Serratia plymuthica HK9-3 enhances tomato resistance against Phytophthora capsici by modulating antioxidant defense systems and rhizosphere micro-ecological condition.

Tomatoes are frequently challenged by various pathogens, among which Phytophthora capsici (P. capsici) is a destructive soil-borne pathogen that seriously threatens the safe production of tomatoes. Plant growth-promoting rhizobacteria (PGPR) positively induced plant resistance against multiple pathogens. However, little is known about the role and regulatory mechanism of PGPR in tomato resistance to P. capsici. Here, we identified a new strain Serratia plymuthica (S. plymuthica), HK9-3, which has a significant antibacterial effect on P. capsici infection. Meanwhile, stable colonization in roots by HK9-3, even under P. capsici infection, improved tomato growth parameters, root system architecture, photosynthetic capacity, and boosted biomass. Importantly, HK9-3 colonization significantly alleviated the damage caused by P. capsici infection through enhancing ROS scavenger ability and inducing antioxidant defense system and pathogenesis-related (PR) proteins in leaves, as evidenced by elevating the activities of peroxidase (POD), superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO), and chitinase, ß-1,3-glucanase, and increasing the transcripts of POD, SOD, CAT, APX1, PAL1, PAL2, PAL5, PPO2, CHI17 and ß-1,3-glucanase genes. Notably, HK9-3 colonization not only effectively improved soil microecology and soil fertility, but also significantly enhanced fruit yield by 44.6% and improved quality. Our study presents HK9-3 as a promising and effective solution for controlling P. capsici infection in tomato cultivation while simultaneously promoting plant growth and increasing yield, which may have implications for P. capsici control in vegetable production.

Diagnostic performance of machine learning in systemic infection following percutaneous nephrolithotomy and identification of associated risk factors.

Objective: This study aims to investigate the predictive performance of machine learning in predicting the occurrence of systemic inflammatory response syndrome (SIRS) and urosepsis after percutaneous nephrolithotomy (PCNL). Methods: A retrospective analysis was conducted on patients who underwent PCNL treatment between January 2016 and July 2022. Machine learning techniques were employed to establish and select the best predictive model for postoperative systemic infection. The feasibility of using relevant risk factors as predictive markers was explored through interpretability with Machine Learning. Results: A total of 1067 PCNL patients were included in this study, with 111 (10.4 %) patients developing SIRS and 49 (4.5 %) patients developing urosepsis. In the validation set, the risk model based on the GBM protocol demonstrated a predictive power of 0.871 for SIRS and 0.854 for urosepsis. Preoperative and postoperative platelet changes were identified as the most significant predictors. Both thrombocytopenia and thrombocytosis were found to be risk factors for SIRS or urosepsis after PCNL. Furthermore, it was observed that when the change in platelet count before and after PCNL surgery exceeded 30*109/L (whether an increase or decrease), the risk of developing SIRS or urosepsis significantly increased. Conclusion: Machine learning can be effectively utilized for predicting the occurrence of SIRS or urosepsis after PCNL. The changes in platelet count before and after PCNL surgery serve as important predictors.

A nomogram based on TFE3 IHC results and clinical factors as a preliminary screening scheme for TFE3-rearranged renal cell carcinoma.

BACKGROUND: TFE3 immunohistochemistry (TFE3-IHC) is controversial in the diagnosis of TFE3-rearranged renal cell carcinoma (TFE3-rearranged RCC). This study is to investigate the accuracy and sensitivity of IHC and establish a predictive model to diagnose TFE3-rearranged RCC. METHODS: Retrospective analysis was performed by collecting IHC and fluorescence in situ hybridization (FISH) results from 228 patients. IHC results were evaluated using three scoring systems. Scoring system 1 is graded based on nuclear staining intensity, scoring system 2 is graded based on the percentage of stained tumor cell nuclei, and scoring system 3 is graded based on both the nuclear staining intensity and the percentage. We collected patients' IHC results and clinical information. Important variables were screened based on univariate logistic regression analysis. Then, independent risk factors were established through multivariate logistic regression, and a nomogram model was constructed. The model was validated in internal test set and external validation set. The receiver operating characteristic curve (ROC curve), calibration curve, and decision curve analysis (DCA) were generated to assess discriminative ability of the model. RESULTS: The accuracy of IHC based on three scoring systems were 0.829, 0.772, and 0.807, respectively. The model included four factors including age, gender, lymph node metastasis and IHC results. Area under the curve (AUC) values were 0.935 for the training set, 0.934 for the internal test set, 0.933 for all 228 patients, and 0.916 for the external validation set. CONCLUSIONS: TFE3 IHC has high accuracy in the diagnosis of TFE3-rearranged RCC. Clinical information such as age and lymph node metastasis are independent risk factors, which can be used as a supplement to the results of TFE3 IHC. This study confirms the value of IHC in the diagnosis of TFE3-rearranged RCC. The accuracy of the diagnosis can be improved by incorporating IHC with other clinical risk factors.

LRP1 induces anti-PD-1 resistance by modulating the DLL4-NOTCH2-CCL2 axis and redirecting M2-like macrophage polarisation in bladder cancer.

The tumour microenvironment (TME) drives bladder cancer (BLCA) progression. Targeting the TME has emerged as a promising strategy for BLCA treatment in recent years. Furthermore, checkpoint blockade therapies are only beneficial for a minority of patients with BLCA, and drug resistance is a barrier to achieving significant clinical effects of anti-programmed cell death protein-1 (PD-1)/programmed death protein ligand-1 (PD-L1) therapy. In this study, higher low-density lipoprotein receptor-related protein 1 (LRP1) levels were related to a poorer prognosis for patients with various cancers, including those with higher grades and later stages of BLCA. Enrichment analysis demonstrated that LRP1 plays a role in the epithelial-mesenchymal transition (EMT), NOTCH signalling pathway, and ubiquitination. LRP1 knockdown in BLCA cells delayed BLCA progression both in vivo and in vitro. Furthermore, LRP1 knockdown suppressed EMT, reduced DLL4-NOTCH2 signalling activity, and downregulated M2-like macrophage polarisation. Patients with BLCA and higher LRP1 levels responded weakly to anti-PD-1 therapy in the IMvigor210 cohort. Moreover, LRP1 knockdown enhanced the therapeutic effects of anti-PD-1 in mice. Taken together, our findings suggest that LRP1 is a potential target for improving the efficacy of anti-PD-1/PD-L1 therapy by preventing EMT and M2-like macrophage polarisation by blocking the DLL4-NOTCH2 axis.

Monolithic silicon for high spatiotemporal translational photostimulation.

Electrode-based electrical stimulation underpins several clinical bioelectronic devices, including deep-brain stimulators1,2 and cardiac pacemakers3. However, leadless multisite stimulation is constrained by the technical difficulties and spatial-access limitations of electrode arrays. Optogenetics offers optically controlled random access with high spatiotemporal capabilities, but clinical translation poses challenges4-6. Here we show tunable spatiotemporal photostimulation of cardiac systems using a non-genetic platform based on semiconductor-enabled biomodulation interfaces. Through spatiotemporal profiling of photoelectrochemical currents, we assess the magnitude, precision, accuracy and resolution of photostimulation in four leadless silicon-based monolithic photoelectrochemical devices. We demonstrate the optoelectronic capabilities of the devices through optical overdrive pacing of cultured cardiomyocytes (CMs) targeting several regions and spatial extents, isolated rat hearts in a Langendorff apparatus, in vivo rat hearts in an ischaemia model and an in vivo mouse heart model with transthoracic optical pacing. We also perform the first, to our knowledge, optical override pacing and multisite pacing of a pig heart in vivo. Our systems are readily adaptable for minimally invasive clinical procedures using our custom endoscopic delivery device, with which we demonstrate closed-thoracic operations and endoscopic optical stimulation. Our results indicate the clinical potential of the leadless, lightweight and multisite photostimulation platform as a pacemaker in cardiac resynchronization therapy (CRT), in which lead-placement complications are common.

Fatty acids metabolism affects the therapeutic effect of anti-PD-1/PD-L1 in tumor immune microenvironment in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a highly invasive and metastatic subtype of kidney malignancy and is correlated with metabolic reprogramming for adaptation to the tumor microenvironment comprising infiltrated immune cells and immunomodulatory molecules. The role of immune cells in the tumor microenvironment (TME) and their association with abnormal fatty acids metabolism in ccRCC remains poorly understood. METHOD: RNA-seq and clinical data of KIRC from The Cancer Genome Atlas (TCGA) and E-MTAB-1980 from the ArrayExpress dataset. The Nivolumab group and Everolimus group of the CheckMate 025 study, the Atezolizumab arm of IMmotion150 and the Atezolizumab plus Bevacizumab group of IMmotion151 cohort were obtained for subsequent analysis. After differential expression genes identification, the signature was constructed through univariate Cox proportional hazard regression and simultaneously the least absolute shrinkage and selection operator (Lasso) analysis and the predictive performance of our signature was assessed by using receiver operating characteristic (ROC), Kaplan-Meier (KM) survival analysis, nomogram, drug sensitivity analysis, immunotherapeutic effect analysis and enrichment analysis. Immunohistochemistry (IHC), qPCR and western blot were performed to measure related mRNA or protein expression. Biological features were evaluated by wound healing, cell migration and invasion assays and colony formation test and analyzed using coculture assay and flow cytometry. RESULTS: Twenty fatty acids metabolism-related mRNA signatures were constructed in TCGA and possessed a strong predictive performance demonstrated through time-dependent ROC and KM survival analysis. Notably, the high-risk group exhibited an impaired response to anti-PD-1/PD-L1 (Programmed death-1 receptor/Programmed death-1 receptor-ligand) therapy compared to the low-risk group. The overall levels of the immune score were higher in the high-risk group. Additionally, drug sensitivity analysis observed that the model could effectively predict efficacy and sensitivity to chemotherapy. Enrichment analysis revealed that the IL6-JAK-STAT3 signaling pathway was a major pathway. IL4I1 could promote ccRCC cells' malignant features through JAK1/STAT3 signaling pathway and M2-like macrophage polarization. CONCLUSION: The study elucidates that targeting fatty acids metabolism can affect the therapeutic effect of PD-1/PD-L1 in TME and related signal pathways. The model can effectively predict the response to several treatment options, underscoring its potential clinical utility.

Activating SIRT1 deacetylates NF-κB p65 to alleviate liver inflammation and fibrosis via inhibiting NLRP3 pathway in macrophages.

Background and aims: Macrophages play a critical role in the development of liver diseases. As an NAD+-dependent histone deacetylase, SIRT1 inhibits liver inflammation and fibrosis, but the mechanisms are not fully understood. Our aim was to investigate the molecular mechanism of SIRT1 in macrophages in liver inflammation and fibrosis. Methods: We employed the CCl4-induced hepatic fibrosis rat models and cultured murine macrophages RAW 264.7 in vitro to explore the anti-fibrosis effect of SIRT1. The content of cytokines was measured with ELISA. The expression of proteins associated with the NF-κB /NLPR3 signaling pathway was detected by Western blot, co-immunoprecipitation, and immunofluorescence. SIRT1, NF-κB, and NLRP3 genes were knocked down in RAW 264.7 cells by small interfering RNA (siRNA) transfection. Results: The expression of NF-κB p65, NLRP3, α-SMA, and iNOS increased in liver tissue, with high plasma LPS level and low expression of SIRT1 in CCl4-induced rat models. Overexpressing SIRT1 could inhibit these protein levels, decrease plasma LPS level, and attenuate liver injury and fibrosis. In vitro, LPS induced cytomorphology changes and up-regulated NF-κB/NLRP3 pathway, with the low expression of SIRT1 in RAW 264.7; meanwhile, the secretion of inflammatory factors increased. Nevertheless, knockdown of NF-κB or NLRP3 and activation of SIRT1 inhibited inflammation of macrophages; inhibition or knockdown of SIRT1 enhanced macrophage inflammation. Furthermore, activation of SIRT1 could inhibit LPS-treated macrophages from activating hepatic stellate cells (HSCs). Conclusions: Activating SIRT1 inhibits the inflammation in macrophages by down-regulating NLRP3 pathway through deacetylating NF-κB p65, which in turn inhibits the activation of HSCs to alleviate hepatic inflammation and fibrosis.

Overexpression of TREM1 is Associated with the Immune-Suppressive Microenvironment and Unfavorable Prognosis in Pan-Cancer.

Background: Triggering receptors expressed by myeloid cells-1 (TREM1) is a receptor belonging to the immunoglobulin superfamily and plays an important role in pro-inflammation in acute and chronic inflammatory disorders. However, the understanding of the immunomodulatory roles of TREM1 in the tumor microenvironment remains incomplete. Methods: The expression patterns of TREM1 mRNA in tumors and adjacent normal tissues were compared by analyzing data obtained from the Genotype-Tissue Expression and The Cancer Genome Atlas datasets. Survival analysis was performed to determine the prognostic value of TREM1. Functional enrichment analysis was applied to decipher the discrepancy in biological processes between high- and low-TREM1 groups across various cancers. The correlation between TREM1 and immune cell infiltration determined by using multiple algorithms was evaluated with the Pearson method. Four independent immunotherapy cohorts were adopted to validate the role of TREM1 as a biomarker. Results: TREM1 was elevated in most cancers as verified with clinical samples. Overexpression of TREM1 was linked with undesirable prognosis in patients. Further analysis revealed that TREM1 was positively correlated with immune response, pro-tumor pathways, and myeloid cell infiltration, while being negatively correlated with CD8+ T cell (including infiltration level and biological processes). Concordantly, tumors with high TREM1 levels were more resistant to immunotherapy. Through connective map analysis, therapeutically potential compounds like tozasertib and TPCA-1 were identified, which can be used synergistically with immunotherapy to improve the poor prognosis of patients with high TREM1 levels. Conclusion: Through a systematic and comprehensive pan-cancer analysis, we demonstrated that overexpression of TREM1 in tumors correlated closely with unfavorable outcome, infiltration of immune-suppressive cells, and immune regulation, which highlights its potential use as a tumor prognostic biomarker and a novel target for immunotherapy.

Development and validation of a novel defined mutation classifier based on Lasso logistic regression for predicting the overall survival of immune checkpoint inhibitor therapy in renal cell carcinoma.

Background: Currently, immune checkpoint inhibitor (ICI)-based therapy has become the first-line treatment for advanced renal cell carcinoma (RCC). However, few biomarkers have been identified to predict the response to ICI therapy in RCC patients. Herein, our research aimed to build a gene mutation prognostic indicator for ICI therapy. Methods: This multi-cohort study explored the mutation patterns in 2 publicly available advanced RCC ICI therapy cohorts, the Memorial Sloan Kettering Cancer Center (MSKCC) advanced RCC ICI therapy cohort and the CheckMate ICI therapy cohort. A total of 261 patients in the CheckMate ICI therapy cohort were randomly assigned to either the training or validation set. Least absolute shrinkage and selection operator (Lasso) logistic regression analysis was subsequently used to develop a mutation classifier utilizing the training set. The classifier was then validated internally in the validation set and externally in 2 ICI therapy cohorts and 2 non-ICI therapy cohorts. Survival analysis, receiver operator characteristic curves and Harrell's concordance index were performed to assess the prognostic value of the classifier. Function and immune microenvironment analysis in each subgroup defined by the classifier were performed. Results: A 10-gene mutation classifier was constructed based on the CheckMate ICI therapy cohort to separate patients into 2 risk groups, with patients in the high-risk group showing significantly lower overall survival probability than those in the low-risk group [the training set (HR: 1.791; 95% CI: 1.207-2.657; P=0.003), the validation set (HR: 1.842; 95% CI: 1.133-2.996; P=0.012) and combination set (HR: 1.819; 95% CI: 1.339-2.470; P<0.001)]. Further validation confirmed that the mutation classifier only showed predictive value for patients receiving ICI therapy instead of non-ICI therapy. Combined with the clinical characteristics, the risk score was proven to be an independent prognostic factor for overall survival in ICI therapy by multivariate Cox regression analysis. Functional and immune infiltration analysis demonstrated that lower risk scores tended to associate with immunologically "hot" status in RCC. Conclusions: Our 10-gene mutation classifier was found to be a biomarker for predicting the overall survival of patients with advanced RCC to ICI therapy.

EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1.

High lymphocyte infiltration and immunosuppression characterize the tumor microenvironment (TME) in renal cell carcinoma (RCC). There is an urgent need to elucidate how tumor cells escape the immune attack and to develop novel therapeutic targets to enhance the efficacy of immune checkpoint blockade (ICB) in RCC. Overactivated IFN-γ-induced JAK/STAT signaling involves in such TME, but the underlying mechanisms remain elusive. Here, EH domain-binding protein 1-like protein 1 (EHBP1L1) is identified as a crucial mediator of IFN-γ/JAK1/STAT1/PD-L1 signaling in RCC. EHBP1L1 is highly expressed in RCC, and high EHBP1L1 expression levels are correlated with poor prognosis and resistance to ICB. EHBP1L1 depletion significantly inhibits tumor growth, which is attributed to enhanced CD8+ T cell-mediated antitumor immunity. Mechanistically, EHBP1L1 interacts with and stabilizes JAK1. By competing with SOCS1, EHBP1L1 protects JAK1 from proteasomal degradation, which leads to elevated JAK1 protein levels and JAK1/STAT1/PD-L1 signaling activity, thereby forming an immunosuppressive TME. Furthermore, the combination of EHBP1L1 inhibition and ICB reprograms the immunosuppressive TME and prevents tumor immune evasion, thus significantly reinforcing the therapeutic efficacy of ICB in RCC patient-derived xenograft (PDX) models. These findings reveal the vital role of EHBP1L1 in immune evasion in RCC, which may be a potential complement for ICB therapy.

The hydroxyapatite modified 3D printed poly L-lactic acid porous screw in reconstruction of anterior cruciate ligament of rabbit knee joint: a histological and biomechanical study.

BACKGROUND: 3D printing technology has become a research hotspot in the field of scientific research because of its personalized customization, maneuverability and the ability to achieve multiple material fabrications. The focus of this study is to use 3D printing technology to customize personalized poly L-lactic acid (PLLA) porous screws in orthopedic plants and to explore its effect on tendon-bone healing after anterior cruciate ligament (ACL) reconstruction. METHODS: Preparation of PLLA porous screws with good orthogonal pore structure by 3D printer. The hydroxyapatite (HA) was adsorbed on porous screws by electrostatic layer-by-layer self-assembly (ELSA) technology, and PLLA-HA porous screws were prepared. The surface and spatial morphology of the modified screws were observed by scanning electron microscopy (SEM). The porosity of porous screw was measured by liquid displacement method. Thirty New Zealand male white rabbits were divided into two groups according to simple randomization. Autologous tendon was used for right ACL reconstruction, and porous screws were inserted into the femoral tunnel to fix the transplanted tendon. PLLA group was fixed with porous screws, PLLA-HA group was fixed with HA modified porous screws. At 6 weeks and 12 weeks after surgery, 5 animals in each group were sacrificed randomly for histological examination. The remaining 5 animals in each group underwent Micro-CT and biomechanical tests. RESULTS: The pores of PLLA porous screws prepared by 3D printer were uniformly distributed and connected with each other, which meet the experimental requirements. HA was evenly distributed in the porous screw by ELSA technique. Histology showed that compared with PLLA group, mature bone trabeculae were integrated with grafted tendons in PLLA-HA group. Micro-CT showed that the bone formation index of PLLA-HA group was better than that of PLLA group. The new bone was uniformly distributed in the bone tunnel along the screw channel. Biomechanical experiments showed that the failure load and stiffness of PLLA-HA group were significantly higher than those of PLLA group. CONCLUSIONS: The 3D printed PLLA porous screw modified by HA can not only fix the grafted tendons, but also increase the inductivity of bone, promote bone growth in the bone tunnel and promote bone integration at the tendon-bone interface. The PLLA-HA porous screw is likely to be used in clinic in the future.

Selenium improved mitochondrial quality and energy supply in the liver of high-fat diet-fed grass carp (Ctenopharyngodon idella) after heat stress.

This study aims to explore the effects of dietary selenium on hepatic mitochondrial quality and energy supply of grass carp (Ctenopharyngodon idella) fed with high-fat diet (HFD) after heat stress (HS). Grass carp were fed with HFD, and HFD contained 0.3 mg/kg nano-selenium for 10 weeks, thereafter exposed to HS from 26 to 34 °C, and named the HFD + HS (control) group and the HFD + Se + HS group, respectively. The results show that selenium significantly prompted the growth, increased glutathione peroxidase (GPX) activity, but reduced malondialdehyde (MDA) content in the liver and the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum of grass carp fed with HFD after HS. Further, selenium alleviated mitochondrial damage and increased the number of mitochondrial DNA copies in the liver of the grass carp fed with HFD after HS. And selenium also maintained mitochondrial homeostasis by upregulating the expression of mitochondrial quality control-related genes (pgc-1α, nrf1/2, tfam, opa1, mfn1/2, and drp1), mitophagy-related genes (beclin1, atg5, atg12, pink1, and parkin), and the protein expression of parkin and LC3-II/I in the liver of grass carp. Finally, selenium reduced the triglyceride (TG) level and increased the free fatty acid (FFA) level and adenosine triphosphate (ATP) production in the liver of grass carp fed with HFD after HS. In conclusion, dietary selenium alleviated liver damage and improved liver mitochondrial quality and ATP production by increasing liver antioxidant capacity and promoting liver mitochondrial quality in grass carp fed with HFD after HS, which help grass carp to resist these two stressors.

Technical aspects and early results of uniportal video-assisted thoracoscopic complex segmentectomy: a 30 case-series study.

BACKGROUND: With the advantages of better cosmetic incision and faster recovery, uniportal video-assisted thoracoscopic surgery (UP-VATS) has developed rapidly worldwide in recent decades, and indications for UP-VATS have been further expanded to those for conventional VATS. Complex segmentectomy that makes several or intricate intersegmental planes, with more complex procedures, continues to be difficult in minimally invasive techniques. However, there are few reports on UP-VATS complex segmentectomy. In this report, we describe the perioperative clinical data and operative techniques and present our early results of UP-VATS complex segmentectomy in our hospital. METHODS: The records of a total of 30 patients who underwent UP-VATS complex segmentectomy by a single surgeon between January 2021 and June 2021 were retrospectively reviewed. We defined cases as complex segmentectomy if they required resection of segments 9 and 10, combined segmentectomy, segmentectomy + subsegmentectomy, subsegmentectomy, or combined subsegmentectomy. RESULTS: The mean age was 52.8 ± 9.9 years old; the mean nodule size was 0.84 ± 0.36 cm; the mean margin width was 2.307 ± 0.309 cm; the median operative time was 229.0 ± 58.06 min; the mean operative hemorrhage was 56.60 ± 17.95 mL; 5.58 ± 1.74 lymph nodes dissected had not metastasized; the mean duration of postoperative chest tube drainage was 4.7 ± 1.4 days; and the mean postoperative hospital stay was 6.5 ± 3.0 days. Although 1 patient experienced a prolonged air leak, the other 29 recovered uneventfully. Another patient failed to reach the 2-cm safe margins and subsequently underwent completion lobectomy. CONCLUSIONS: UP-VATS complex segmentectomy is a safe and effective procedure in the treatment of lung cancers, sparing more pulmonary parenchyma and ensuring safe margins, with the disadvantage being the lengthy operative times during early skill acquisition.

TP53/BRAF mutation as an aid in predicting response to immune-checkpoint inhibitor across multiple cancer types.

Immunotherapy with checkpoint inhibitors, such as PD-1/PD-L1 blockage, is becoming standard of practice for an increasing number of cancer types. However, the response rate is only 10%-40%. Thus, identifying biomarkers that could accurately predict the ICI-therapy response is critically important. We downloaded somatic mutation data for 46,697 patients and tumor-infiltrating immune cells levels data for 11070 patients, then combined TP53 and BRAF mutation status into a biomarker model and found that the predict ability of TP53/BRAF mutation model is more powerful than some past models. Commonly, patients with high-TMB status have better response to ICI therapy than patients with low-TMB status. However, the genotype of TP53MUTBRAFWT in high-TMB status cohort have poorer response to ICI therapy than the genotype of BRAFMUTTP53WT in low-TMB status (Median, 18 months vs 47 month). Thus, TP53/BRAF mutation model can add predictive value to TMB in identifying patients who benefited from ICI treatment, which can enable more informed treatment decisions.

The impact of tumor size on the survival of patients with small renal masses: A population-based study.

BACKGROUND: Active surveillance (AS) with delayed intervention has gained acceptance as a management strategy for small renal masses (SRMs). However, during AS, there is a risk of tumor growth. Thus, we aim to investigate whether tumor growth in patients with SRMs leads to tumor progress. METHODS: In this study, we enrolled 16,070 patients from the Surveillance, Epidemiology, and End Results database with T1a renal cell carcinoma (RCC) between 2004 and 2017. The 16,070 patients were divided into three groups: 10,526 in the partial nephrectomy (PN) group, 2768 in the local ablation (LA) group, and 2776 in the AS group. Associations of tumor size with all-cause and cancer-specific mortality were evaluated using Kaplan-Meier analyses and Cox regression models. RESULTS: Four tumor size categories were delineated (≤1, >1-2, >2-3, and > 3-4 cm in diameter), and 10-year all-cause and cancer-specific mortality both significantly increased with increasing tumor size in the PN, LA, and AS groups (all p < 0.05). Tumors were substaged based on diameter: T1aA (≤2 cm) and T1aB (>2-4 cm). All-cause and cancer-specific mortality were significantly higher in T1aB tumors than T1aA tumors in each group (hazard ratio = 1.395 and 1.538, respectively; all p < 0.05). CONCLUSIONS: Tumor growth relates to worse prognosis of T1a RCC, and 2 cm serves as a size threshold that is prognostically relevant for patients with T1a RCC. Because of the lack of accurate predictors of tumor growth rate, AS for patients with SRMs incurs a risk of tumor progression.

Preoperative Predictors of Early Mortality Risk in People with Osteosarcoma of the Extremities Treated with Standard Therapy.

PURPOSE: More precise identification of osteosarcoma patients with high early death risk and enhanced early follow-up of these patients, such as increasing the frequency of postoperative chest computed tomography (CT) and local magnetic resonance imaging (MRI) examinations, may improve the overall survival of patients. The primary purpose of this research is to explore the risk factors related to early mortality in patients with osteosarcoma under standard treatment. PATIENTS AND METHODS: Our research included 87 osteosarcoma patients who had undergone standard treatment and had a Karnofsky (KPS) ≥70. We define patients who die within 2 years of diagnosis as early death. The clinical characteristics and laboratory indicators of patients with osteosarcoma were collected and analyzed retrospectively. RESULTS: The median follow-up time was 32 months (4-91 months). Early deaths occurred in 13 patients. Early death of patients with osteosarcoma is related to tumor metastasis (P < 0.001), tumor size >5cm (P = 0.049), high-level neutrophil-lymphocyte ratio (NLR) (P = 0.035), high-level fibrinogen (FIB) (P = 0.038), and higher D-dimer (DD) (P = 0.025). According to our results of multivariate Cox analysis, tumor metastasis status at diagnosis (P < 0.001), NLR (P = 0.039) and FIB (P = 0.023) are independent risk factors in predicting early mortality in osteosarcoma patients. The "Osteosarcoma Early Mortality Nomogram" has a C index of 0.871, and the calibration curve performs best compared with the ideal model in predicting mortality in 1 year. CONCLUSION: Tumor metastasis status, NLR, and FIB are independent risk factors in predicting early mortality in osteosarcoma patients. The early follow-up of patients with tumor metastasis, high NLR, and high FIB should be strengthened.

Identification of Linear Peptide Immunogens with Verified Broad-spectrum Immunogenicity from the Conserved Regions within the Hemagglutinin Stem Domain of H1N1 Influenza Virus.

BACKGROUND: Influenza A viruses (IAVs) induce acute respiratory disease and cause severe epidemics and pandemics. Since IAVs exhibit antigenic variation and genome reassortment, the development of broad-spectrum influenza vaccines is crucial. The stem of the hemagglutinin (HA) is highly conserved across IAV strains and thus has been explored in broad-spectrum influenza vaccine studies. The present study aimed to identify viral epitopes capable of eliciting effective host immune responses, which can be explored for the development of broad-spectrum non-strain specific prophylactic options against IAV. METHODS: In this study, a series of conserved linear sequences from the HA stem of IAV (H1N1) was recognized by sequence alignment and B/T-cell epitope prediction after being chemically coupled to the Keyhole Limpet Hemocyanin (KLH) protein. The predicted linear epitopes were identified by enzyme-linked immunosorbent assay (ELISA) after animal immunization and then fused with ferritin carriers. RESULTS: Three predicted linear epitopes with relatively strong immunogenicity, P3, P6 and P8 were fused with ferritin carriers P3F, P6F and P8F, respectively to further improve their immunogenicity. Antibody titre of the sera of mice immunized with the recombinant immunogens revealed the elicitation of specific antibody-binding activities by the identified sequences. While hemagglutinin-inhibition activities were not detected in the antisera, neutralizing antibodies against the H1 and H3 virus subtypes were detected by the microneutralization assay. CONCLUSION: The linear epitopes fused with ferritin identified in this study can lay the foundation for future advancements in development of broad-spectrum subunit vaccine against IAV (H1N1), and give rise to the potential future applicability of ferritin-based antigen delivery nanoplatforms.

Identification of ZDHHC1 as a Pyroptosis Inducer and Potential Target in the Establishment of Pyroptosis-Related Signature in Localized Prostate Cancer.

Pyroptosis or cellular inflammatory necrosis is a programmed cell death kind. Accumulating evidence shows that pyroptosis plays a crucial role in the invasion, metastasis, and proliferation of tumor cells, thus affecting the prognosis of tumors and therapeutic effects. Prostate cancer (PCa), a common malignancy among men, is associated with inflammation. Pathophysiological effects of pyroptosis on tumor development and progression, as well as the mediation of PCa, are known, but its effects on the potential prognosis for PCa warrant in-depth investigation. Herein, we built a risk model of six pyroptosis-related genes and verified their predictive abilities for prognostic and therapeutic effects. Higher risk scores indicated a higher probability of biochemical recurrence (BCR), higher immune infiltration, and worsened clinicopathological features. To derive scientific and reliable predictions for BCR in patients having PCa, the findings of the current study were verified in the Gene Expression Omnibus (GEO) cohort following evaluation in The Cancer Genome Atlas (TCGA) dataset. Additionally, after evaluating the six genes in the model, ZDHHC1 was found to be an important component. Its antitumor role was further assessed through in vivo and in vitro experiments, and its promoting effect on pyroptosis was further evaluated and verified. The above results provided a new perspective for further studies on pyroptosis and its clinical utility for PCa.

Localization of external urethral orifice in coronary sulcus during urethroplasty in case of severe hypospadias accompanied by prostatic utricle cyst.

BACKGROUND: To explore whether opening the external urethral orifice in the coronal sulcus can reduce the incidence of epididymitis after operating on hypospadias with prostatic utricle cyst (PUC) connecting to the vas deferens. Group A consisted of 3 patients with severe hypospadias and PUC undergoing cystostomy, hypospadias correction and urethroplasty, along with the relocation of the external orifice of the urethra to the coronal sulcus. Group B consisted of 4 patients having initial hypospadias repaired with meatus in the orthotopic position in the glans, presenting with multiple epididymitis after hypospadias surgery and unsuccessful conservative treatment. MR confirmed that all the Group B patients had PUC connecting to the vas deferens. Group B patients underwent urethral dilatation along with urethral catheterization, cutting of the original corpus cavernosum that encapsulated the urethra, and extension of the position of the external urethral orifice to the coronal sulcus. RESULTS: In group A, 3 children underwent bladder fistula removal 2 weeks after the operation. The penis developed normally without any complications. Four children in group B underwent stent removal 12 weeks after operation, and one patient was still stenosed and dilated again. All patients in group B were followed without epididymitis recurrence. CONCLUSIONS: For patients with hypospadias complicating with a PUC, connecting to one side of the vas deferens, the positioning of the external urethral orifice in the coronary sulcus would be helpful to reduce the occurrence of epididymitis.

Positive feedback regulation of lncRNA PVT1 and HIF2α contributes to clear cell renal cell carcinoma tumorigenesis and metastasis.

Long noncoding RNAs (lncRNAs) have been reported to exert important roles in tumors, including clear cell renal cell carcinoma (ccRCC). PVT1 is an important oncogenic lncRNA which has critical effects on onset and development of various cancers, however, the underlying mechanism of PVT1 functioning in ccRCC remains largely unknown. VHL deficiency-induced HIF2α accumulation is one of the major factors for ccRCC. Here, we identified the potential molecular mechanism of PVT1 in promoting ccRCC development by stabilizing HIF2α. PVT1 was significantly upregulated in ccRCC tissues and high PVT1 expression was associated with poor prognosis of ccRCC patients. Both gain-of-function and loss-of function experiments revealed that PVT1 enhanced ccRCC cells proliferation, migration, and invasion and induced tumor angiogenesis in vitro and in vivo. Mechanistically, PVT1 interacted with HIF2α protein and enhanced its stability by protecting it from ubiquitination-dependent degradation, thereby exerting its biological significance. Meanwhile, HIF2α bound to the enhancer of PVT1 to transactivate its expression. Furthermore, HIF2α specific inhibitor could repress PVT1 expression and its oncogenic functions. Therefore, our study demonstrates that the PVT1/ HIF2α positive feedback loop involves in tumorigenesis and progression of ccRCC, which may be exploited for anticancer therapy.