Nucleoside-diphosphate kinase of uropathogenic Escherichia coli inhibits caspase-1-dependent pyroptosis facilitating urinary tract infection.

Uropathogenic Escherichia coli (UPEC) is the most common causative agent of urinary tract infection (UTI). UPEC invades bladder epithelial cells (BECs) via fusiform vesicles, escapes into the cytosol, and establishes biofilm-like intracellular bacterial communities (IBCs). Nucleoside-diphosphate kinase (NDK) is secreted by pathogenic bacteria to enhance virulence. However, whether NDK is involved in UPEC pathogenesis remains unclear. Here, we find that the lack of ndk impairs the colonization of UPEC CFT073 in mouse bladders and kidneys owing to the impaired ability of UPEC to form IBCs. Furthermore, we demonstrate that NDK inhibits caspase-1-dependent pyroptosis by consuming extracellular ATP, preventing superficial BEC exfoliation, and promoting IBC formation. UPEC utilizes the reactive oxygen species (ROS) sensor OxyR to indirectly activate the regulator integration host factor, which then directly activates ndk expression in response to intracellular ROS. Here, we reveal a signaling transduction pathway that UPEC employs to inhibit superficial BEC exfoliation, thus facilitating acute UTI.

cGAS suppresses hepatocellular carcinoma independent of its cGAMP synthase activity.

Cyclic GMP-AMP synthase (cGAS) is a key innate immune sensor that recognizes cytosolic DNA to induce immune responses against invading pathogens. The role of cGAS is conventionally recognized as a nucleotidyltransferase to catalyze the synthesis of cGAMP upon recognition of cytosolic DNA, which leads to the activation of STING and production of type I/III interferon to fight against the pathogen. However, given that hepatocytes are lack of functional STING expression, it is intriguing to define the role of cGAS in hepatocellular carcinoma (HCC), the liver parenchymal cells derived malignancy. In this study, we revealed that cGAS was significantly downregulated in clinical HCC tissues, and its dysregulation contributed to the progression of HCC. We further identified cGAS as an immune tyrosine inhibitory motif (ITIM) containing protein, and demonstrated that cGAS inhibited the progression of HCC and increased the response of HCC to sorafenib treatment by suppressing PI3K/AKT/mTORC1 pathway in cellular and animal models. Mechanistically, cGAS recruits SH2-containing tyrosine phosphatase 1 (SHP1) via ITIM, and dephosphorylates p85 in phosphatidylinositol 3-kinase (PI3K), which leads to the suppression of AKT-mTORC1 pathway. Thus, cGAS is identified as a novel tumor suppressor in HCC via its function independent of its conventional role as cGAMP synthase, which indicates a novel therapeutic strategy for advanced HCC by modulating cGAS signaling.

LncRNA SNHG1 overexpression alleviates osteoarthritis via activating PI3K/Akt signal pathway and suppressing autophagy.

We hereby intend to further explore and confirm the underlying mechanism of Small nucleolar RNA Host Gene 1 (SNHG1) in osteoarthritis (OA). For in vitro assays, OA was induced in primary chondrocytes with interleukin-1ß (IL-1ß) treatment; while for in vivo tests, OA model was established in mice using the destabilization of the medial meniscus (DMM) method. Cell viability and apoptosis were assessed with MTT and flow cytometry assays, respectively. Cartilage tissue was stained by Safranin-O/Fast Green Staining. The mRNA and protein levels were separately determined via quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. SNHG1 overexpression promoted the viability yet inhibited the apoptosis of chondrocytes injured by IL-1ß. Moreover, the overexpression of SNHG1 promoted B-cell lymphoma-2 (Bcl-2) expression and activated phosphoinositol-3 kinase (PI3K)/protein kinase B (Akt) pathway but suppressed the process of autophagy, which led to down-regulation of light chain 3 (LC3)-II/I level and up-regulation of P62 level. However, rapamycin (RAPA, an autophagy activator) and LY294002 (a PI3K inhibitor) reversed the effects of SNHG1 overexpression on the viability and apoptosis of chondrocytes as well as on the proteins related to PI3K/Akt pathway and autophagy. In OA-modeled mice, SNHG1 overexpression prevented the loss of chondrocytes via the activation of PI3K/Akt pathway and the suppression of autophagy. SNHG1 overexpression might inhibit the apoptosis of chondrocytes by promoting PI3K/Akt pathway and inhibiting autophagy.

[Blocking Effects of Foliar Conditioners on Cadmium, Arsenic, and Lead Accumulation in Wheat Grain in Compound-contaminated Farmland].

Heavy metal contamination of soil has become a hot issue of social concern due to its impact on the safety of agricultural products in recent years. Wheat is one of the most dominant staple food crops worldwide and has become a major source of toxic metals in human diets. Foliar application was considered to be a more efficient and economical method of heavy metal remediation. Field experiments were carried out in Cd-, As-, and Pb-contaminated farmland soils. The effects of foliar conditioners on the accumulation of Cd, As, and Pb in wheat grains were investigated after being sprayed with Zn (0.2% ZnSO4), Mg (0.4% MgSO4), and Mn (0.2% MnSO4) separately and in combination. Thus, the effective foliar conditioners were selected to block the accumulation of Cd, As, and Pb in wheat grains grown in combined heavy metal-contaminated farmland in north China. The results showed that, compared with that in the control, the Cd, As, and Pb contents in wheat grains of the Zn+Mg+Mn foliar treatment were significantly decreased by 18.96%, 23.87%, and 51.31%, respectively, and TFgrain/straw decreased by 14.62%, 27.73%, and 47.70%, respectively. Thus, spraying the compound foliar conditioner of Zn+Mg+Mn could effectively reduce heavy metal accumulation in wheat grains through inhibition translocation of those metals from stem leaves to grain. In addition, the results indicated that Cd and As were mainly distributed at the central endosperm (34.08%-37.08%), whereas Pb was primarily distributed at the pericarp and seed coat (27.78%) of the wheat grain. Compared with that in the control, spraying the compound foliar conditioner of Zn+Mg+Mn extremely decreased Cd and As accumulation in the aleurone layer of the wheat grain by 81.10% and 82.24%, respectively. Except for the pericarp, seed coat, and central endosperm layers, the Pb content in each grain layer was dramatically decreased by 42.85% to 91.15%. There was only a significant negative correlation between heavy metal content and Zn content in the aleurone layer (P2) of wheat flour. In summary, the accumulation of Cd, As, and Pb in wheat grains, especially in the aleurone layer, could be effectively reduced by foliar conditioner application at the jointing, booting, and early filling stages of wheat, separately. Furthermore, besides the foliar treatment, removing wheat bran to reduce Cd contamination in wheat grains is highly recommended to ensure the safe production of wheat.

How to assess the long-term recovery outcomes of patients with cauda equina syndrome before surgery: a retrospective cohort study.

BACKGROUND: Factors influencing recovery after decompression surgery for cauda equina syndrome (CES) are not completely identified. We aimed to investigate the most valuable predictors (MVPs) of poor postoperative recovery (PPR) in patients with CES and construct a nomogram for discerning those who will experience PPR. METHODS: 356 patients with CES secondary to lumbar degenerative diseases treated at *** Hospital were randomly divided into training (N=238) and validation (N=118) cohorts at a 2:1 ratio. Moreover, 92 patients from the **** Hospital composed the testing cohort. Least Absolute Shrinkage and Selection Operator regression (LASSO) was used for selecting MVPs. The nomogram was developed by integrating coefficients of MVPs in the logistic regression, and its discrimination, calibration, and clinical utility were validated in all three cohorts. RESULTS: After 3 to 5 years of follow-up, the residual rates of bladder dysfunction, bowel dysfunction, sexual dysfunction, and saddle anesthesia were 41.9%, 44.1%, 63.7%, and 29.0%, respectively. MVPs included stress urinary incontinence, overactive bladder, low stream, difficult defecation, fecal incontinence, and saddle anesthesia in order. The discriminatory ability of the nomogram was up to 0.896, 0.919, and 0.848 in the training, validation, and testing cohorts, respectively. Besides, the nomogram showed good calibration and clinical utility in all cohorts. Furthermore, the optimal cut-off value of the nomogram score for distinguishing those who will experience PPR was 148.02, above which postoperative outcomes tend to be poor. CONCLUSION: The first pre-treatment nomogram for discerning CES patients who will experience PPR was developed and validated, which will aid clinicians in clinical decision-making.

Salmonella enterica serovar Typhimurium remodels mitochondrial dynamics of macrophages via the T3SS effector SipA to promote intracellular proliferation.

Mitochondrial dynamics are critical in cellular energy production, metabolism, apoptosis, and immune responses. Pathogenic bacteria have evolved sophisticated mechanisms to manipulate host cells' mitochondrial functions, facilitating their proliferation and dissemination. Salmonella enterica serovar Typhimurium (S. Tm), an intracellular foodborne pathogen, causes diarrhea and exploits host macrophages for survival and replication. However, S. Tm-associated mitochondrial dynamics during macrophage infection remain poorly understood. In this study, we showed that within macrophages, S. Tm remodeled mitochondrial fragmentation to facilitate intracellular proliferation mediated by Salmonella invasion protein A (SipA), a type III secretion system effector encoded by Salmonella pathogenicity island 1. SipA directly targeted mitochondria via its N-terminal mitochondrial targeting sequence, preventing excessive fragmentation and the associated increase in mitochondrial reactive oxygen species, loss of mitochondrial membrane potential, and release of mitochondrial DNA and cytochrome c into the cytosol. Macrophage replication assays and animal experiments showed that mitochondria and SipA interact to facilitate intracellular replication and pathogenicity of S. Tm. Furthermore, we showed that SipA delayed mitochondrial fragmentation by indirectly inhibiting the recruitment of cytosolic dynamin-related protein 1, which mediates mitochondrial fragmentation. This study revealed a novel mechanism through which S. Tm manipulates host mitochondrial dynamics, providing insights into the molecular interplay that facilitates S. Tm adaptation within host macrophages.

Chronic cauda equina syndrome decompression surgery recovery is very "bad"? Based on patient self-assessment.

BACKGROUND: Symptoms of cauda equina syndrome (CES) secondary to degenerative lumbar spine diseases are sometimes mild and tend to be ignored by patients, resulting in delayed treatment. In addition, the long-term efficacy of surgery is unclear. OBJECTIVE: To determine the predictive factors of CES and post-operative recovery in patients with symptoms lasting > 3 months. METHODS: From January 2011 to December 2020, data of 45 patients with CES secondary to lumbar disk herniation/lumbar spinal stenosis were collected from a single center. The patients had bladder, bowel or sexual dysfunction and decreased perineal sensation that lasted for > 3 months. A 2-year post-operative follow-up was conducted to evaluate recovery outcomes, which were measured by validated self-assessment questionnaires conducted by telephone and online. RESULTS: Overall, 45 CES patients (57.8% female; mean age, 56 years) were included. The duration of pre-operative CES symptoms was 79.6 weeks (range, 13-730 weeks). The incidence of saddle anesthesia before decompression was 71.1% (n = 32), bladder dysfunction 84.4% (n = 38), bowel dysfunction 62.2% (n = 28) and sexual dysfunction 64.4% (n = 29). The overall recovery rate of CES after a 2-year follow-up was 64.4%. The rates of the residual symptoms at the last follow-up were as follows: saddle anesthesia 22.2%, bladder dysfunction 33.3%, bowel dysfunction 24.4% and sexual dysfunction 48.9%. Pre-operative saddle anesthesia, overactive bladder and sexual dysfunction were risk factors for poor prognosis after decompression. CONCLUSION: CES patients with symptoms lasting > 3 months may recover after surgery. Sexual dysfunction has a high residual rate and should not be ignored during diagnosis and treatment.

[Distribution and Transport of Cadmium and Arsenic in Different Aboveground Parts of Wheat After Flowering].

To investigate the effects of leaves and stems on the accumulation and transport of cadmium(Cd) and arsenic(As) in wheat shoots after flowering, a field experiment was conducted in a typical Cd and As co-contaminated agricultural land to explore the distribution and translocation of Cd and As in the different parts of two wheat cultivars after flowering. The results showed that Cd was mainly distributed in the nodes of two varieties, and the translocation factors of Cd from internode 3 to node 2, from internode 2 to node 1, and from sheath 1 to node 1 were markedly higher than those of other aboveground parts during the grain-filling stage. However, Cd was mainly distributed in the leaves, and the translocation factors of Cd from sheath to leaf and from node 1 to rachis was significantly higher than those of other parts at the mature stage. In addition, the transport capacity of Cd from glume to rachis and from rachis to grain in JM22 was significantly lower than that in SN28, which significantly reduced Cd concentrations in the rachis, glume, and grain of JM22 by 22.3%, 40.8%, and 44.4%, respectively. Meanwhile, As was mainly distributed in the wheat leaves from the grain-filling stage to the mature stage, and As concentrations in the glume and grain of JM22 were 25.8% and 33.3% lower than those of SN28, respectively. Additionally, the translocation factors of As from the sheath to the node were significantly 438% and 190% higher than that from leaf to sheath and from node to internode during the whole grain filling stage and mature stage. Moreover, the translocation factors of As from glumes to grains and from rachis to grains in JM22 were 40.6% and 44.4% lower than that in SN28, respectively. In summary, flag leaf, node 1, and the rachis had regulated Cd transport and accumulation in wheat grains, whereas leaf 3, flag leaf, node 1, the glumes, and the rachis were mainly responsible for As transport and accumulation in wheat grains.

Targeting CDK1 in cancer: mechanisms and implications.

Cyclin dependent kinases (CDKs) are serine/threonine kinases that are proposed as promising candidate targets for cancer treatment. These proteins complexed with cyclins play a critical role in cell cycle progression. Most CDKs demonstrate substantially higher expression in cancer tissues compared with normal tissues and, according to the TCGA database, correlate with survival rate in multiple cancer types. Deregulation of CDK1 has been shown to be closely associated with tumorigenesis. CDK1 activation plays a critical role in a wide range of cancer types; and CDK1 phosphorylation of its many substrates greatly influences their function in tumorigenesis. Enrichment of CDK1 interacting proteins with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted to demonstrate that the associated proteins participate in multiple oncogenic pathways. This abundance of evidence clearly supports CDK1 as a promising target for cancer therapy. A number of small molecules targeting CDK1 or multiple CDKs have been developed and evaluated in preclinical studies. Notably, some of these small molecules have also been subjected to human clinical trials. This review evaluates the mechanisms and implications of targeting CDK1 in tumorigenesis and cancer therapy.

Quantitative analysis on the oil content of oilfield wastewater based on a convolutional neural network model and ultraviolet transmission spectroscopy.

Oil content (OC) is one of the important evaluation indicators in oilfield wastewater (OW) treatment. The purpose of this study is to realize online real-time detection of OC in OW by combining ultraviolet spectrophotometry with the convolutional neural network (CNN). In this paper, 80 groups of OW transmission data were measured for model establishment. Three CNN models with different structures are established to generalize the super parametric optimization process of the model. Furthermore, as a common method used in spectroscopy, the synergy interval partial least squares (siPLS) model is built in order to compare its accuracy with the CNN model. The results indicated the CNN model has a better performance than siPLS, in which the CNN model numbered Model 3 has the lowest root mean square error (MSE) of prediction (RMSEP) of 1.606 mg/L. As a consequence, the CNN model can be used in the monitoring of OW. This article will guide a rapid analysis of the OC of OW.

The Swin-Transformer network based on focal loss is used to identify images of pathological subtypes of lung adenocarcinoma with high similarity and class imbalance.

PURPOSE: The classification of primary lung adenocarcinoma is complex and varied. Different subtypes of lung adenocarcinoma have different treatment methods and different prognosis. In this study, we collected 11 datasets comprising subtypes of lung cancer and proposed FL-STNet model to provide the assistance for improving clinical problems of pathologic classification in primary adenocarcinoma of lung. METHODS: Samples were collected from 360 patients diagnosed with lung adenocarcinoma and other subtypes of lung diseases. In addition, an auxiliary diagnosis algorithm based on Swin-Transformer, which used Focal Loss for function in training, was developed. Meanwhile, the diagnostic accuracy of the Swin-Transformer was compared to pathologists. RESULTS: The Swin-Transformer captures not only information in the overall tissue structure but also the local tissue details in the images of lung cancer pathology. Furthermore, training FL-STNet with the Focal Loss function can further balance the difference in the amount of data between different subtypes, improving recognition accuracy. The average classification accuracy, F1, and AUC of the proposed FL-STNet reached 85.71%, 86.57%, and 0.9903. The average accuracy of the FL-STNet was higher by 17% and 34%, respectively, than in the senior pathologist and junior pathologist group. CONCLUSION: The first deep learning based on an 11-category classifier was developed for classifying lung adenocarcinoma subtypes based on WSI histopathology. Aiming at the deficiencies of the current CNN and Vit, FL-STNet model is proposed in this study by introducing Focal Loss and combining the advantages of Swin-Transformer model.

AAV9-HGF cooperating with TGF-beta/Smad inhibitor attenuates silicosis fibrosis via inhibiting ferroptosis.

Silicosis is a devastating interstitial lung disease characterized by silicon nodules and diffuse pulmonary fibrosis. To date, inefficient therapy is still a challenge of this disease due to its complicated pathogenesis. Hepatocyte growth factor (HGF) which is highly expressed in hepatocyte with anti-fibrotic and anti-apoptotic function was downregulated in silicosis. In addition, the upregulation of transforming growth factor-beta (TGF-ß), another pathological molecular was observed to aggravate the severity and accelerate the progression of silicosis. Here AAV expressed HGF with targeting pulmonary capillaries and SB431542, the inhibitor of TGF-ß signal pathway, were simultaneously adopted to synergistically reduce silicosis fibrosis. In vivo result demonstrated that the cooperation of HGF with SB431542 showed strong anti-fibrosis effects on the silicosis mice via tracheal administration of silica, compared to the separate treatment. The high efficacy was mainly achieved by remarkably by reducing ferroptosis of lung tissue. In our point, the combination of AAV9-HGF with SB431542 provide an alternative to relieve silicosis fibrosis from the perspective of targeting pulmonary capillaries.

L-distance ratio: a new distance ratio-based evaluation method for the diagnosis of cirrhosis using enhanced computed tomography.

Background: Early detection of liver cirrhosis is of great significance to the formulation of treatment plans and improving prognosis. Computed tomography (CT) is commonly used in the assessment of patients with chronic liver disease. In this study, we proposed a new distance ratio method for accurate diagnosis of cirrhosis using CT images. Methods: This was a retrospective study of a consecutive series of patients in Guangdong Provincial People's Hospital. Sixty-two patients with pathologically diagnosed cirrhosis but whose morphologic changes were insufficient to diagnose cirrhosis were included in the cirrhosis group. Those who were pathologically confirmed to be free of cirrhosis and fibrosis and without a history of chronic hepatic were classified as the control group. A total of 124 patients underwent abdominal dynamic enhanced CT. Both the L-distance ratio-the ratio of the distance from the right portal vein bifurcation point to the anterior and posterior edges of the liver-and the caudate-right lobe ratio were measured by two independent radiologists. Intraclass correlation coefficients (ICCs) were used to assess the agreement between the radiologists. Binary logistic regression was performed for univariate analysis, and the odds ratio (OR) was also calculated. The discrimination ability of the two methods was evaluated by the area under the receiver operating characteristic curve (AUC). Results: For both the L-distance ratio and the caudate-right lobe ratio, high agreement was observed between the two radiologists, although the ICC value of the L-distance ratio was slightly higher than that of the caudate-right lobe ratio (0.916 vs. 0.907). Binary logistic regression suggested that higher ratios were correlated with cirrhosis [the L-distance ratio, high vs. low OR =4.41, 95% confidence interval (CI): 2.08-9.36, P<0.001; the caudate-right lobe ratio, high vs. low OR =2.19, 95% CI: 1.07-4.49, P=0.031]. The AUCs of the L-distance ratio and the caudate-right lobe ratio were 0.823 (95% CI: 0.752-0.894) and 0.663 (95% CI: 0.569-0.757), respectively. Conclusions: The L-distance ratio method proposed in this paper is more simple, accurate, and reliable than the caudate-right lobe ratio method in the diagnosis of cirrhosis.

Frequently mutated genes in predicting the relapse of stage I lung adenocarcinoma.

PURPOSE: Approximately, 45-65% stage I non-small cell lung cancer (NSCLC) patients with surgical resection relapse within 5 years. Therefore, it is urgent to identify the predictors involved in the relapse of stage I NSCLC. METHODS/PATIENTS: Targeted sequencing was used to examine the mutation of tumor tissues and matched adjacent normal tissues from 35 patients with stage I lung adenocarcinoma (LUAD). Then, tissue microarrays containing tumor tissues from 149 stage I LUAD patients were used to assess protein expression of frequently mutated genes by immunohistochemistry. COX regression model was used to evaluate the impacts of frequently mutated genes and their protein expression on relapse-free survival (RFS) in stage I LUAD. RESULTS AND CONCLUSIONS: Three hundred and twenty-nine non-synonymous somatic variants were identified in 161 genes among these 35 patients. EGFR, TP53, LRP1B, RBM10, KRAS, NTRK3, RB1, ALK, APC, FAT2, KEAP1, MED12 and MLL3 were described as frequently mutated genes with prevalence more than 10%. Patients harboring KRAS mutation had more relapse in 1 year after surgical resection. For the expression of these frequently mutated genes in 149 stage I patients, multivariate Cox regression analyses showed that the expression of RBM10 was positively associated with RFS in all patients (HR 0.40, 95% CI 0.15-1.0, p = 0.052), and the expression of APC was negative associated with RFS in patients with EGFR mutations (HR 3.10, 95% CI 1.54-6.26, p = 0.002). Stage I LUAD patients with KRAS mutation or low RBM10 expression are inclined to receive more positive intervention rather than just disease surveillance.

A comprehensive pan-cancer analysis reveals cancer-associated robust isomiR expression landscapes in miRNA arm switching.

MicroRNAs (miRNAs), important regulators of gene expression, play critical roles in various biological processes and tumorigenesis. To reveal the potential relationships between multiple isomiRs and arm switching, we performed a comprehensive pan-cancer analysis to discuss their roles in tumorigenesis and cancer prognosis. Our results showed that many miR-#-5p and miR-#-3p pairs from the two arms of pre-miRNA may have abundant expression levels, and they are often involved in distinct functional regulatory networks by targeting different mRNAs, although they may also interact with common targets. The two arms may show diverse isomiR expression landscapes, and their expression ratio might vary, mainly depending on tissue type. Dominantly expressed isomiRs can be used to determine distinct cancer subtypes that are associated with clinical outcome, indicating that they may be potential prognostic biomarkers. Our findings indicate robust and flexible isomiR expression landscapes that will enrich the study of miRNAs/isomiRs and aid in revealing the potential roles of multiple isomiRs yielded by arm switching in tumorigenesis.

Overexpressed ski efficiently promotes neurorestoration, increases neuronal regeneration, and reduces astrogliosis after traumatic brain injury.

Traumatic brain injury (TBI) survivors suffer from long-term disability and neuropsychiatric sequelae due to irreparable brain tissue destruction. However, there are still few efficient therapies to promote neurorestoration in damaged brain tissue. This study aimed to investigate whether the pro-oncogenic gene ski can promote neurorestoration after TBI. We established a ski-overexpressing experimental TBI mouse model using adenovirus-mediated overexpression through immediate injection after injury. Hematoxylin-eosin staining, MRI-based 3D lesion volume reconstruction, neurobehavioral tests, and analyses of neuronal regeneration and astrogliosis were used to assess neurorestorative efficiency. The effects of ski overexpression on the proliferation of cultured immature neurons and astrocytes were evaluated using imaging flow cytometry. The Ski protein level increased in the perilesional region at 3 days post injury. ski overexpression further elevated Ski protein levels up to 14 days post injury. Lesion volume was attenuated by approximately 36-55% after ski overexpression, with better neurobehavioral recovery, more newborn immature and mature neurons, and less astrogliosis in the perilesional region. Imaging flow cytometry results showed that ski overexpression elevated the proliferation rate of immature neurons and reduced the proliferation rate of astrocytes. These results show that ski can be considered a novel neurorestoration-related gene that effectively promotes neurorestoration, facilitates neuronal regeneration, and reduces astrogliosis after TBI.

Systematic analysis of cancer-specific synthetic lethal interactions provides insight into personalized anticancer therapy.

The concept of synthetic lethality has great potential for anticancer therapy as a new strategy to specifically kill cancer cells while sparing normal cells. To further understand the potential molecular interactions and gene characteristics involved in synthetic lethality, we performed a comprehensive analysis of predicted cancer-specific genetic interactions. Many genes were identified as cancer-associated genes that contributed to multiple biological processes and pathways, and the gene features were not random, indicating their potential roles in human carcinogenesis. Some relevant genes detected in multiple cancers were prone to be enriched in specific biological progresses and pathways, especially processes associated with DNA damage, chromosome-related functions and cancer pathways. These findings strongly implicated potential roles for these genes in cancer pathophysiology and functional relationships, as well as applications for future anticancer drug discovery. Further experimental validation indicated that the synthetic lethal interaction of APC and GFER may provide a potential anticancer strategy for patients with APC-mutant colon cancer. These results will contribute to further exploration of synthetic lethal interactions and broader application of the concept of synthetic lethality in anticancer therapeutics.

Prognostic Significance of Tumor Mutation Burden among Patients with Non-small Cell Lung Cancer Who Received Platinum-based Adjuvant Chemotherapy: An Exploratory Study.

This study aimed to investigate the prognostic significance of tumor mutation burden (TMB) among patients with non-small cell lung cancer (NSCLC) who received platinum-based adjuvant chemotherapy. Tumor tissue specimens after surgical resection were collected for DNA extraction. Somatic mutation detection and TMB analysis were conducted using next-generation sequencing (NGS). Recurrence status of the patients was assessed in the hospital during the adjuvant chemotherapy period, and long-term survival data of patients were obtained by telephone follow-up. Univariate analysis between TMB status and prognosis was carried out by survival analysis. A retrospective review of 78 patients with non-squamous NSCLC who received platinum-based adjuvant chemotherapy showed a median disease-free survival of 3.6 years and median overall survival (OS) of 5.3 years. NGS analysis exhibited that the most common mutated somatic genes among the 78 patients were tumor suppressor protein p53 (TP53), epidermal growth factor receptor, low-density lipoprotein receptor related protein 1B, DNA methyltransferase 3 alpha and FAT atypical cadherin 3, and their prevalence was 56.4%, 48.7%, 37.2%, 30.7%, and 25.6%, respectively. TMB status was divided into TMB-L (≤ 4.5/Mb) and TMB-H (> 4.5/Mb) based on the median TMB threshold. Relevance of TMB to prognosis suggested that the median OS of patients with TMB-L was significantly longer than that of patients with TMB-H (NR vs. 4.6, P = 0.014). Higher TMB status conferred a worse implication on OS among patients with non-squamous NSCLC who received platinum-based adjuvant chemotherapy.

Identification and Validation of Three-Gene Signature in Lung Squamous Cell Carcinoma by Integrated Transcriptome and Methylation Analysis.

Since DNA methylation (DNAm) is associated with the carcinogenesis of various cancers, this study aimed to explore potential DNAm prognostic signatures of lung squamous cell carcinoma (LUSC). First, transcriptomic and methylation profiles of LUSC were obtained from The Cancer Genome Atlas database (TCGA). DNAm-related genes were screened by integrating DNAm and transcriptome profiles via MethylMix package. Subsequently, a prognostic signature was conducted with the least absolute shrinkage and selector operation (LASSO) Cox analysis. This signature combined with the clinicopathological parameters was then utilized to construct a prognostic nomogram via the rms package. A signature based on three DNAm-related genes claudin 1 (CLDN1), ATP-binding cassette subfamily C member 5 (ABCC5), and cystatin A (CSTA) that were hypomethylated and upregulated in LUSC was constructed. Univariate and multivariate Cox regression analysis suggested that this signature, combined with age and TNM.N stage, was significantly correlated with survival rate. Time-dependent receiver operating characteristics and calibration curves suggested the nomogram constructed with age and TNM.N stage variables could accurately evaluate the 3- and 5-year outcome of LUSC. Finally, the average mRNA and protein expression levels of CLDN1, ABCC5, and CSTA in LUSC were verified to be significantly higher than those in paracancerous tissues. Moreover, silencing CLDN1, ABCC5, and CSTA expressions could significantly reduce the carcinogenesis of the A549 cell line. The DNAm-driven prognostic signature consists of CLDN1, ABCC5, and CSTA incorporated with age and TNM. N stage could facilitate the prediction outcome of LUSC.

MIG-23 is involved in sperm migration by modulating extracellular ATP levels in Ascaris suum.

In nematodes, spermiogenesis is a process of sperm activation in which nonmotile spermatids are transformed into crawling spermatozoa. Sperm motility acquisition during this process is essential for successful fertilization, but the underlying mechanisms remain to be clarified. Herein, we have found that extracellular adenosine-5'-triphosphate (ATP) level regulation by MIG-23, which is a homolog of human ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase), was required for major sperm protein (MSP) filament dynamics and sperm motility in the nematode Ascaris suum. During sperm activation, a large amount of ATP was produced in mitochondria and was stored in refringent granules (RGs). Some of the produced ATP was released to the extracellular space through innexin channels. MIG-23 was localized in the sperm plasma membrane and contributed to the ecto-ATPase activity of spermatozoa. Blocking MIG-23 activity resulted in a decrease in the ATP hydrolysis activity of spermatozoa and an increase in the depolymerization rate of MSP filaments in pseudopodia, which eventually affected sperm migration. Overall, our data suggest that MIG-23, which contributes to the ecto-ATPase activity of spermatozoa, regulates sperm migration by modulating extracellular ATP levels.