Infection-specific phosphorylation of glutamyl-prolyl tRNA synthetase induces antiviral immunity.

The mammalian cytoplasmic multi-tRNA synthetase complex (MSC) is a depot system that regulates non-translational cellular functions. Here we found that the MSC component glutamyl-prolyl-tRNA synthetase (EPRS) switched its function following viral infection and exhibited potent antiviral activity. Infection-specific phosphorylation of EPRS at Ser990 induced its dissociation from the MSC, after which it was guided to the antiviral signaling pathway, where it interacted with PCBP2, a negative regulator of mitochondrial antiviral signaling protein (MAVS) that is critical for antiviral immunity. This interaction blocked PCBP2-mediated ubiquitination of MAVS and ultimately suppressed viral replication. EPRS-haploid (Eprs+/-) mice showed enhanced viremia and inflammation and delayed viral clearance. This stimulus-inducible activation of MAVS by EPRS suggests an unexpected role for the MSC as a regulator of immune responses to viral infection.

MARCH5-dependent NLRP3 ubiquitination is required for mitochondrial NLRP3-NEK7 complex formation and NLRP3 inflammasome activation.

The NLRP3 inflammasome plays a key role in responding to pathogens, and endogenous damage and mitochondria are intensively involved in inflammasome activation. The NLRP3 inflammasome forms multiprotein complexes and its sequential assembly is important for its activation. Here, we show that NLRP3 is ubiquitinated by the mitochondria-associated E3 ligase, MARCH5. Myeloid cell-specific March5 conditional knockout (March5 cKO) mice failed to secrete IL-1ß and IL-18 and exhibited an attenuated mortality rate upon LPS or Pseudomonas aeruginosa challenge. Macrophages derived from March5 cKO mice also did not produce IL-1ß and IL-18 after microbial infection. Mechanistically, MARCH5 interacts with the NACHT domain of NLRP3 and promotes K27-linked polyubiquitination on K324 and K430 residues of NLRP3. Ubiquitination-defective NLRP3 mutants on K324 and K430 residues are not able to bind to NEK7, nor form NLRP3 oligomers leading to abortive ASC speck formation and diminished IL-1ß production. Thus, MARCH5-dependent NLRP3 ubiquitination on the mitochondria is required for NLRP3-NEK7 complex formation and NLRP3 oligomerization. We propose that the E3 ligase MARCH5 is a regulator of NLRP3 inflammasome activation on the mitochondria.

Negative regulation of NEMO signaling by the ubiquitin E3 ligase MARCH2.

NF-κB essential modulator (NEMO) is a key regulatory protein that functions during NF-κB- and interferon-mediated signaling in response to extracellular stimuli and pathogen infections. Tight regulation of NEMO is essential for host innate immune responses and for maintenance of homeostasis. Here, we report that the E3 ligase MARCH2 is a novel negative regulator of NEMO-mediated signaling upon bacterial or viral infection. MARCH2 interacted directly with NEMO during the late phase of infection and catalyzed K-48-linked ubiquitination of Lys326 on NEMO, which resulted in its degradation. Deletion of MARCH2 resulted in marked resistance to bacterial/viral infection, along with increased innate immune responses both in vitro and in vivo. In addition, MARCH2-/- mice were more susceptible to LPS challenge due to massive production of cytokines. Taken together, these findings provide new insight into the molecular regulation of NEMO and suggest an important role for MARCH2 in homeostatic control of innate immune responses.

African swine fever virus B175L inhibits the type I interferon pathway by targeting STING and 2'3'-cGAMP.

IMPORTANCE: African swine fever virus (ASFV), the only known DNA arbovirus, is the causative agent of African swine fever (ASF), an acutely contagious disease in pigs. ASF has recently become a crisis in the pig industry in recent years, but there are no commercially available vaccines. Studying the immune evasion mechanisms of ASFV proteins is important for the understanding the pathogenesis of ASFV and essential information for the development of an effective live-attenuated ASFV vaccines. Here, we identified ASFV B175L, previously uncharacterized proteins that inhibit type I interferon signaling by targeting STING and 2'3'-cGAMP. The conserved B175L-zf-FCS motif specifically interacted with both cGAMP and the R238 and Y240 amino acids of STING. Consequently, this interaction interferes with the interaction of cGAMP and STING, thereby inhibiting downstream signaling of IFN-mediated antiviral responses. This novel mechanism of B175L opens a new avenue as one of the ASFV virulent genes that can contribute to the advancement of ASFV live-attenuated vaccines.

SIAH1 modulates antiviral immune responses by targeting deubiquitinase USP19.

Tight control of the type I interferon (IFN) signaling pathway is critical for maintaining host innate immune responses, and the ubiquitination and deubiquitination of signaling molecules are essential for signal transduction. Deubiquitinase ubiquitin-specific protein 19 (USP19) is known to be involved in deubiquitinating Beclin1, TRAF3, and TRIF for downregulation of the type I IFN signaling. Here, we show that SIAH1, a cellular E3 ubiquitin ligase that is involved in multicellular pathway, is a potent positive regulator of virus-mediated type I IFN signaling that maintains homeostasis within the antiviral immune response by targeting USP19. In the early stages of virus infection, stabilized SIAH1 directly interacts with the USP19 and simultaneously mediates K27-linked ubiquitination of 489, 490, and 610 residues of USP19 for proteasomal degradation. Additionally, we found that USP19 specifically interacts with MAVS and deubiquitinates K63-linked ubiquitinated MAVS for negative regulation of type I IFN signaling. Ultimately, we identified that SIAH1-mediated degradation of USP19 reversed USP19-mediated deubiquitination of MAVS, Beclin1, TRAF3, and TRIF, resulting in the activation of antiviral immune responses. Taken together, these findings provide new insights into the molecular mechanism of USP19 and SIAH1, and suggest a critical role of SIAH1 in antiviral immune response and homeostasis.

Effects of exercise during active surveillance for prostate cancer: A systematic review and meta-analysis.

PURPOSE: The efficacy of exercise in men with prostate cancer (PCa) on active surveillance (AS) remains unclear. In this meta-analysis, we aimed to examine the effects of exercise in PCa patients on AS. METHODS: A literature search was conducted in PubMed, EMBASE, and the Cochrane Library using search terms, including exercise, PCa, AS, and randomized controlled trials (RCTs). The means and standard deviations for peak oxygen consumption (VO2peak), prostate-specific antigen (PSA) levels, and quality of life (QoL) were extracted for the intervention and control groups. A random-effects model was used to summarize the effects of exercise. RESULTS: Of the 158 identified studies, six RCTs with 332 patients were included. The interventions included lifestyle modifications (aerobic exercise + diet) in three studies and different exercise modalities in three studies. The intervention duration was 2-12 months; three interventions were supervised and three were self-directed. The pooled weighted mean difference between exercise and usual care for VO2peak was 1.42 mL/kg/min (95% confidence interval [CI]: 0.30 to 2.54, P ≤ 0.001). A non-significant effect was observed for QoL (pooled standardized mean difference [SMD]: 0.24, 95% CI: - 0.03 to 0.51, P = 0.08) which became statistically significant and stronger after excluding one outlier study (P < 0.001). Exercise also had a positive effect on PSA levels (pooled SMD: - 0.43, 95% CI: - 0.87 to 0.01, P = 0.05). CONCLUSION: Exercise improves cardiorespiratory fitness and may improve QoL and PSA levels in men with PCa on AS. Further studies with larger sample sizes are warranted to obtain more reliable results.

Novel role of LLGL2 silencing in autophagy: reversing epithelial-mesenchymal transition in prostate cancer.

PURPOSE: Prostate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo. METHODS: PC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model. RESULTS: In patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition. CONCLUSION: Defective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.

Medial sesamoid position in moderate to severe hallux valgus: Correlation between three radiographic measurements.

BACKGROUND: In hallux valgus surgery, it is essential to accurately assess the position of the sesamoids both pre- and postoperatively. Weight-bearing foot anteroposterior, tangential sesamoid, and semi-weight-bearing computed tomography axial views are radiographic methods used to assess the medial sesamoid position. This study aimed to measure the medial sesamoid position and evaluate the correlation between these three radiographic methods. METHODS: This retrospective study comprised 59 feet from 49 patients who underwent hallux valgus surgery. The mean age of patients was 54.6 (range, 22-70) years. We took preoperative and postoperative measurements using the weight-bearing anteroposterior, tangential sesamoid, and semi-weight-bearing computed tomography axial views to assess the medial sesamoid position. RESULTS: The mean grades of the medial sesamoid position preoperatively and 6 months postoperatively were 2.5 and 0.8, 1.6 and 0.4, and 1.3 and 0.3 points based on the anteroposterior, tangential sesamoid, and computed tomography axial views, respectively (P < 0.001). Preoperatively, there was a strong positive correlation between the computed tomography axial and tangential sesamoid views (P < 0.001, r = 0.645) and anteroposterior and computed tomography axial views (P < 0.001, r = 0.468). In contrast, the tangential sesamoid and anteroposterior views showed a weak positive correlation (P = 0.03, r = 0.283). Six months postoperatively, there was a positive correlation between the computed tomography axial and tangential sesamoid views (P < 0.001, r = 0.473), anteroposterior and computed tomography axial views (P < 0.001, r = 0.470), and tangential sesamoid and anteroposterior views (P < 0.001, r = 0.480). CONCLUSIONS: We observed that the anteroposterior view exhibited a higher degree of medial sesamoid position displacement than the computed tomography axial and tangential sesamoid views. For the preoperative evaluation of the medial sesamoid position, the correlation between the computed tomography axial and tangential sesamoid views was stronger than that between the tangential sesamoid and anteroposterior views. However, all three views showed strong correlations postoperatively.

The African Swine Fever Virus Virulence Determinant DP96R Suppresses Type I IFN Production Targeting IRF3.

DP96R of African swine fever virus (ASFV), also known as uridine kinase (UK), encodes a virulence-associated protein. Previous studies have examined DP96R along with other genes in an effort to create live attenuated vaccines. While experiments in pigs have explored the impact of DP96R on the pathogenicity of ASFV, the precise molecular mechanism underlying this phenomenon remains unknown. Here, we describe a novel molecular mechanism by which DP96R suppresses interferon regulator factor-3 (IRF3)-mediated antiviral immune responses. DP96R interacts with a crucial karyopherin (KPNA) binding site within IRF3, disrupting the KPNA-IRF3 interaction and consequently impeding the translocation of IRF3 to the nucleus. Under this mechanistic basis, the ectopic expression of DP96R enhances the replication of DNA and RNA viruses by inhibiting the production of IFNs, whereas DP96R knock-down resulted in higher IFNs and IFN-stimulated gene (ISG) transcription during ASFV infection. Collectively, these findings underscore the pivotal role of DP96R in inhibiting IFN responses and increase our understanding of the relationship between DP96R and the virulence of ASFV.

African Swine Fever Virus EP364R and C129R Target Cyclic GMP-AMP To Inhibit the cGAS-STING Signaling Pathway.

African swine fever virus (ASFV) is a highly pathogenic swine DNA virus with high mortality that causes African swine fever (ASF) in domestic pigs and wild boars. For efficient viral infection, ASFV has developed complex strategies to evade key components of antiviral innate immune responses. However, the immune escape mechanism of ASFV remains unclear. Upon ASFV infection, cyclic GMP-AMP (2',3'-cGAMP) synthase (cGAS), a cytosolic DNA sensor, recognizes ASFV DNA and synthesizes the second messenger 2',3'-cGAMP, which triggers interferon (IFN) production to interfere with viral replication. In this study, we demonstrated a novel immune evasion mechanism of ASFV EP364R and C129R, which blocks cellular cyclic 2',3'-cGAMP-mediated antiviral responses. ASFV EP364R and C129R with nuclease homology inhibit IFN-mediated responses by specifically interacting with 2',3'-cGAMP and exerting their phosphodiesterase (PDE) activity to cleave 2',3'-cGAMP. Particularly notable is that ASFV EP364R had a region of homology with the stimulator of interferon genes (STING) protein containing a 2',3'-cGAMP-binding motif and point mutations in the Y76S and N78A amino acids of EP364R that impaired interaction with 2',3'-cGAMP and restored subsequent antiviral responses. These results highlight a critical role for ASFV EP364R and C129R in the inhibition of IFN responses and could be used to develop ASFV live attenuated vaccines. IMPORTANCE African swine fever (ASF) is a highly contagious hemorrhagic disease in domestic pigs and wild boars caused by African swine fever virus (ASFV). ASF is a deadly epidemic disease in the global pig industry, but no drugs or vaccines are available. Understanding the pathogenesis of ASFV is essential to developing an effective live attenuated ASFV vaccine, and investigating the immune evasion mechanisms of ASFV is crucial to improve the understanding of its pathogenesis. In this study, for the first time, we identified the EP364R and C129R, uncharacterized proteins that inhibit type I interferon signaling. ASFV EP364R and C129R specifically interacted with 2',3'-cGAMP, the mammalian second messenger, and exerted phosphodiesterase activity to cleave 2',3'-cGAMP. In this study, we discovered a novel mechanism by which ASFV inhibits IFN-mediated antiviral responses, and our findings can guide the understanding of ASFV pathogenesis and the development of live attenuated ASFV vaccines.

Anhydrous Alum Inhibits α-MSH-Induced Melanogenesis by Down-Regulating MITF via Dual Modulation of CREB and ERK.

Melanogenesis, the intricate process of melanin synthesis, is central to skin pigmentation and photoprotection and is regulated by various signaling pathways and transcription factors. To develop potential skin-whitening agents, we used B16F1 melanoma cells to investigate the inhibitory effects of anhydrous alum on melanogenesis and its underlying molecular mechanisms. Anhydrous alum (KAl(SO4)2) with high purity (>99%), which is generated through the heat-treatment of hydrated alum (KAl(SO4)2·12H2O) at 400 °C, potentiates a significant reduction in melanin content without cytotoxicity. Anhydrous alum downregulates the master regulator of melanogenesis, microphthalmia-associated transcription factor (MITF), which targets key genes involved in melanogenesis, thereby inhibiting α-melanocyte-stimulating hormone (α-MSH)-induced melanogenesis. Phosphorylation of the cAMP response element-binding protein, which acts as a co-activator of MITF gene expression, is attenuated by anhydrous alum, resulting in compromised MITF transcription. Notably, anhydrous alum promoted extracellular signal-regulated kinase phosphorylation, leading to the impaired nuclear localization of MITF. Overall, these results demonstrated the generation and mode of action of anhydrous alum in B16F1 cells, which constitutes a promising option for cosmetic or therapeutic use.

Foot-and-mouth disease virus VP1 target the MAVS to inhibit type-I interferon signaling and VP1 E83K mutation results in virus attenuation.

VP1, a pivotal capsid protein encoded by the foot-and-mouth disease virus (FMDV), plays an important role in receptor-mediated attachment and humoral immune responses. Previous studies show that amino acid changes in the VP1 protein of cell culture-adapted strains of FMDV alter the properties of the virus. In addition, FMDV VP1 modulates host IFN signal transduction. Here, we examined the ability of cell culture-adapted FMDV VP1(83K) and wild-type FMDV VP1(83E) to evade host immunity by blocking mitochondrial antiviral signaling protein (MAVS)/TNF Receptor Associated Factor 3 (TRAF3) mediated cellular innate responses. Wild-type FMDV VP1(83E) interacted specifically with C-terminal TRAF3-binding site within MAVS and this interaction inhibited binding of TRAF3 to MAVS, thereby suppressing interferon-mediated responses. This was not observed for cell culture-adapted FMDV VP1(83K). Finally, chimeric FMDV harboring VP1(83K) showed very low pathogenicity in pigs. Collectively, these data highlight a critical role of VP1 with respect to suppression of type-I IFN pathway and attenuation of FMDV by the E83K mutation in VP1.

Optical genome mapping identifies clinically relevant genomic rearrangements in prostate cancer biopsy sample.

BACKGROUND: Prostate cancer (PCa) is characterized by complex genomic rearrangements such as the ETS oncogene family fusions, yet the clinical relevance is not well established. While paneled genetic tests of DNA repair genes are recommended in advanced PCa, conventional genomic or cytogenetic tools are not ideal for genome-wide screening of structural variations (SVs) such as balanced translocation due to cost and/or resolution issues. METHODS: In this study, we tested the feasibility of whole-genome optical genomic mapping (OGM), a newly developed platform for genome-wide SV analysis to detect complex genomic rearrangements in consecutive unselected PCa samples from MRI/US-fusion targeted biopsy. RESULTS: We tested ten samples, and nine (90%) passed quality check. Average mapping rate and coverage depth were 58.1 ± 23.7% and 157.3 ± 97.7×, respectively (mean ± SD). OGM detected copy number alterations such as chr6q13 loss and chr8q12-24 gain. Two adjacent tumor samples were distinguished by inter/intra-chromosomal translocations, revealing that they're from the same ancestor. Furthermore, OGM detected large deletion of chr13q13.1 accompanied by inter-chromosomal translocation t(13;20)(q13.1;p13) occurring within BRCA2 gene, suggesting complete loss of function. CONCLUSION: In conclusion, clinically relevant genomic SVs were successfully detected in PCa samples by OGM. We suggest that OGM can complement panel sequencing of DNA repair genes BRCA1/2 or ATM in high-risk PCa.

Probiotic effects of Pseudoalteromonas ruthenica: Antibacterial, immune stimulation and modulation of gut microbiota composition.

This study aimed to characterise and evaluate the probiotic properties of a newly isolated marine bacterium, strain S6031. The isolated strain was identified as Pseudoalteromonas ruthenica. In vivo experiments were conducted with P. ruthenica-immersed larvae and P. ruthenica-enriched Artemia fed to adult zebrafish. Disease tolerance of larval zebrafish against Edwardsiella piscicida was demonstrated by 66.34% cumulative per cent survival (CPS) in the P. ruthenica-exposed group, which was higher than the CPS of the control (46.67%) at 72 h post challenge (hpc). Heat-stressed larvae had 55% CPS in the P. ruthenica-immersed group, while the control had 30% CPS at 60 hpc. Immune-stress response gene transcripts (muc5.1, muc5.2, muc5.3, alpi2, alpi3, hsp70, and hsp90a) were induced, while pro-inflammatory genes (tnfα, il1b, and il6) were downregulated in P. ruthenica-immersed larvae compared to the control. This trend was confirmed by low pro-inflammatory and high stress-responsive protein expression levels in P. ruthenica-exposed larvae. Adult zebrafish had higher CPS (27.2%) in the P. ruthenica-fed group than the control (9.52%) upon E. piscicida challenge, suggesting increased disease tolerance. Histological analysis demonstrated modulation of goblet cell density and average villus height in the P. ruthenica-supplemented group. Metagenomics analysis clearly indicated modulation of alpha diversity indices and the relative abundance of Proteobacteria in the P. ruthenica-supplemented zebrafish gut. Furthermore, increased Firmicutes colonisation and reduced Bacteroidetes abundance in the gut were observed upon P. ruthenica supplementation. Additionally, this study confirmed the concentration-dependent increase of colony dispersion and macrophage uptake upon mucin treatment. In summary, P. ruthenica possesses remarkable functional properties as a probiotic that enhances host defence against diseases and thermal stress.

Sessile serrated lesions in patients with adenoma on index colonoscopy do not increase metachronous advanced adenoma risk.

OBJECTIVES: Post-polypectomy surveillance intervals should be determined based on index colonoscopy findings. However, the risk of metachronous lesions, resulting from the coexistence of adenoma and sessile serrated lesions (SSLs), has rarely been addressed. We evaluated the impact of synchronous SSL on the risk of metachronous lesions within similar adenoma risk groups. METHODS: We retrieved individuals with one or more adenomas on index colonoscopy in a single-center retrospective cohort and stratified them into four groups depending on the presence of SSL and low-risk/high-risk adenoma (LRA/HRA). Participants who underwent surveillance colonoscopies at least 12 months apart were included. We compared the risks of metachronous lesions including HRA, advanced adenoma (AA), or SSL within similar adenoma risk groups according to the presence of SSL. RESULTS: Overall 4493 individuals were included in the analysis. The risk of metachronous HRA/AA was not significantly higher in the adenoma with SSL group compared with the adenoma without SSL group, irrespective of LRA (HRA, 6/86 vs. 231/3297, P = 1.00; AA, 0/86 vs. 52/3297, P = 0.64) or HRA (HRA, 11/64 vs. 240/1046, P = 0.36; AA, 3/64 vs. 51/1046, P = 1.00). However, the risk of metachronous SSL in individuals with synchronous SSL was higher than that in those without SSL for both LRA (15/86 vs. 161/3297, P < 0.001) and HRA groups (11/64 vs. 61/1046, P = 0.002). CONCLUSION: The presence of synchronous SSL did not increase the risk of metachronous HRA/AA, compared with isolated adenoma, but increased the risk of metachronous SSL.

Characteristics of BRCA2 Mutated Prostate Cancer at Presentation.

Genetic alterations of DNA repair genes, particularly BRCA2 in patients with prostate cancer, are associated with aggressive behavior of the disease. It has reached consensus that somatic and germline tests are necessary when treating advanced prostate cancer patients. Yet, it is unclear whether the mutations are associated with any presenting clinical features. We assessed the incidences and characteristics of BRCA2 mutated cancers by targeted sequencing in 126 sets of advanced prostate cancer tissue sequencing data. At the time of diagnosis, cT3/4, N1 and M1 stages were 107 (85%), 54 (43%) and 35 (28%) samples, respectively. BRCA2 alterations of clinical significance by AMP/ASCO/CAP criteria were found in 19 of 126 samples (15.1%). The BRCA2 mutated cancer did not differ in the distributions of TNM stage, Gleason grade group or histological subtype compared to BRCA2 wild-type cancers. Yet, they had higher tumor mutation burden, and higher frequency of ATM and BRCA1 mutations (44% vs. 10%, p = 0.002 and 21% vs. 4%, p = 0.018, respectively). Of the metastatic subgroup (M1, n = 34), mean PSA was significantly lower in BRCA2 mutated cancers than wild-type (p = 0.018). In the non-metastatic subgroup (M0, n = 64), PSA was not significantly different (p = 0.425). A similar trend was noted in multiple metastatic prostate cancer public datasets. We conclude that BRCA2 mutated metastatic prostate cancers may present in an advanced stage with relatively low PSA.

Hepatocyte-Specific Deficiency of DAX-1 Protects Mice from Acetaminophen-Induced Hepatotoxicity by Activating NRF2 Signaling.

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but its overdose can cause acute liver failure. The dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1, NR0B1), is an orphan nuclear receptor that acts as a transcriptional co-repressor of various genes. In this study, we identified the role of DAX-1 in APAP-induced liver injury using hepatocyte-specific Dax-1 knockout (Dax-1 LKO) mice. Mouse primary hepatocytes were used as a comparative in vitro study. APAP overdose led to decreased plasma alanine aminotransferase and aspartate aminotransferase levels in Dax-1 LKO mice compared to C57BL/6J (WT) controls, accompanied by reduced liver necrosis. The expression of the genes encoding the enzymes catalyzing glutathione (GSH) synthesis and metabolism and antioxidant enzymes was increased in the livers of APAP-treated Dax-1 LKO mice. The rapid recovery of GSH levels in the mitochondrial fraction of APAP-treated Dax-1 LKO mice led to reduced reactive oxygen species levels, resulting in the inhibition of the prolonged JNK activation. The hepatocyte-specific DAX-1 deficiency increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) compared with WT controls after APAP administration. These results indicate that DAX-1 deficiency in hepatocytes protects against APAP-induced liver injury by Nrf2-regulated antioxidant defense.

Fas-associated factor 1 mediates NADPH oxidase-induced reactive oxygen species production and proinflammatory responses in macrophages against Listeria infection.

Fas-associated factor 1 is a death-promoting protein that induces apoptosis by interacting with the Fas receptor. Until now, FAF1 was reported to interact potentially with diverse proteins and to function as a negative and/or positive regulator of several cellular possesses. However, the role of FAF1 in defense against bacterial infection remains unclear. Here, we show that FAF1 plays a pivotal role in activating NADPH oxidase in macrophages during Listeria monocytogenes infection. Upon infection by L. monocytogenes, FAF1 interacts with p67phox (an activator of the NADPH oxidase complex), thereby facilitating its stabilization and increasing the activity of NADPH oxidase. Consequently, knockdown or ectopic expression of FAF1 had a marked effect on production of ROS, proinflammatory cytokines, and antibacterial activity, in macrophages upon stimulation of TLR2 or after infection with L. monocytogenes. Consistent with this, FAF1gt/gt mice, which are knocked down in FAF1, showed weaker inflammatory responses than wild-type mice; these weaker responses led to increased replication of L. monocytogenes. Collectively, these findings suggest that FAF1 positively regulates NADPH oxidase-mediated ROS production and antibacterial defenses.

Clinical Outcomes After Urinary Diversion for Malignant Ureteral Obstruction Secondary to Non-urologic Cancer: An Analysis of 778 Cases.

BACKGROUND: This study investigated patient outcomes after urinary diversion in order to manage malignant ureteral obstruction caused by non-urologic cancers and to evaluate predictive factors for overall survival. METHODS: The study retrospectively reviewed patients with non-urologic malignancies who underwent ureteral stenting or percutaneous nephrostomy for ureteral obstruction between 2006 and 2014. The variables for predicting overall survival were identified by Cox regression analysis. RESULTS: The study enrolled 778 patients, including 522 patients who underwent ureteral stenting and 256 patients who underwent percutaneous nephrostomy. Renal function was assessed immediately and then 2 weeks after urinary diversion. The median survival period was 5 months (interquartile range [IQR] 2-12 months). A total of 708 patients died. The patients who received chemotherapy after urinary diversion had a survival gain of 7 months compared with the patients who did not receive subsequent chemotherapy (p < 0.001). The survival rate did not differ between the various types of urinary diversion (p = 0.451). In the multivariate analysis, lower survival rates were significantly associated with male sex; previous chemotherapy without radiotherapy; an increasing number of events related to malignant dissemination; low preoperative hemoglobin (< 10 mg/dL), albumin (< 3 g/dL), and estimated glomerular filtration (< 60 mL/min/1.73 m2) rates; and no subsequent chemotherapy or radiotherapy. CONCLUSIONS: In cases of ureteral obstruction caused by non-urologic malignancies, the overall survival was poor. However, the patients who received chemotherapy after urinary diversion had a survival gain of 7 months. Therefore, urinary diversion could be considered to preserve renal function for subsequent chemotherapy, whereas patients with the poor prognostic factors should be presented with the option of no intervention.

Development of a risk scoring system for predicting acute kidney injury after minimally invasive partial and radical nephrectomy: a retrospective study.

BACKGROUND: Acute kidney injury after partial or radical nephrectomy remains an unsolved problem even when using minimally invasive techniques. We aimed to identify risk factors for acute kidney injury (AKI) after minimally invasive nephrectomy and to develop a clinical risk scoring system. METHODS: Medical records of 1762 patients who underwent minimally invasive laparoscopic or robot-assisted laparoscopic partial (n = 1009) or radical (n = 753) nephrectomy from December 2005 to November 2018 were reviewed. Candidate risk factors were screened using univariate analysis and ranked using linear discriminant analysis; top ranking factors were incorporated into a multivariate logistic regression model. Then, the final clinical scoring system was created based on the estimated odds ratios. RESULTS: The incidence of acute kidney injury after partial or radical nephrectomy was 20.3 and 61.6%, respectively. Risk factors incorporated into the scoring system included: size of the parenchymal mass removed (3 < parenchymal mass ≤ 4 cm, 1 point; 4 < parenchymal mass ≤ 6 cm, 3 points; parenchymal mass > 6 cm, 5 points), male sex (2 points), diabetes mellitus (1 point), warm ischemia time ≥ 25 min (1 point), and immediate postoperative neutrophil count ≥ 12,000 µl-1 (1 point) in patients with partial nephrectomy, and sex (male, 10 points; female, 7 points) in patients with radical nephrectomy. For risk scores of 0-4, 5-6, 7, 8-9, and 10 points, the probabilities of acute kidney injury were approximately 10, 20, 40, 60, and 80%, respectively. The predictive accuracy of the scoring system was 0.827 (95% CI 0.789-0.865). CONCLUSION: Our risk scoring system could help clinicians identify those at risk of acute kidney injury after minimally invasive partial or radical nephrectomy, thereby optimizing postoperative management.