Case Report: Intravesical and extravesical urachal cyst in children with lower abdominal pain and hematuria.

Bladder urachal cysts in children are a rare form of urachal abnormality. In this paper, we present a case of atypical imaging that presented with lower abdominal pain accompanied by hematuria, resulting in the formation of both internal and external urachal cysts in a child. A 6-year-old male child presented with repeated abdominal pain over a span of 4 days. Color ultrasound and pelvic CT scans revealed a soft tissue lesion on the right anterior wall of the bladder with an unclear boundary from the bladder wall. Voiding Cystourethrography (VCUG) showed no significant abnormalities in the bladder, while routine urine testing was positive for hematuria. A cystoscopy was simultaneously performed with a laparoscopic resection of the urachal cyst. Intraoperative cystoscopy identified the intravesical lesion, which was precisely removed using a cystoscope-assisted laparoscopy. Postoperative pathology confirmed that both extravesical and intravesical lesions were consistent with a urachal cyst. No complications were observed after the operation, and no recurrence was noted during a six-month follow-up. Therefore, for urachal cysts at the bladder's end, the possibility of intravesical urachal cysts should not be excluded, especially in patients with microscopic hematuria. We recommend performing cystoscopy simultaneously with laparoscopic urachal cyst removal to avoid missing intravesical lesions.

Influence of preoperative urine culture and bacterial species on urogenital sepsis after ureteral flexible lithotripsy in patients with upper urinary tract stones.

Objective: This retrospective study aims to identify risk factors for urogenic sepsis in patients with upper urinary tract stones following ureteral flexible lithotripsy (FURL). Additionally, we analyze the clinical characteristics of bacterial infections post-surgery. Methods: A total of 759 patients who underwent FURL at the Urology Department of Zunyi Medical University were included. Univariate and multivariate Logistic regression analyses were conducted to identify independent risk factors for urogenic sepsis post-FURL. The distribution of bacteria based on preoperative urine cultures was also analyzed. Statistical analysis was performed using R4.2.2 software. Results: Of the 759 patients, positive preoperative urine culture, urine nitrite positivity, urine white blood cell count (WBC) ≥ 200 cells/µL, residual stones, and neutrophil-to-lymphocyte ratio (NLR) were found to be independent risk factors for urogenic sepsis after FURL. Among the 164 patients with positive preoperative urine cultures, 32 developed urogenic sepsis post-surgery, with 68.75% having positive preoperative cultures. The leading pathogens causing postoperative urogenic sepsis were Escherichia coli (E. coli), Enterococcus faecium, Proteus mirabilis, and Klebsiella pneumoniae. The probabilities of progression to urogenic sepsis were as follows: E. coli 19% (n = 12), Enterococcus faecium 43% (n = 3), Proteus mirabilis 33.3% (n = 1), and Klebsiella pneumoniae 33.3% (n = 1). The ages of affected patients were 47.17 ± 13.2, 53.7, 41, and 79 years, respectively. Rates of comorbid diabetes were 36.4, 66.7, 50, 100%, with nitrite positivity rates at 72.7, 33.3, 50, 0%. Ten female patients were infected with E. coli, while patients infected with Klebsiella pneumoniae had an NLR of 7.62. Conclusion: Positive preoperative urine culture, urine nitrite positivity, urine WBC ≥ 200 cells/µL, residual stones, and NLR are independent risk factors for urogenic sepsis after FURL. Escherichia coli is the predominant pathogen post-FURL, with notable female prevalence and nitrite-positive urine in infections. Enterococcus faecium infections are associated with diabetes.

Controversial role of γδ T cells in colorectal cancer.

Colorectal cancer (CRC) is the third most frequent type of cancer, and the second leading cause of cancer-related deaths worldwide. Current treatments for patients with CRC do not substantially improve the survival and quality of life of patients with advanced CRC, thus necessitating the development of new treatment strategies. The emergence of immunotherapy has revitalized the field, showing great potential in advanced CRC treatment. Owing to the ability of tumor cells to evade the immune system through major histocompatibility complex shedding and heterogeneous and low antigen spreading, only a few patients respond to immunotherapy. γδ T cells have heterogeneous structures and functions, and their key roles in immune regulation, tumor immunosurveillance, and specific primary immune responses have increasingly been recognized. γδ T cells recognize and kill CRC cells efficiently, thus inhibiting tumor progress through various mechanisms. However, γδ T cells can potentially promote tumor development and metastasis. Thus, given this dual role in prognosis, these cells can act as either a "friend" or "foe" of CRC. In this review, we explore the characteristics of γδ T cells and their functions in CRC, highlighting their application in immunotherapy.

Construction and validation of the nomogram predictive model for post-percutaneous nephrolithotomy urinary sepsis.

OBJECTIVE: This study aimed to construct and validate a simple and accurate clinical nomogram for predicting the occurrence of post-percutaneous nephrolithotomy sepsis, aiming to assist urologists in the early identification, warning, and early intervention of urosepsis, and to provide certain evidence-based medicine basis. METHODS: This study included patients who underwent PCNL surgery due to kidney or upper ureteral stones at the Department of Urology, Affiliated Hospital of Zunyi Medical University, from January 2019 to September 2022. This study utilized univariate and multivariate logistic regression analysis to screen and evaluate the risk factors for sepsis and construct a predictive model. An evaluation was performed using the receiver operating characteristic curve, calibration curve, and decision curve analysis curve. All statistical analyses were conducted using R version 4.2. RESULTS: A total of 946 patients who underwent post-PCNL were included in this study, among whom 69 patients (7.29%) developed post-PCNL urinary sepsis. Multiple-factor logistic regression analysis identified four independent risk factors associated with post-PCNL urinary sepsis, including positive urinary nitrite (OR = 5.9, P < 0.001), positive urine culture (OR = 7.54, P < 0.001), operative time ≥ 120 min (OR = 20.93, P = 0.0052), and stone size ≥ 30 mm (OR = 13.81, P = 0.0015). The nomogram model demonstrated good accuracy with an AUC value of 0.909, and in the validation cohort, the AUC value was 0.922. The calibration curve indicated a better consistency between the predictive line chart and the actual occurrence of post-PCNL urinary sepsis. The decision curve analysis curve showed favorable clinical utility. CONCLUSION: Preoperative positive urine culture, positive urinary nitrite, operative time ≥ 120 min, and stone size ≥ 30 mm are independent risk factors for developing post-PCNL urinary sepsis. The constructed line chart based on these factors effectively assesses the risk of urinary sepsis in patients after PCNL.

Case report: Page kidney with multiple serosal effusions caused by bilateral spontaneous renal subcapsular hemorrhage.

Page kidney is caused by the perirenal or subcapsular accumulation of blood or fluid pressing on the renal parenchyma and is a rare cause of secondary hypertension. In this study, we report a case of Page caused by bilateral spontaneous subcapsular renal hematoma, the main manifestations of which were secondary hypertension, multiple serous effusions, and renal insufficiency. After admission, drug blood pressure control was ineffective. After bilateral perirenal effusion puncture and drainage were performed to relieve bilateral perirenal compression, blood pressure gradually dropped to normal, multi-serous cavity effusion (pericardial, thoracic, and abdominal effusion) gradually disappeared, and kidney function returned to normal. Secondary hypertension caused by Page kidney can be treated. When Page kidney is complicated with multiple serous effusions, the effect of antihypertensive drugs alone is poor, and early perineal puncture drainage can achieve better clinical efficacy.

Misdiagnosis of eosinophilic cystitis: A case report and literature review.

RATIONALE: Eosinophilic cystitis (EC) is a rare and specific transmural inflammatory disease in clinic. At present, its etiology is unknown, its clinical manifestations are diverse, and its auxiliary examination lacks specificity, so it is easy to be missed or misdiagnosed in clinical practice. PATIENT CONCERNS: A 72-year-old male patient with symptoms of lower urinary tract obstruction accompanied by hematuria was diagnosed with benign prostatic hyperplasia with bleeding by B-ultrasound and urinary CT examination. After being treated with catheterization, anti-infection and hemostasis, he was selectively treated with transurethral resection of prostate, but he saw a pattern mass on the right back wall of the bladder during the operation. Considering bladder tumor, he removed the lesion and gave pirarubicin for bladder perfusion. However, the postoperative pathological result was EC. DIAGNOSIS: The diagnosis of EC can only rely on pathological examination, and the accurate and positive rate of biopsy can be improved by obtaining muscle tissue as much as possible at the same time of multi-point biopsy. INTERVENTION: Prednisone and cetirizine were given orally after transurethral resection of lesions, and tamsulosin and finasteride were given regularly to treat benign prostatic hyperplasia. OUTCOMES: No recurrence and abnormal urination were found during the follow-up for half a year, and the upper urinary tract function was normal. LESSONS: The clinical manifestations of EC are atypical, the laboratory examination and imaging examination are not specific, and it is difficult to make a definite diagnosis before operation. The diagnosis depends on pathological examination. Transurethral resection of the lesion can obviously improve the positive rate of biopsy while completely removing the lesion, and the combined drug treatment can achieve satisfactory results in a short period of time. Active follow-up after operation is very important to identify the recurrence of the disease and prevent the upper urinary tract function from being damaged.

Development and validation of a predictive model for post-percutaneous nephrolithotomy urinary sepsis: a multicenter retrospective study.

BACKGROUND: The objective of this retrospective, multicenter study was to analyze the factors associated with the development of urogenital sepsis after percutaneous nephrolithotomy (PCNL) and to establish a nomogram prediction model of urogenital sepsis after PCNL. METHODS: A total of 2066 postoperative PCNL patients were included from three medical institutions: Zunyi Medical University Hospital, Beijing Jishuitan Hospital Guizhou Hospital, and Fenggang County People's Hospital. Clinical data of 1623 patients from the Department of Urology of Zunyi Medical University Hospital were randomized into a training cohort (Zunyi training cohort, N.=1139) and an internal validation cohort (Zunyi internal validation cohort, N.=484) using computer generated random numbers in a 7:3 ratio. Univariate and multivariate logistic regression analyses were performed on the compliance training cohort to identify risk factors for urogenital sepsis after PCNL and to develop a column line graph prediction model based on these risk factors. Finally, Zunyi internal validation cohort and two external validation cohorts (Guiyang external cohort, N.=306; Fenggang external cohort, N.=137) were used to validate the prognostic accuracy of the nomogram prediction model. R4.2.2 statistical software was used for all statistical data analyses. RESULTS: Multifactorial logistic regression analysis of the Zuiyi training cohort (N.=1139) identified five independent risk factors associated with urogenital sepsis after PCNL, including urine culture positivity (odds ratio [OR]=5.29, P<0.001), urine nitrite positivity (OR=5.97, P<0.001), operation time ≥60 min (OR=4.4, P=0.0037), residual stone (OR=5.18, P<0.001), and size ≥30 mm (OR=3.22, P=0.0086). Nomogram were constructed based on these independent risk factors. The area under the curve (AUC) of the nomogram model was 0.907 in the in-progress sample and 0.948 after internal validation. The AUC of the model was 0.855 and 0.804 after external validation of the Guiyang external validation cohort and the Fenggang validation cohort, respectively, indicating good discrimination ability. The calibration curves of the nomogram showed good agreement, and the decision curve analysis demonstrated high clinical utility. CONCLUSIONS: Based on the clinical independent risk factors such as positive urine culture, positive urine nitrite, operation time ≥60min, stone residue, stone size ≥30mm, nomogram prediction model of urogenital sepsis after PCNL was established, which can provide reference for urologists to develop preoperative evaluation and treatment strategies for patients with percutaneous nephrolithotomy.

Comparative analysis of MVD and RHZ in the treatment of primary glossopharyngeal neuralgia: A clinical report on 61 cases.

Objective: Clinical data on 61 patients (grouped by their treatment with MVD or RHZ) with glossopharyngeal neuralgia were analyzed retrospectively. A summary analysis of the effective rate and surgical complications of MVD and RHZ in the treatment of glossopharyngeal neuralgia was performed to observe the new surgical options for GN. Method: From March 2013 to March 2020, 63 patients with GN were admitted to our hospital by the professional group of cranial nerve diseases. Two patients diagnosed with tongue and pharynx pain secondary to tongue cancer and upper esophageal cancer, respectively were excluded from the group. The remaining patients all met the diagnosis of GN, some of them were treated with MVD and others were treated with RHZ. The pain relief rate, long-term results, and complications of the patients in the two groups were well-organized and analyzed. Result: Of the 61 patients, 39 were treated with MVD and 22 were treated with RHZ. In the early-stage patients (the first 23 patients), all of them were operated on with the MVD procedure except one patient without vascular compression. In the later-stage patients, MVD was performed for evident single arterial compression according to the intraoperative situation. And for compression of arteries with greater tension or PICA + VA complex compression, RHZ was performed. It was also performed in cases where vessels with tight adhesions to the arachnoid and nerves could not be easily separated, or where it was easy to damage the perforating arteries after separating the blood vessels, causing vasospasm, which affects the blood supply to the brainstem and cerebellum. RHZ was also performed if there was no clear vascular compression. The efficiency of both groups was 100%. In the MVD group, one case recurred 4 years after the initial operation, and RHZ was performed for reoperation. Complications related to the operation included one case of swallowing and coughing in the MVD group, and three cases in the RHZ group; two cases of uvula not centering in the MVD group, and five cases in the RHZ group. There was 2 patients in RHZ group lost taste in 2/3 of the backing of the tongue, though these symptoms mostly disappeared or decreased after follow-up. One patient in the RHZ group had developed tachycardia by the time of the long-term follow-up, but whether it was related to the surgery is still uncertain. In terms of serious complications, there were two cases of postoperative bleeding in the MVD group. Based on the clinical characteristics of the patients' bleeding, it was judged that the cause of the bleeding was ischemia and was related to an intraoperative injury to the penetrating artery of the PICA artery and vasospasm. Conclusion: MVD and RHZ are effective methods for the treatment of primary glossopharyngeal neuralgia. MVD is recommended for cases where vascular compression is clear and easy to handle. However, for cases with complex vascular compression, tight vascular adhesions, difficult separation, and without clear vascular compression, RHZ could be performed. Its efficiency is equivalent to MVD, and there is no significant increase in complications such as cranial nerve disorders. There are few cranial nerve complications that seriously affect the quality of life of patients. RHZ helps to reduce the risk of ischemia and bleeding during surgery by reducing the risk of arterial spasms and injury to the penetrating arteries by separating the vessels due to separation of vessels during MVD. At the same time, it may reduce the postoperative recurrence rate.

Efficacy and safety of enfortumab vedotin in the treatment of advanced urothelial carcinoma: a systematic review and meta-analysis.

This study aimed to investigate whether Enfortumab vedotin (EV) is suitable for patients with locally advanced or metastatic urothelial carcinoma and to perform a meta-analysis of its efficacy and safety. Five studies involved 584 patients were included in the meta-analysis. The results of single-arm meta-analysis showed that with EV at 1.25 mg/kg, the objective response rate (ORR) was 47%. The meta-analysis indicated that EV showed good efficacy and safety in the patient population of locally advanced or metastatic urothelial carcinoma.

Accuracy of novel urinary biomarker tests in the diagnosis of prostate cancer: A systematic review and network meta-analysis.

Objective: The purpose of this study was to conduct a network meta-analysis comparing the diagnostic value of different urinary markers for prostate cancer. Methods: As of June 2022, the literature was retrieved by searching Pubmed, EMBASE, Web of Science databases and other databases. The methodological quality of included studies was assessed using the Cochrane Collaboration's risk of bias tool, and publication bias was assessed using funnel plots. The surface under the cumulative ranking curve (SUCRA) values ​​was used to determine the most effective diagnostic method and the data were analyzed accordingly using data analysis software. Results: A total of 16 articles was included including 9952 patients. The ranking results of network meta-analysis showed that the diagnostic performance of the four urine markers Selectmdx, MIPS, PCA3 and EPI was better than that of PSA. Among them, the specificity, positive predictive value and diagnostic accuracy of Selectmdx ranked first in the SUCRA ranking (SUCRA values: 85.2%, 88.3%, 97.1%), and the sensitivity ranked second in the SUCRA ranking (SUCRA value: 54.4%), and the negative predictive value ranked fourth in SUCRA (SUCRA value: 51.6%). The most sensitive screening tool was MIPS (SUCRA value: 67.1%), and it was also the second screening tool ranked higher in specificity, positive predictive value, negative predictive value and diagnostic accuracy (SUCRA value: 56.5%, respectively)., 57.1%, 67.9%, 74.3%). The high negative predictive value SUCRA ranking is EPI (SUCRA value: 68.0%), its sensitivity ranks third (SUCRA value: 45.6%), and its specificity, positive predictive value and diagnostic accuracy are ranked fourth (SUCRA values are: 45%, 38.2%, 35.8%). Conclusion: According to the network ranking diagram, we finally concluded that Selectmdx and MIPS can be used as the most suitable urine markers for prostate cancer screening and diagnosis. To further explore the diagnostic value of different urinary markers in the screening of PCa patients. Systematic Review Registration: https://inplasy.com/, identifier INPLASY202290094.

Kinesin family member 15 can promote the proliferation of glioblastoma.

Glioblastoma is one of the most dangerous tumors for patients in clinical practice at present, and since glioblastoma originates from the brain, it will have a serious impact on patients. Therefore, more effective clinical therapeutic targets are still needed at this stage. Kinesin family member 15 (KIF15) promotes proliferation in several cancers, but its effect on glioblastoma is unclear. In this study, differentially expressed gene analysis and network analysis were performed to identify critical genes affecting glioma progression. The samples were divided into a KIF15 high-expression group and KIF15 low-expression group, and the association between FIK15 expression level and clinical characteristics was summarized and analyzed by performing medical data analysis; the effect of KIF15 on glioblastoma cell proliferation was detected by employing colony formation and MTT assays. The effect of KIF15 on tumor growth in mice was determined. It was found that KIF15 was a potential gene affecting the progression of glioblastoma. In addition, KIF15 was highly expressed in glioblastoma tumor tissues, and KIF15 was correlated with tumor size, clinical stage and other clinical characteristics. After the KIF15 gene was knocked out, the proliferation ability of glioblastoma was significantly inhibited. KIF15 also contributed to the growth of glioblastoma tumors in mice. Therefore, we found KIF15 to be a promising clinical therapeutic target.

The Proliferation of Glioblastoma Is Contributed to Kinesin Family Member 18A and Medical Data Analysis of GBM.

Background: Glioblastoma (GBM) is widely known as a classical kind of malignant tumor originating in the brain with high morbidity and mortality. Targeted therapy has shown great promise in treating glioblastoma, but more promising targets, including effective therapeutic targets, remain to be identified. 18A (KIF18A) is a microtubule-based motor protein that is dysregulated and involved in the progression of multiple human cancers. However, the possible effects of KIF18A on GBM progression are still unclear. Methods: We performed DEG analysis, medical data analysis, and network analysis to identify critical genes affecting glioma progression. We also performed immunohistochemical analysis of the KIF18A levels in 94 patients with glioblastoma and the associated surrounding tissues. Patients were divided into two groups according to the high and low expression. Using a clinical analysis, we showed the potential associations between KIF18A expression and clinical characteristics of 94 GBM patients. We then investigated the effects of KIF18A on GBM cell proliferation by colony establishment, MTT, and immune blogging. The possible effect of KIF18A on GBM tumor growth was determined in mice. Results: We identified KIF18A as a potential gene affecting GBM progression. We further demonstrated that GBM tissues expressed KIF18A much higher, and its presentation was associated with recurrence in glioblastoma patients. We believe KIF18A promotes GBM cell proliferation. Conclusion: We demonstrated that KIF18A could be a promising target in treating GBM.

Discovery of small-molecule activators of nicotinamide phosphoribosyltransferase (NAMPT) and their preclinical neuroprotective activity.

The decline of nicotinamide adenine dinucleotide (NAD) occurs in a variety of human pathologies including neurodegeneration. NAD-boosting agents can provide neuroprotective benefits. Here, we report the discovery and development of a class of potent activators (NATs) of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway. We obtained the crystal structure of NAMPT in complex with the NAT, which defined the allosteric action of NAT near the enzyme active site. The optimization of NAT further revealed the critical role of K189 residue in boosting NAMPT activity. NATs effectively increased intracellular levels of NAD and induced subsequent metabolic and transcriptional reprogramming. Importantly, NATs exhibited strong neuroprotective efficacy in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) without any overt toxicity. These findings demonstrate the potential of NATs in the treatment of neurodegenerative diseases or conditions associated with NAD level decline.

A systematic review and meta-analysis of minimally invasive surgery in children with occult tethered cord syndrome.

Background: At present, the surgical treatment of occult tethered cord syndrome (OTCS) in children is mostly two types of minimally invasive surgery: filum terminalis laxity or filum terminalectomy. The clinical efficacy and safety of minimally invasive treatment and conservative treatment are still unclear. Therefore, this study will use the advantages of systematic review and meta-analysis to evaluate the objectivity, and explore the effect of minimally invasive surgery on children with occult tethered cord syndrome. Methods: A computer search was used to search PubMed, Embase, CNKI, Wanfang Database and other literature search websites about the randomized controlled trials (RCTs) of minimally invasive surgery in children with occult tethered cord syndrome and spinal lipoma. Professional journals were manually searched to avoid omissions. The search keywords were: occult myelolipoma, occult tethered cord syndrome, surgical treatment of tethered cord syndrome, occult tethered cord syndrome. Results: A total of 6 relevant literatures that could be used for meta-analysis were selected. A total of 425 subjects were included in the article, of which 132 were treated conservatively and 293 were treated surgically. The heterogeneity detection test statistics of the included studies were Chi2 (Chi-squared test) =8.18, df (degree of freedom) =5, I2=39%<50%, Z=2.53, and the homogeneity of the included studies was good. The number of unimproved cases under conservative treatment was 40, accounting for 30.30%; the number of unimproved cases under surgical treatment was 33, accounting for 11.26%, and the total unimproved rate of the two groups accounted for 17.17%. The unimproved rate of the experimental group was significantly lower than that of the control group, and the difference was statistically significant (P=0.01). The results of bias analysis showed that there was no significant bias in the literature included in this study. Discussion: Meta-analysis results confirmed that minimally invasive surgery has a significant effect on the treatment of occult children with tethered cord syndrome. However, due to the small sample size of the included literature, further evaluation of the treatment risk is required.

Optimization of NAMPT activators to achieve in vivo neuroprotective efficacy.

NAMPT is the rate-limiting enzyme in the NAD salvage pathway, which makes it an attractive target for the treatment of many diseases associated with NAD exhaustion such as neurodegenerative diseases. Herein, we present the systematic optimization of NAT, an initial hit of NAMPT activator discovered by us through high-throughput screening, based on the co-crystal structure of the NAMPT-NAT complex. Over 80 NAT derivatives have been designed and synthesized, among which compound 72 showed notably improved potency as NAMPT activator and effectively protected cultured cells from FK866-mediated toxicity. Moreover, compound 72 exhibited strong neuroprotective efficacy in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) without any overt toxicity, which renders it a promising candidate for the development of novel neuroprotective agents.

MUC21 induces the viability and migration of glioblastoma via the STAT3/AKT pathway.

Glioblastoma (GBM) is a malignant tumor with one of the fastest increasing morbidity and mortality rates. As such, more therapeutic targets need to be developed to combat this disease. Mucin 21 (MUC21) is a human counterpart of mouse epiglycanin and mediates multiple cellular functions. However, its possible effects on GBM and its possible mechanism remain unclear. The current study aimed to clarify the role or MUC21 in the progression of GBM by performing a series of in vitro assays, including Cell Counting Kit-8, colony formation, wound closure, transwell, and in vivo assays. In the present study, the aberrantly high expression of MUC21 in human GBM tissues and cell lines was observed and it was revealed that it was associated with the clinicopathological feature, tumor recurrence, in patients with GBM. MUC21 promoted the viability and motility of GBM cells in vitro and stimulated tumor growth in vivo. It was further confirmed that MUC21 promoted the progression of GBM via the STAT3/AKT pathway and it was considered that MUC21 could serve as a promising target for the treatment of GBM.

Establishment of an immune-related gene pair model to predict colon adenocarcinoma prognosis.

BACKGROUND: Colon cancer is the most common type of gastrointestinal cancer and has high morbidity and mortality. Colon adenocarcinoma (COAD) is the main pathological type of colon cancer, and much evidence has supported the correlation between the prognosis of COAD and the immune system. The current study aimed to develop a robust prognostic immune-related gene pair (IRGP) model to estimate the overall survival of patients with COAD. METHODS: The gene expression profiles and clinical information of patients with colon adenocarcinoma were obtained from the TCGA and GEO databases and were divided into training and validation cohorts. Immune genes were selected that showed a significant association with prognosis. RESULTS: Among 1647 immune genes, a model with 17 IRGPs was built that was significantly associated with OS in the training cohort. In the training and validation datasets, the IRGP model divided patients into the high-risk group and low-risk group, and the prognosis of the high-risk group was significantly worse (P<0.001). Univariate and multivariate Cox proportional hazard analyses confirmed the feasibility of this model. Functional analysis confirmed that multiple tumor progression and stem cell growth-related pathways were upregulated in the high-risk groups. Regulatory T cells and macrophages M0 were significantly highly expressed in the high-risk group. CONCLUSION: We successfully constructed an IRGP model that can predict the prognosis of COAD, providing new insights into the treatment strategy of COAD.

Functional suppression of Ripk1 blocks the NF-κB signaling pathway and induces neuron autophagy after traumatic brain injury.

Traumatic brain injury (TBI), known as intracranial injury, has been a serious threat to human health. Evidence exists indicating that autophagy and inflammatory responses contribute to secondary brain injury after TBI. Notably, receptor-interacting protein kinase 1 (Ripk1) exerts an important role in cell autophagy. Therefore, this study aims to explore the effect of Ripk1 on neuron autophagy and apoptosis in TBI. Initially, blood samples of patients with TBI and healthy persons were collected to detect the expression of Ripk1, nuclear factor-kappa B (NF-κB), and NF-kB inhibitor α (IKBα). Then rat models with TBI were successfully established and, respectively, treated with shRNA targeting Ripk1 (sh-Ripk1), Ripk1 overexpression plasmid (oe-Ripk1), or IKKα inhibitor (BAY 11-7082). Subsequently, reverse transcription quantitative polymerase chain reaction and Western blot analysis were conducted to detect the expression of Ripk1, IKBα, NF-κB signaling pathway-, and apoptosis-related factors. Enzyme-linked immunosorbent assay was used to detect the expression of inflammatory cytokines. Compared with healthy persons, the expression of Ripk1, NF-κB and IKBα in blood of TBI patients was significantly upregulated. After silencing of Ripk1 or inhibition of the NF-κB signaling pathway, the expression of IL-1ß, IL-6, TNF-α, Bax, and cleaved-caspase-3 was downregulated, and the expression of Bcl-2, ATG5, and LC3II/LC3I was upregulated. Furthermore, neuron injury and apoptosis were notably reduced and neuron autophagy increased significantly by Ripk1 downregulation or IKKα inhibitor. Ripk1 overexpression contributed to activation of NF-κB signaling pathway, whereby aggravating TBI-induced damage. Silencing Ripk1 suppresses TBI by inhibiting inflammation and promoting autophagy of neurons via inhibition of NF-κB signaling pathway.

TMAVA, a Metabolite of Intestinal Microbes, Is Increased in Plasma From Patients With Liver Steatosis, Inhibits γ-Butyrobetaine Hydroxylase, and Exacerbates Fatty Liver in Mice.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease is characterized by excessive hepatic accumulation of triglycerides. We aimed to identify metabolites that differ in plasma of patients with liver steatosis vs healthy individuals (controls) and investigate the mechanisms by which these might contribute to fatty liver in mice. METHODS: We obtained blood samples from 15 patients with liver steatosis and 15 controls from a single center in China (discovery cohort). We performed untargeted liquid chromatography with mass spectrometry analysis of plasma to identify analytes associated with liver steatosis. We then performed targeted metabolomic analysis of blood samples from 2 independent cohorts of individuals who underwent annual health examinations in China (1157 subjects with or without diabetes and 767 subjects with or without liver steatosis; replication cohorts). We performed mass spectrometry analysis of plasma from C57BL/6J mice, germ-free, and mice given antibiotics. C57BL/6J mice were given 0.325% (m/v) N,N,N-trimethyl-5-aminovaleric acid (TMAVA) in their drinking water and placed on a 45% high-fat diet (HFD) for 2 months. Plasma, liver tissues, and fecal samples were collected; fecal samples were analyzed by 16S ribosomal RNA gene sequencing. C57BL/6J mice with CRISPR-mediated disruption of the gene encoding γ-butyrobetaine hydroxylase (BBOX-knockout mice) were also placed on a 45% HFD for 2 months. Hepatic fatty acid oxidation (FAO) in liver tissues was determined by measuring liberation of 3H2O from [3H] palmitic acid. Liver tissues were analyzed by electron microscopy, to view mitochondria, and proteomic analyses. We used surface plasmon resonance analysis to quantify the affinity of TMAVA for BBOX. RESULTS: Levels of TMAVA, believed to be a metabolite of intestinal microbes, were increased in plasma from subjects with liver steatosis compared with controls, in the discovery and replication cohorts. In 1 replication cohort, the odds ratio for fatty liver in subjects with increased liver plasma levels of TMAVA was 1.82 (95% confidence interval [CI], 1.14-2.90; P = .012). Plasma from mice given antibiotics or germ-free mice had significant reductions in TMAVA compared with control mice. We found the intestinal bacteria Enterococcus faecalis and Pseudomonas aeruginosa to metabolize trimethyllysine to TMAVA; levels of trimethyllysine were significantly higher in plasma from patients with steatosis than controls. We found TMAVA to bind and inhibit BBOX, reducing synthesis of carnitine. Mice given TMAVA had alterations in their fecal microbiomes and reduced cold tolerance; their plasma and liver tissue had significant reductions in levels of carnitine and acyl-carnitine and their hepatocytes had reduced mitochondrial FAO compared with mice given only an HFD. Mice given TMAVA on an HFD developed liver steatosis, which was reduced by carnitine supplementation. BBOX-knockout mice had carnitine deficiency and decreased FAO, increasing uptake and liver accumulation of free fatty acids and exacerbating HFD-induced fatty liver. CONCLUSIONS: Levels of TMAVA are increased in plasma from subjects with liver steatosis. In mice, intestinal microbes metabolize trimethyllysine to TMAVA, which reduces carnitine synthesis and FAO to promote steatosis.

Nucleobindin-2 Promotes the Growth and Invasion of Glioblastoma.

Background: Glioblastoma is one of the most malignant tumors in the brain with high mortality. In recent years, immunotherapy and targeted therapy show great prospects in the treatments for glioblastoma, whereas more effective therapeutic targets are still urgently needed to be developed. Nucleobindin-2 (NUCB2) is the precursor protein of nesfatin-1, which have a variety of metabolic functions, such as food intake and temperature regulation. In recent years, the potential link between NUCB2 and the development of multiple cancer was gradually revealed; however, the effects of NUCB2 on the progression of glioblastoma are still unclear. Methods: Immunohistochemical assays were performed to explore the NUCB2 expression levels in 94 samples of glioblastoma and corresponding nontumor tissues; patients were divided into NUCB2 high expression group and low expression group. Clinical analysis related to the clinical features, the potential link between NUCB2 expression levels, and clinical features were analyzed; the effects of NUCB2 on cell proliferation and invasion of glioblastoma were detected through colony formation and MTT assay, and transwell assay respectively. The possible effects of NUCB2 on tumor growth and metastasis were measured in mice. Results: In this study, we demonstrated that NUCB2 over-expression was correlated with the high degree of recurrence of patients with glioblastoma. Further, we also revealed that NUCB2 promoted cell proliferation and invasion of glioblastoma in vitro and promoted the growth and metastasis of glioblastoma in mice. Conclusion: This study provided evidence that NUCB2 might be a novel therapeutic target of glioblastoma.