Robotic-assisted laparoscopic radical hysterectomy for early-stage cervical cancer: The more experienced the bedside assistant, the better?

Background: Aim to investigate the impact of bedside assistant's work experience and learning curve on the short-term safety and efficacy in robotic-assisted laparoscopic radical hysterectomy for early-stage cervical cancer. Methods: Our research retrospectively retrieved 120 cases of early-stage cervical cancer patients who underwent robotic-assisted laparoscopic radical hysterectomy at the First Affiliated Hospital of Guangxi Medical University. According to the different work experiences of the two bedside assistants (BA), patients were divided into a research group (inexperienced BA 1) and a control group (experienced BA 2). Furthermore, the learning curves of these BAs were plotted separately and divided into two distinct phases by cumulative summation: the first learning phase and the second master phase. Result: In terms of work experience, comparing BA 1 with BA 2 who was more experienced, although the average operative time was prolonged by 29 min (P＜0.001), it did not increase the incidence of operative complication [24.4 % VS 29.1 %, P = 0.583], positive resection margin [4.9 % VS 7.6 %, P = 0.714], intraoperative organ damage [0 % VS 2.5 %, P = 0.546] and there was no significant difference in the number of lymph nodes [19 VS 15, P = 0.103]. Additionally, comparing two distinct phases of the same bedside assistant, there was no significant increasing rate in terms of operative complication, positive resection margin, intraoperative organ damage, and the number of lymph nodes (P＞0.05) neither BA 1 nor BA 2, except for a slight extension of operative time about 20 min in learning phase (P＜0.05). Conclusion: In robotic-assisted laparoscopic radical hysterectomy for early-stage cervical cancer, work inexperience and the learning phase of BA only result in a slight extension of operative time, without causing worse short-term surgical outcomes.

Synergistic effects and competitive relationships between DOC and DOX as acting on DNA molecules: Studied with confocal Raman spectroscopy and molecular docking technology.

Docetaxel (DOC) is one of the second-generation antineoplastic drugs of the taxanes family with excellent antitumor activity. However, the mechanism of DOC inducing tumor cell apoptosis and treating cancer diseases, especially its interaction with DNA in the nucleus, and its adjuvant or combined Doxorubicin (DOX) acting on DNA molecules are unclear. In this study, the interaction mechanism between DOC and DNA, as well as the synergistic effects and competitive relationships among DOC and DOX when they simultaneously interact with DNA molecules were studied by laser confocal Raman spectroscopy combined with UV-visible absorption spectroscopy and molecular docking technology. The spectroscopic results showed that the binding constant of DOC to DNA is 5.25 × 103 M-1, the binding modes of DOC and DNA are non-classical intercalation and electrostatic binding, and the DNA-DOC complex has good stability. When DOC or DOX interacts with DNA alone, both of them can bind with bases and phosphate backbone of DNA, and also lead to DNA conformation changes; when DOC and DOX interact with DNA at the same time, the orders of interaction not only affect their binding sites with DNA, but also cause changes in the surrounding environment of the binding sites. In addition, the molecular docking results further verified that DOC and DOX have synergy and competition when they interact with DNA molecules simultaneously. The docking energies of DNA-DOC and DNA-DOX indicate the important role of van der Waals forces and hydrogen bonds. This study has practical significance for the design and development of antitumor drugs with less toxic based on the taxanes family and the combination with other drugs for the treatment of cancer.

Integrated analysis identified the role of three family members of ARHGAP in pancreatic adenocarcinoma.

The Rho GTPase activating protein family (ARHGAPs) is expressed in pancreatic adenocarcinoma (PAAD) but its function is unclear. The aim of this study was to explore the role and potential clinical value of ARHGAPs in PAAD. Using TCGA and GEO databases to analyze expression of ARHGAPs in PAAD and normal tissues. Survival curve was drawn by Kaplan-Meier. ARHGAPs were integrated analyzed by GEPIA2, TIMER, UCLCAN, cBioPortal and R language. Protein level and prognostic value were evaluated via IHC staining or survival analysis. We totally identify 18 differentially expressed (DE) ARHGAPs in PAAD. Among the 18 DE genes, 8 were positively correlated with tumor grade; abnorrmal expression of 5 was positively correlated with copy number variation; expression of 4 was positively correlated with promoter hypomethylation. Multivariate Cox regression identified ARHGAP5, ARHGAP11A, and ARHGAP12 as independent prognostic factors of PAAD. The function of ARHGAPs was mainly related to GTPase activity and signaling, axon guidance, proteoglycans in cancer and focal adhesion. Expression of 7 ARHGAPs was strongly correlated with immune infiltration. Immunohistochemistry showed increased protein levels of ARHGAP5, ARHGAP11A, and ARHGAP12 in PAAD tissues. Survival analysis confirmed a negative correlation between ARHGAP5, ARHGAP11A, and ARHGAP12 expression and patient prognosis. Multivariate Cox regression proved ARHGAP5, ARHGAP11A, and ARHGAP12 could serve as independent prognostic indicators for PAAD. Finally, this study verified ARHGAP5, ARHGAP11A, and ARHGAP12 as independent prognostic factors in PAAD, suggesting their significance for the diagnosis and treatment of PAAD.

Tissue-specific nonheritable influences drive endometrial immune system variation.

Although human twin studies have revealed the combined contribution of heritable and environmental factors in shaping immune system variability in blood, the contribution of these factors to immune system variability in tissues remains unexplored. The human uterus undergoes constant regeneration and is exposed to distinct environmental factors. To assess uterine immune system variation, we performed a system-level analysis of endometrial and peripheral blood immune cells in monozygotic twins. Although most immune cell phenotypes in peripheral blood showed high genetic heritability, more variation was found in endometrial immune cells, indicating a stronger influence by environmental factors. Cytomegalovirus infection was identified to influence peripheral blood immune cell variability but had limited effect on endometrial immune cells. Instead, hormonal contraception shaped the local endometrial milieu and immune cell composition with minor influence on the systemic immune system. These results highlight that the magnitude of human immune system variation and factors influencing it can be tissue specific.

MOF-Derived CeO2 Nanorod as a Separator Coating Enabling Enhanced Performance for Lithium-Sulfur Batteries.

The deployment of Li-S batteries in the commercial sector faces obstacles due to their low electrical conductivity, slow redox reactions, quick fading of capacity, and reduced coulombic efficiency. These issues stem from the "shuttle effect" associated with lithium polysulfides (LiPSs). In this work, a haystack-like CeO2 derived from a cerium-based metal-organic framework (Ce-MOF) is obtained for the modification of a polypropylene separator. The carbon framework and CeO2 coexist in this haystack-like structure and contribute to a synergistic effect on the restriction of LiPSs shuttling. The carbon network enhances electron transfer in the conversion of LiPSs, improving the rate performance of the battery. Moreover, CeO2 enhances the redox kinetics of LiPSs, effectively reducing the "shuttle effect" in Li-S batteries. The Li-S battery with the optimized CeO2 modified separator shows an initial discharge capacity of 870.7 mAh/g at 2 C, maintaining excellent capacity over 500 cycles. This research offers insights into designing functional separators to mitigate the "shuttle effect" in Li-S batteries.

Studying the Effects and Competitive Mechanisms of YOYO-1 on the Binding Characteristics of DOX and DNA Molecules Based on Surface-Enhanced Raman Spectroscopy and Molecular Docking Techniques.

Revealing the interaction mechanisms between anticancer drugs and target DNA molecules at the single-molecule level is a hot research topic in the interdisciplinary fields of biophysical chemistry and pharmaceutical engineering. When fluorescence imaging technology is employed to carry out this kind of research, a knotty problem due to fluorescent dye molecules and drug molecules acting on a DNA molecule simultaneously is encountered. In this paper, based on self-made novel solid active substrates NpAA/(ZnO-ZnCl2)/AuNPs, we use a surface-enhanced Raman spectroscopy method, inverted fluorescence microscope technology, and a molecular docking method to investigate the action of the fluorescent dye YOYO-1 and the drug DOX on calf thymus DNA (ctDNA) molecules and the influencing effects and competitive relationships of YOYO-1 on the binding properties of the ctDNA-DOX complex. The interaction sites and modes of action between the YOYO-1 and the ctDNA-DOX complex are systematically examined, and the DOX with the ctDNA-YOYO-1 are compared, and the impact of YOYO-1 on the stability of the ctDNA-DOX complex and the competitive mechanism between DOX and YOYO-1 acting with DNA molecules are elucidated. This study has helpful experimental guidance and a theoretical foundation to expound the mechanism of interaction between drugs and biomolecules at the single-molecule level.

Serum PRO-C3 is useful for risk prediction and fibrosis assessment in MAFLD with chronic kidney disease in an Asian cohort.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is an emerging risk factor for chronic kidney disease (CKD). N-terminal propeptide of collagen type 3 (PRO-C3) is a biomarker of advanced fibrosis in MAFLD and PRO-C3 may be involved in renal fibrosis. We aimed to use PRO-C3 measurements to generate a new algorithmic score to test the prediction of MAFLD with chronic kidney disease (MAFLD-CKD). METHODS: A derivation and independent validation cohort of 750 and 129 Asian patients with biopsy-confirmed MAFLD were included. Serum PRO-C3 concentration was measured and regression analyses were performed to examine associations with MAFLD-CKD. A derivative algorithm for MAFLD-CKD risk prediction was evaluated with receiver operator characteristic (ROC) curve analysis. RESULTS: The study included two Asian cohorts (n = 180 with MAFLD-CKD; mean-eGFR: 94.93 mL/min/1.73 m2; median-urinary albumin-to-creatinine ratio: 6.58 mg/mmol). PRO-C3 was associated with the severity of MAFLD-CKD and independently associated with MAFLD-CKD (adjusted odds ratio = 1.16, 95% confidence interval [CI]: 1.08-1.23, p < .001). A new non-invasive score (termed PERIOD) including PRO-C3 efficiently predicted MAFLD-CKD (AUROC = .842, 95% CI: .805-.875). Accuracy, specificity and negative predictive values were 80.2%, 85.1% and 88.4%, respectively. In the validation cohort, the PERIOD score had good diagnostic performance (AUROC = .807, 95% CI: .691-.893) with similar results in all patient subgroups. In the MAFLD-CKD subgroup, the accuracy for identifying advanced fibrosis was further improved by combining the PRO-C3-based ADAPT with the Agile 3+ scores (AUROC = .90, 95% CI: .836-.964). CONCLUSIONS: The PERIOD score is helpful for accurately predicting the risk of MAFLD-CKD. PRO-C3 can also be used to assess liver fibrosis in people with MAFLD-CKD.

Influence of microplastics on the availability of antibiotics in soils.

Microplastics (MPs) and antibiotics, as two major types of emerging pollutants, inevitably coexist in the soil environment due to agricultural film residue, sewage irrigation and sludge application. However, the impact of MPs on antibiotic availability in soils with varying characteristics has not been extensively studied. Therefore, in this study, an interference experiment was conducted using three types of MPs (polyethylene (PE), polyvinyl chloride (PVC) and polypropylene (PP)) in red soil, paddy soil and cinnamon soil. The available antibiotics in soils were evaluated using diffusive gradients in thin-films (DGT). Results showed that MPs had a significant impact on the amount of antibiotics adsorbed on soil solid (Cs) by providing additional binding sites or altering soil characteristics (e.g., pH and dissolved organic carbon). The most significant effects on Cs were observed in cinnamon soil, and the Cs values were dependent on concentration of MPs. The available antibiotics, as measured by DGT significantly decreased after the addition of MPs. This decrease was influenced by the soil characteristics. However, the concentration of antibiotics in soil solutions (Cd) was only slightly impacted by MPs. Therefore, the influence of MPs on the migration of antibiotics was reflected by their impact on the soil/water partition coefficient (Kd), while the resupply ability (R) from the soil solid phase was less influential. Moreover, the dosage of MPs had a significant effect on the availability of antibiotics in CS by promoting the adsorption of antibiotics on the solid phase, while in RS and PS, the soil properties played a dominate role in the changes in antibiotic availability after MP addition. These results indicate that the impact of MPs on available antibiotics mainly depends on soil properties. In addition, DGT measurement is more sensitive than soil solution to investigate the effects of coexisting pollutants on the behavior of antibiotics in soil.

Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile.

BACKGROUND: Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells. METHODS: In order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059. RESULTS: GenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile. CONCLUSION: GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer.

The Segmentation of Multiple Types of Uterine Lesions in Magnetic Resonance Images Using a Sequential Deep Learning Method with Image-Level Annotations.

Fully supervised medical image segmentation methods use pixel-level labels to achieve good results, but obtaining such large-scale, high-quality labels is cumbersome and time consuming. This study aimed to develop a weakly supervised model that only used image-level labels to achieve automatic segmentation of four types of uterine lesions and three types of normal tissues on magnetic resonance images. The MRI data of the patients were retrospectively collected from the database of our institution, and the T2-weighted sequence images were selected and only image-level annotations were made. The proposed two-stage model can be divided into four sequential parts: the pixel correlation module, the class re-activation map module, the inter-pixel relation network module, and the Deeplab v3 + module. The dice similarity coefficient (DSC), the Hausdorff distance (HD), and the average symmetric surface distance (ASSD) were employed to evaluate the performance of the model. The original dataset consisted of 85,730 images from 316 patients with four different types of lesions (i.e., endometrial cancer, uterine leiomyoma, endometrial polyps, and atypical hyperplasia of endometrium). A total number of 196, 57, and 63 patients were randomly selected for model training, validation, and testing. After being trained from scratch, the proposed model showed a good segmentation performance with an average DSC of 83.5%, HD of 29.3 mm, and ASSD of 8.83 mm, respectively. As far as the weakly supervised methods using only image-level labels are concerned, the performance of the proposed model is equivalent to the state-of-the-art weakly supervised methods.

SRPK1 Promotes Glioma Proliferation, Migration, and Invasion through Activation of Wnt/ß-Catenin and JAK-2/STAT-3 Signaling Pathways.

Currently, the treatment of gliomas still relies primarily on surgery and radiochemotherapy. Although there are various drugs available, including temozolomide, the overall therapeutic effect is unsatisfactory, and the prognosis remains poor. Therefore, the in-depth study of the mechanism of glioma development and a search for new therapeutic targets are the keys to improving the therapeutic treatment of gliomas and improving the prognosis of patients. Immunohistochemistry is used to detect the expression of relevant molecules in tissues, qPCR and Western blot are used to detect the mRNA and protein expression of relevant molecules, CCK-8 (Cell Counting Kit-8) is used to assess cell viability and proliferation capacity, Transwell is used to evaluate cell migration and invasion ability, and RNA transcriptome sequencing is used to identify the most influential pathways. SRPK1 (SRSF protein kinase 1) is highly expressed in gliomas but is not expressed in normal tissues. Its expression is positively correlated with the grades of gliomas and negatively correlated with prognosis. SRPK1 significantly promotes the occurrence and development of gliomas. Knocking down SRPK1 leads to a significant decrease in the proliferation, migration, and invasion abilities of gliomas. Loss of SRPK1 expression induces G2/M phase arrest and mitotic catastrophe, leading to apoptosis in cells. Overexpression of SRPK1 activates the Wnt/ß-catenin (wingless-int1/ß-catenin) and JAK-2/STAT-3 (Janus kinase 2/signal transducer and activator of transcription 3) signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Overexpression of SRPK1 rescues the reduced cell proliferation, migration, and invasion abilities caused by the silencing of ß-catenin or JAK-2. A stable shRNA-LN229 cell line was constructed, and using a nude mouse model, it was found that stable knockout of SRPK1 significantly reduced the tumorigenic ability of glioma cells, as evidenced by a significant decrease in the subcutaneous tumor volume and weight in nude mice. We have demonstrated that SRPK1 is highly expressed in gliomas. Overexpression of SRPK1 activates the Wnt/ß-catenin and JAK-2/STAT-3 signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Silencing SRPK1-related signaling pathways may provide potential therapeutic options for glioma patients.

Developing and validating a prediction model of live birth in patients with moderate-to-severe intrauterine adhesions: a new approach with endometrial morphology measurement by 3D transvaginal ultrasound.

Background: There is no reliable method to predict the live birth rate among patients with moderate-to-severe intrauterine adhesions (IUA) after second-look hysteroscopy. Therefore, we aimed to construct a practical prediction model mainly based on the features of 3D transvaginal ultrasound (3D-TVUS). and other clinical characteristics. Methods: From January 2018 to February 2020, a total of 870 IUA patients with fertility requirements were retrospectively enrolled based on the same method. First, the predictors were screened by logistic regression analysis. A nomogram was constructed based on the screened predictive factors in the derivation cohort. Next, receiver operating characteristic (ROC), calibration curve, and decision curve analysis (DCA) were used to assess the predictive accuracy and discriminability of the model. Finally, correlation analysis was performed to analyze the correlation between the results of 3D-TVUS and second-look hysteroscopy. Results: A total of 558 (64.14%) participants had live births. Age, endometrial thickness, assisted reproductive technology, a homogeneous endometrial echo, a lower segment of scar contraction, and upper segmentation of the endometrial absence were included in the model. The predictive model showed good predictive performance in the derivation cohort (area under the curve, 0.837) and validation cohort (0.857). DCA demonstrated its clinical utility. A homogeneous endometrial echo was related to no segmentation of scar contraction (r=0.219; P<0.001) or no segmentation of the endometrial absence (r=0.226; P<0.001). Thicker endometrium was associated with no segmentation of the endometrial absence (r=-0.145; P=0.007). Conclusions: The proposed method can effectively predict live birth. 3D-TVUS should be an important means for evaluating the endometrium of moderate-to-severe patients with IUA preparing for pregnancy after operation.

Target-induced hot spot construction for sensitive and selective surface-enhanced Raman scattering detection of matrix metalloproteinase MMP-9.

Studies have found that matrix metalloproteinase-9 (MMP-9) plays a significant role in cancer cell invasion, metastasis, and tumor growth. But it is a challenge to go for highly sensitive and selective detection and targeting of MMP-9 due to the similar structure and function of the MMP proteins family. Herein, a novel surface-enhanced Raman scattering (SERS) sensing strategy was developed based on the aptamer-induced SERS "hot spot" formation for the extremely sensitive and selective determination of MMP-9. To develop the nanosensor, one group of gold nanospheres was modified with MMP-9 aptamer and its complementary strand DNA1, while DNA2 (complementary to DNA1) and the probe molecule 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) were grafted on the surface of the other group of gold nanospheres. In the absence of MMP-9, DTNB located on the 13-nm gold nanospheres has only generated a very weak SERS signal. However, when MMP-9 is present, the aptamer preferentially binds to the MMP-9 to construct MMP-9-aptamer complex. The bare DNA1 can recognize and bind to DNA2, which causes them to move in close proximity and create a SERS hot spot effect. Due to this action, the SERS signal of DTNB located at the nanoparticle gap is greatly enhanced, achieving highly sensitive detection of MMP-9. Since the hot spot effect is caused by the aptamer that specifically recognizes MMP-9, the approach exhibits excellent selectivity for MMP-9 detection. Based on the benefits of both high sensitivity and excellent selectivity, this method was used to distinguish the difference in MMP-9 levels between normal and cancer cells as well as the expression of MMP-9 from cancer cells with different degrees of metastasis. In addition, this strategy can accurately reflect the dynamic changes in intracellular MMP-9 levels, stimulated by the MMP-9 activator and inhibitor. This strategy is expected to be transformed into a new technique for diagnosis of specific cancers related to MMP-9 and assessing the extent of cancer occurrence, development and metastasis.

Highly sensitive and selective SERS detection of caspase-3 during cell apoptosis based on the target-induced hotspot effect.

Caspase-3 is an important biomarker for the process of apoptosis, which is a key target for cancer treatment. Due to its low concentration in single cells and the structural similarity of caspase family proteins, it is exceedingly challenging to accurately determine the intracellular caspase-3 during apoptosis in situ. Herein, a biosensing strategy based on the target-induced SERS "hot spot" formation has been developed for the simultaneous highly sensitive and selective detection of intracellular caspase-3 level. The nanosensor is composed of gold nanoparticles modified with the probe molecule 4-mercaptophenylboronic acid (4-MPBA) and a peptide chain. The well-designed peptide chain contains two distinct functional domains, one with a sulfhydryl group for bonding to the gold nanoparticles and the other a fragment specifically recognized by caspase-3. When caspase-3 is present, the negatively charged segment (NH2-Asp-Asp-Asp-Glu-Val-Asp-OH) of the peptide chain is specifically hydrolyzed, leaving a positively charged fragment coated on the surface of the gold nanoparticles. At this time, the golden nanoparticles undergo significant coupling aggregation due to the electrostatic interaction, resulting in a large number of SERS "hot spot" formation. The SERS signal of the 4-MPBA located at the nano-gap is significantly boosted because of the local plasma enhancement effect. The highly sensitive determination of caspase-3 can be achieved according to the altered SERS signal intensity of 4-MPBA. The turn-on of the SERS signal-induced target contributes to the excellent selectivity and the formation of the SERS "hot spot" effect that further improves the sensitivity of caspase-3 detection. The advantages of this biosensing technique allow for the precise in situ monitoring of the dynamic changes in caspase-3 levels during apoptosis. In addition, the differences in caspase-3 levels during the apoptosis of various cell types were compared. Monitoring the caspase-3 levels can be used to track the cellular apoptosis process, evaluate the effect of drugs on cancer cells in real time, and provide guidance for the selection of the appropriate drug dosage.

Integration of genomics and transcriptomics highlights the crucial role of chromosome 5 open reading frame 34 in various human malignancies.

Although some data suggest that chromosome 5 open reading frame 34 (C5orf34) plays a pivotal part in the onset and disease progression of various cancers, there is no pan-cancer investigation of C5orf34 at present. This study sought to establish the predictive importance of C5orf34 in a variety of human malignancies and to understand its fundamental immunological function. In our research, we applied a combination of several bioinformatics techniques and basic experiments to investigate the differential expression of C5orf34, and its relationship with prognosis, methylation, single nucleotide variant, clinical characteristics, microsatellite instability, tumor mutational burden, copy number variation, and immune cell infiltration of several cancers from the database that is publicly available with the aim of identifying the potential prognostic markers. In this study we found that C5orf34 expression differed significantly among cancers types, according to the findings. The expression level of C5orf34 is markedly increased in the majority of malignancies when compared to normal tissues, which is significantly correlated with an unfavorable prognosis of patients. Immunohistochemical staining confirmed the findings that C5orf34 expression was remarkably up-regulated in a variety of gynecologic cancers. Moreover, C5orf34 expression was shown to be correlated with the clinical features of patients. C5orf34 was also found to be expressed with genes that code for the major immune suppressors, chemokines, immune activators, chemokine receptors, and histocompatibility complex. Finally, our study shows that C5orf34 has the potential to be employed as a prognostic biomarker. Moreover, it might regulate the immune microenvironment in a variety of malignancies.

Treatment cessation in HBeAg-negative chronic hepatitis B: clinical response is associated with increase in specific proinflammatory cytokines.

Patients with HBeAg-negative chronic hepatitis B may experience an immune response after stopping nucleos(t)ide analogue (NA)therapy, which may potentially trigger HBsAg loss or off-therapy sustained viral control. The immunological mechanisms determining clinical response remain poorly understood. To identify inflammatory signatures associated with defined outcomes, we analysed plasma cytokines and chemokines from 57 HBeAg-negative patients enrolled in the Nuc-Stop Study at baseline and 12 weeks after NA cessation. Clinical response at 12 weeks was classified into four groups: immune control, viral relapse, evolving clinical relapse, and resolving clinical relapse. Twelve weeks after treatment cessation 17 patients (30%) experienced immune control, 19 (33%) viral relapse, 6 (11%) evolving clinical relapse, and 15 (26%) resolving clinical relapse. There was a significant increase in interferon-γ-induced protein 10 (IP-10; p = 0.012) and tumor necrosis factor (TNF; p = 0.032) in patients with evolving clinical relapse. Sparse partial least-squares multivariate analyses (sPLS-DA) showed higher first component values for the clinical relapse group compared to the other groups, separation was driven mainly by IP-10, TNF, IL-9, IFN-γ, MIP-1ß, and IL-12. Our results demonstrate that evolving clinical relapse after NA cessation is associated with a systemic increase in the proinflammatory cytokines IP-10 and TNF.Clinical trial registration: ClinicalTrials.gov, Identifier: NCT03681132.

Short-hairpin RNA-mediated suppression of cortactin may inhibit the migration and invasion abilities of endometrial cancer cells by reducing lamellipodia.

Objectives: The prognosis of endometrial cancer (EC) is significantly affected by tumor infiltration and metastasis. Cortactin (CTTN) regulates infiltration and metastasis in other tumors. Studies on the role and mechanism of CTTN in EC are limited and further studies are needed. Materials and Methods: Quantitative PCR and immunohistochemistry were used to detect Ras-associated C3 botulinum toxin substrate 1 (Rac1) and CTTN in EC and normal tissues. The relationship between the expression of these two genes and their prognostic factors was analyzed. A CTTN-RNAi lentiviral system was constructed and transfected into EC cells. Migration and invasion were evaluated by scratch assay, transwell migration, and invasion assays. Pseudopodia formation was observed by immunofluorescence staining. Western blotting was performed to detect the expression of Rac1. Results: The expression levels of Rac1 and CTTN in EC tissues were significantly higher than those in normal tissues. In the EC group, Rac1 and CTTN levels were correlated. The protein expression levels of Rac1 and CTTN were related to myometrial invasion and stage. After CTTN knockdown, the migration rate, invasiveness, and migratory ability of EC cells decreased significantly. Lamellipodia was observed to disappear with the appearance of blebs. Rac1 protein expression was decreased after CTTN knockdown. Conclusion: CTTN may promote the invasion and migration of EC by lamellipodia. This effect may be related to the regulation of Rac1 by CTTN.

Effect of Proinflammatory S100A9 Protein on Migration and Proliferation of Microglial Cells.

Alzheimer's disease (AD) is a multifactorial disease affecting aging population worldwide. Neuroinflammation became a focus of research as one of the major pathologic processes relating to the disease onset and progression. Proinflammatory S100A9 is the central culprit in the amyloid-neuroinflammatory cascade implicated in AD and other neurodegenerative diseases. We studied the effect of S100A9 on microglial BV-2 cell proliferation and migration. The responses of BV-2 cells to S100A9 stimulation were monitored in real-time using live cell microscopy, transcriptome sequencing, immunofluorescence staining, western blot analysis, and ELISA. We observed that a low dose of S100A9 promotes migration and proliferation of BV-2 cells. However, acute inflammatory condition (i.e., high S100A9 doses) causes diminished cell viability; it is uncovered that S100A9 activates TLR-4 and TLR-7 signaling pathways, leading to TNF-α and IL-6 expression, which affect BV-2 cell migration and proliferation in a concentration-dependent manner. Interestingly, the effects of S100A9 are not only inhibited by TNF-α and IL-6 antibodies. The addition of amyloid-ß (Aß) 1-40 peptide resumes the capacities of BV-2 cells to the level of low S100A9 concentrations. Based on these results, we conclude that in contrast to the beneficial effects of low S100A9 dose, high S100A9 concentration leads to impaired mobility and proliferation of immune cells, reflecting neurotoxicity at acute inflammatory conditions. However, the formation of Aß plaques may be a natural mechanism that rescues cells from the proinflammatory and cytotoxic effects of S100A9, especially considering that inflammation is one of the primary causes of AD.

Smart Ratiometric SERS Nanoprobe for Real-Time Monitoring Hydrogen Peroxide in Living Cells during NADH Treatment Associated with Ferroptosis.

Studying the oxidative stress, especially the reactive oxygen species (ROS) response of ferroptosis, is crucial for the diagnosis and treatment of cancer based on ferroptosis. However, reliable quantitative analysis of intracellular ROS in cancer treatment for drug screening is still a challenge. Herein, a superior ratiometric SERS nanoprobe was developed for in situ, real-time, and highly sensitive detection of content variation of H2O2 within living cells. The SERS nanoprobe was prepared by coassembly of the internal standard molecule p-mercaptobenzonitrile and the reporter molecule p-mercaptophenylboronic acid on the surface of gold nanoparticles, used for synergistic calibration and detection of H2O2, which enables reliable detection of the true content of intracellular H2O2 without the interference of other substances in cells. Based on the nanoprobe, we found that the level of intracellular H2O2 of cancer cells was increased after the nicotinamide adenine dinucleotide (NADH) treatment, with a dose-dependence to the concentration of NADH. High doses of NADH (above 20 mM) can induce cell death by means of ferroptosis associated with the level elevation of intracellular lipid hydroperoxides. This study highlights the potential of the SERS nanoprobe for tracking content variation of cellular H2O2 and understanding its roles in screening new anticancer drugs.

The association of chest computed tomography-defined visual emphysema and prognosis in patients with nonsmall cell lung cancer.

Background: Although computed tomography (CT)-defined emphysema is considered a predictor of lung cancer risk, it is not fully clear whether CT-defined emphysema is associated with the prognosis of lung cancer. We aimed to assess the clinical impact of CT-defined emphysema on the survival of lung cancer. Methods: In the prospective cohort study of nonsmall cell lung cancer (NSCLC), the correlation between CT-defined emphysema and clinical variables was analysed. A multivariable Cox regression model was built to assess the association between CT-defined emphysema and overall survival (OS) for up to 8.8 years. The differences in survival analyses were derived by Kaplan-Meier analysis and log-rank testing. Low attenuation area (LAA%) was defined as the per cent of voxels below -950 HU. Results: 854 patients were included and CT-defined emphysema was present in 300 (35.1%) at diagnosis. Epidermal growth factor receptor (EGFR) wild-type (OR 1.998; p<0.001) and anaplastic lymphoma kinase (ALK) wild-type (OR 2.277; p=0.004) were associated with CT-defined emphysema. CT-defined emphysema remained a significant predictor of prognosis adjusting for age, sex, smoking history, tumour histology and Eastern Cooperative Oncology Group Performance Status (ECOG PS), whether in I-IIIA stage (adjusted hazard ratio (HR) 1.745; p=0.017) or in IIIB-IV stage (adjusted HR 1.291; p=0.022). Stratified analyses showed that OS rate among the driver oncogene groups with different CT-defined emphysema status differed significantly (log-rank p<0.001). Furthermore, patients with centrilobular emphysema (CLE) with LAA% >17% displayed poorer survival than those with LAA% ≤17% (median 432 versus 670 days; HR 1.564; p=0.020). Conclusions: CT-defined emphysema, especially CLE with LAA%>17%, is an independent predictor of NSCLC prognosis. Moreover, prospective studies are needed to further explore this association.