondrial respiration of ADSCs in vitro, but hypoxia signals also activate HIF-1α to initiate mitophagy and maintain the activities of ADSCs. Pre-enhancing mitophagy by rapamycin effectively improves mitochondrial respiration in ADSCs after grafting and ultimately improves AFT outcomes.

Adenomyoma of the small intestine in children: a 12-year experience in a tertiary referral center.

BACKGROUND: Adenomyoma of the small intestine is rare in children and the clinical characteristics is not clear. The study was to document the clinical characteristics and treatment of children with adenomyoma of the small intestine. METHODS: A retrospective study was conducted in children with intestinal adenomyoma from 2010 to 2022. We recorded age, gender, symptoms, location, tumour size and treatment options. RESULTS: Thirteen patients with adenomyoma of the small bowel were included. The median age was 20 months with a male-to-female ratio of 10:3 and more than half of the patients were younger than 2 years old. The mean tumour size was 2.0 cm. The lesion was found accidentally in one patient, and the others presented with symptoms of intussusception. A pathological lead point was found on ultrasound in seven patients. All tumours were located in the ileum, ranging from 24 to 260 cm proximal to the ileocecal valve. The tumour was found in an antimesenteric site in eight patients. Three patients suffered intestinal necrosis, and segmental resection of the ileum was performed. Three patients without intestinal necrosis underwent tumour rection, while intestinal resection and anastomosis were performed in the remaining seven. All patients recovered well except one, who developed intussusception 7 days after surgery; that patient underwent surgery and recovered uneventfully. CONCLUSIONS: Adenomyoma of the small intestine has a male predominance in children and intussusception is a common presentation. The ultrasound feature is a mass of mixed echogenicity containing several small cystic areas. Surgery is the primary treatment option and the procedure should be chosen based on intraoperative findings.

Berberine ameliorate inflammation and apoptosis via modulating PI3K/AKT/NFκB and MAPK pathway on dry eye.

BACKGROUND: Dry eye disease (DED) is a multifactorial disease in ocular surface, and inflammation plays an etiological role. Berberine (BBR) has shown efficacy in treating inflammatory diseases. Yet, there was no adequate information related to the therapeutic effects of BBR for DED. PURPOSE: To detect the effects and explore the potential mechanisms of BBR on DED. STUDY DESIGN: In vitro, in vivo study and network pharmacology analysis were involved. METHOD: The human corneal epithelium cells viability was evaluated with different concentrations of BBR. Dry eye murine model was established by exposing to the desiccating stress, and Ciclosporin (CSA), BBR eye drops or vehicle were topical administration for 7 days. The phenol red cotton tests, Oregon-green-dextran staining and Periodic acid-Schiff staining were performed and evaluated the dry eye after treatment. Inflammation and apoptosis levels of ocular surface were quantified. The potential targets related to berberine and dry eye were collected from databases. The Protein-Protein interaction network analysis and GO & KEGG enrichment analysis were realized by STRING database, Metascape platform and Cytoscape software to find core targets and signaling pathways. The SchrÖdinger software was used to molecular docking and PyMOL software to visualization. Finally, the levels of PI3K/AKT/NFκB and MAPK pathways were detected. RESULT: The data revealed BBR could rescue impaired HCE under hyperosmotic conditions. In addition, BBR eye drops could ameliorate dry eye. And BBR eye drops suppressed the inflammatory factors and CD4+T cells infiltration in conjunctiva. Besides, BBR eye drops protected ocular surface by avoiding the severe apoptosis and decreasing the level of MMP-3 and MMP-9. 148 common targets intersection between BBR and dry eye were found via network pharmacology analysis. Core proteins and core pathways were identified through PPI and GO&KEGG enrichment analysis. Molecular docking displayed excellent binding between BBR and those core targets. Finally, in vivo study verified that BBR eye drops had a therapeutic effect in dry eye by inhibiting PI3K/AKT/NFκB and MAPK pathways. CONCLUSION: The research provided convincing evidence that BBR could be a candidate drug for dry eye.

miR-491-5p regulates the susceptibility of glioblastoma to ferroptosis through TP53.

BACKGROUND: Ferroptosis has excellent potential in glioblastoma (GBM) therapy. In this study, we attempted to explore the effect of miR 491-5p on ferroptosis in GBM. METHODS: In this study, publicly available ferroptosis-related genome maps were used to screen genes upregulated in GBM and their target genes. The Spearman correlation coefficient was applied to analyze the correlation between the tumor protein p53 gene (TP53) and miR-491-5p. The expressions of miR-491-5p and TP53 were determined. The protein abundances of the TP53-encoded factors p53 and p21 were measured. Cell proliferation, migration and invasion were assessed. We pretreated U251MG cells and GBM mice with a ferroptosis inducer (erastin). The mitochondrial state was observed. The contents of reactive oxygen species (ROS), total Fe and Fe2+ were calculated. RESULTS: The level of TP53 was significantly increased in GBM and negatively correlated with miR-491-5p. miR-491-5p overexpression promoted U251MG cell proliferation, migration and invasion and interfered with the p53/p21 pathway. TP53 supplement reversed the effects of miR-491-5p. U251MG cells and GBM mice exhibited significant accumulations of ROS and iron. Erastin promoted the expression of TP53. Inhibition of TP53 reversed erastin-induced physiological phenotypes. Moreover, miR-491-5p overexpression caused a decrease in the number of damaged mitochondria and the contents of ROS, total Fe and Fe2+. TP53 supplement disrupted miR-491-5p-repressed ferroptosis. Erastin could inhibit GBM growth, and miR-491-5p overexpression impeded the therapeutic effect of erastin. CONCLUSIONS: Our findings reveal the functional diversity of miR-491-5p in GBM and suggest that miR-491-5p/TP53 signaling hinders the sensitivity of GBM to ferroptosis through the p53/p21 pathway.

Single-cell RNA sequencing reveals that HSD17B2 in cancer-associated fibroblasts promotes the development and progression of castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) responds poorly to existing therapy and appears as the lethal consequence of prostate cancer (PCa) progression. The tumour microenvironment (TME) has been thought to play a crucial role in CRPC progression. Here, we conducted single-cell RNA sequencing analysis on two CRPC and two hormone-sensitive prostate cancer (HSPC) samples to reveal potential leading roles in castration resistance. We described the single-cell transcriptional landscape of PCa. Higher cancer heterogeneity was explored in CRPC, with stronger cell cycling status and heavier copy number variant burden of luminal cells. Cancer-associated fibroblasts (CAFs), which are one of the most critical components of TME, demonstrated unique expression and cell-cell communication features in CRPC. A CAFs subtype with high expression of HSD17B2 in CRPC was identified with inflammatory features. HSD17B2 catalyses the conversion of testosterone and dihydrotestosterone to their less active forms, which was associated with steroid hormone metabolism in PCa tumour cells. However, the characteristics of HSD17B2 in PCa fibroblasts remained unknown. We found that HSD17B2 knockdown in CRPC-CAFs could inhibit migration, invasion, and castration resistance of PCa cells in vitro. Further study showed that HSD17B2 could regulate CAFs functions and promote PCa migration through the AR/ITGBL1 axis. Overall, our study revealed the important role of CAFs in the formation of CRPC. HSD17B2 in CAFs regulated AR activation and subsequent ITGBL1 secretion to promote the malignant behaviour of PCa cells. HSD17B2 in CAFs could serve as a promising therapeutic target for CRPC.

Regulating the molecule and electrode interface of a single-molecule junction via the side chain.

Here, we report that the molecule-electrode interface of a single-molecule junction can be regulated by a side chain. Based on this regulation, a single-molecule junction probe, PyCHO, was developed, which could distinguish cysteine (Cys) and homocysteine (Hcy) with high selectivity and sensitivity. PyCHO reacts with Cys/Hcy at ambient conditions to form thiazolidine/thiazinane products PyCHO+Cys/PyCHO+Hcy. Single molecular conductance measurement shows PyCHO+Cys and PyCHO+Hcy have different conductance. Control experiments and theoretical results reveal that the side thiazolidine/thiazinane rings have a distinct effect on the Au-π interaction of the pyridine anchor, resulting in their different conductances.

IgG4-related autoimmune hepatitis: A case report.

IgG-4-related autoimmune hepatitis (IgG4-AIH) is a rare disease. We report here a case of IgG4-AIH in an elderly male patient who was admitted to hospital because of unexplained hepatic insufficiency. After excluding viral hepatitis, alcoholic liver disease, drug-induced liver disease, parasitic infection, hepatolenticular degeneration and other diseases, and observing elevated levels of IgG-4, humoral immunity index, abnormal liver disease antibody spectrum and liver biopsy results, we made a diagnosis of IgG4-AIH. Following treatment with prednisone and ursodeoxycholic acid, the patient's liver function improved significantly and the patient was discharged from hospital.

Arsenic and iron bioavailability in Caco-2 cells: The influence of their co-existence and concentration.

Arsenic (As) exposure in humans is primarily caused through food and drinking water. Iron (Fe) is one of the most common element of the human and can influence the toxicity and bioavailability of As. However, information on the interaction between As and Fe when present together is limited. In this study, the interaction effects of Fe(III) (0, 3, and 10 mg/L) and As (As(III) at 0, 0.05, 0.1 mg/L, and As(V) at 0, 0.1, and 2 mg/L, respectively) on their absorption and bioavailability in Caco-2 cells were analyzed. As(III) absorption significantly decreased with the addition of Fe, while Fe absorption significantly increased. Compared with 0.1 mg/L As(III) addition alone, 3 and 10 mg/L Fe(III) addition significantly reduced the As(III) absorption by 8.6 and 11 µg/L, respectively. The absorption of As and Fe(III) and the bioavailability of Fe(III) significantly increased with the addition of As(III/V). Compared with 10 mg/L Fe(III) alone, the absorption of As(III) was significantly increased by 1 and 1.3 mg/L with 0.05 and 0.1 mg/L As(III) addition, respectively. Furthermore, the absorption and bioavailability of Fe(III) were significantly increased by 1.2 mg/L and 8% and 1.2 mg/L and 8.2%, respectively, after adding 0.1 and 2 mg/L As(V).

Overexpression of complement C5a indicates poor survival and therapeutic response in metastatic renal cell carcinoma.

INTRODUCTION: Complement C5a is an important component of the innate immune system. An increasing number of reports have revealed the relevance of C5a in tumor progression; however, its exact role in metastatic renal cell carcinoma (mRCC) remains unknown. METHODS: We evaluated C5a expression in tumor tissue microarrays of 231 mRCC patients and analyzed the relationship between C5a levels and clinical outcomes, and the expression of epithelial-mesenchymal transition (EMT)-related proteins, programmed cell death protein 1 (PD-1), and programmed cell death-ligand 1 (PD-L1). In-vitro functional experiments using exogenous C5a stimulation and C5a silencing in renal cell carcinoma cells were used to validate the tissue findings. RESULTS: High C5a expression was associated with poor therapeutic responses, poor overall and progression-free survival, and high expression of EMT-related proteins and PD-1/PD-L1 in mRCC patients. Exogenous C5a promoted proliferation, migration, and invasion of renal cell carcinoma cells, and induced the expression of EMT-related proteins and PD-1/PD-L1. Conversely, C5a silencing inhibited migration and invasion of renal cell carcinoma cells and decreased the expression of EMT-related proteins and PD-1/PD-L1. CONCLUSIONS: Our findings indicate that elevated C5a expression is associated with poor outcomes in patients with mRCC, and this effect may be partly attributed to the ability of C5a to promote EMT and PD-1/PD-L1 expression. C5a may be a potential novel target for the treatment of mRCC.

D-beta-hydroxybutyrate protects against microglial activation in lipopolysaccharide-treated mice and BV-2 cells.

Microglial activation is a key event in neuroinflammation, which, in turn, is a central process in neurological disorders. In this study, we investigated the protective effects of D-beta-hydroxybutyrate (BHB) against microglial activation in lipopolysaccharide (LPS)-treated mice and BV-2 cells. The effects of BHB in mice were assessed using behavioral testing, morphological analysis and immunofluorescence labeling for the microglial marker ionizing calcium-binding adaptor molecule 1 (IBA-1) and the inflammatory cytokine interleukin-6 (IL-6) in the hippocampus. Moreover, we examined the levels of the inflammatory IL-6 and tumor necrosis factor-α (TNF-α), as well as those of the neuroprotective brain-derived neurotrophic factor (BDNF) and transforming growth factor-ß (TGF-ß) in the brain. In addition, we examined the effects of BHB on IL-6, TNF-α, BDNF, TGF-ß, reactive oxygen species (ROS) level and cell viability in LPS-stimulated BV-2 cells. BHB treatments attenuated behavioral abnormalities, reduced the number of IBA-1-positive cells and the intensity of IL-6 fluorescence in the hippocampus, with amelioration of microglia morphological changes in the LPS-treated mice. Furthermore, BHB inhibited IL-6 and TNF-α generation, but promoted BDNF and TGF-ß production in the brain of LPS-treated mice. In vitro, BHB inhibited IL-6 and TNF-α generation, increased BDNF and TGF-ß production, reduced ROS level, ameliorated morphological changes and elevated cell viability of LPS-stimulated BV-2 cells. Together, our findings suggest that BHB exerts protective effects against microglial activation in vitro and in vivo, thereby reducing neuroinflammation.

A novel prognostic model for prostate cancer based on androgen biosynthetic and catabolic pathways.

Prostate cancer (PCa) is one of the most common malignancies in males globally, and its pathogenesis is significantly related to androgen. As one of the important treatments for prostate cancer, androgen deprivation therapy (ADT) inhibits tumor proliferation by controlling androgen levels, either surgically or pharmacologically. However, patients treated with ADT inevitably develop biochemical recurrence and advance to castration-resistant prostate cancer which has been reported to be associated with androgen biosynthetic and catabolic pathways. Thus, gene expression profiles and clinical information of PCa patients were collected from TCGA, MSKCC, and GEO databases for consensus clustering based on androgen biosynthetic and catabolic pathways. Subsequently, a novel prognostic model containing 13 genes (AFF3, B4GALNT4, CD38, CHRNA2, CST2, ADGRF5, KLK14, LRRC31, MT1F, MT1G, SFTPA2, SLC7A4, TDRD1) was constructed by univariate cox regression, lasso regression, and multivariate cox regression. Patients were divided into two groups based on their risk scores: high risk (HS) and low risk (LS), and survival analysis was used to determine the difference in biochemical recurrence-free time between the two. The results were validated on the MSKCC dataset and the GEO dataset. Functional enrichment analysis revealed some pivotal pathways that may have an impact on the prognosis of patients including the CDK-RB-E2F axis, G2M checkpoint, and KRAS signaling. In addition, somatic mutation, immune infiltration, and drug sensitivity analyses were performed to further explore the characteristics of HS and LS groups. Besides, two potential therapeutic targets, BIRC5 and RHOC, were identified by us in prostate cancer. These results indicate that the prognostic model may serve as a predictive tool to guide clinical treatment and provide new insight into the basic research in prostate cancer.

Minimally invasive complete urinary tract drainage in the treatment of vesicovaginal fistula: A case report.

Vesicovaginal fistula is one of the most common types of female genitourinary fistulas encountered in clinical practice, and its treatment is determined by the disease characteristics and at the discretion of the attending physician. The present study describes a unique conservative approach to the management of vesicovaginal fistulas. A 56-year-old woman developed a vesicovaginal fistula after laparoscopic hysterectomy. A bilateral ureteral single-J tube drainage through suprapubic bladder puncture with indwelling catheterization was performed. Thus, urine diversion and bladder emptying were achieved. In addition, the healing of the vesicovaginal fistula was promoted and the trauma of open or laparoscopic surgery was avoided. This minimally invasive method is simple and convenient, has few complications, and may be used as an alternative method for treating vesicovaginal fistulas.

Delayed Surgery to Preserve Kidney with Grade IV Injury.

Background: Since the introduction of the ALARA ("as low as reasonably achievable") concept, the management of severe renal trauma has shifted. Our hospital promotes delayed surgical intervention for grade IV closed renal injury, to preserve renal function. In this study, we retrospectively reviewed the management and outcomes of patients with grade IV closed renal injury in our hospital. Objective: To evaluate the management and outcome of grade IV closed renal injury. Methods: We retrospectively reviewed the medical records of 45 patients with grade IV closed renal injury; namely, 36 men and 9 women with an average age of 35.6 years. All patients were diagnosed with grade IV closed renal injury in accordance with the guidelines of the American Association for the Surgery of Trauma. All hemodynamically-stable patients with renal trauma were treated conservatively for approximately 13 days and then underwent surgery only to clear the perirenal hematoma and not to repair or resect the affected kidney. Abstracted data included patient demographics, mechanism of injury, admission hemodynamics, CT findings, and mortality. The primary outcome was the success rate of nonsurgical treatment, and the secondary outcome was the complication of nonsurgical treatment. Results: All patients responded and were discharged, and no patients died. We followed 35 (77.8%) patients for at least 1 year. One patient with partially devitalized renal parenchyma underwent surgery to remove the affected kidney. Eleven patients (31.4%) suffered complications, namely, three (8.6%) cases of hypertension, four (11.4%) cases of hematuria, two cases (5.7%) of urinary tract infection, and two (5.7%) cases of urinoma. Conclusions: Delayed exploratory surgery only to remove the hematoma should be considered in hemodynamically-stable patients with grade IV closed renal injury. This approach can avoid high nephrectomy rates associated with emergency surgery and reduce the complications that result from conservative treatment without surgery.

Identification of MRAP protein family as broad-spectrum GPCR modulators.

BACKGROUND: The melanocortin receptor accessory proteins (MRAP1 and MRAP2) are well-known endocrine regulators for the trafficking and signalling of all five melanocortin receptors (MC1R-MC5R). The observation of MRAP2 on regulating several non-melanocortin G protein-coupled receptors (GPCRs) has been sporadically reported, whereas other endogenous GPCR partners of the MRAP protein family are largely unknown. METHODS: Here, we performed single-cell transcriptome analysis and drew a fine GPCR blueprint and MRAPs-associated network of two major endocrine organs, the hypothalamus and adrenal gland at single-cell resolution. We also integrated multiple bulk RNA-seq profiles and single-cell datasets of human and mouse tissues, and narrowed down a list of 48 GPCRs with strong endogenous co-expression correlation with MRAPs. RESULTS: 36 and 46 metabolic-related GPCRs were consequently identified as novel interacting partners of MRAP1 or MRAP2, respectively. MRAPs exhibited protein-protein interactions and varying pharmacological properties on the surface translocation, constitutive activities and ligand-stimulated downstream signalling of these GPCRs. Knockdown of MRAP2 expression by hypothalamic administration of adeno-associated virus (AAV) packed shRNA stimulated body weight gain in mouse model. Co-injection of corticotropinreleasing factor (CRF), the agonist of corticotropin releasing hormone receptor 1 (CRHR1), suppressed feeding behaviour in a MRAP2-dependent manner. CONCLUSIONS: Collectively, our study has comprehensively elucidated the complex GPCR networks in two major endocrine organs and redefined the MRAP protein family as broad-spectrum GPCR modulators. MRAP proteins not only serve as a vital endocrine pivot on the regulation of global GPCR activities in vivo that could explain the composite physiological phenotypes of the MRAP2 null murine model but also provide us with new insights of the phenotyping investigation of GPCR-MRAP functional complexes.