Dietary inflammatory index is associated with severe depression in older adults with stroke: a cross-sectional study.

Inflammation is involved in the pathogenesis of stroke and depression. We aimed to investigate the association between the dietary inflammatory index (DII) and depression in American adults with stroke. Adults with stroke were enrolled in the National Health and Nutrition Examination Survey between 2005 and 2018 in the USA. The DII was obtained from a 24-h dietary recall interview for each individual. Multivariate regression and restricted cubic spline analyses were conducted to evaluate the association between DII and depression in adults with stroke. The mean age of the 1239 participants was 63·85 years (50·20 % women), and the prevalence of depression was 18·26 %. DII showed a linear and positive association with severe depression in adults with stroke (OR 1·359; 95 % CI 1·021, 1·810; P for non-linearity = 0·493). Compared with those in the lowest tertile of the DII, adults with stroke in the third tertile of the DII had a 3·222-fold higher risk of severe depression (OR 3·222; 95 % CI 1·150, 9·026). In the stratified analyses, the association between DII score and severe depression was more significant in older adults (P for interaction = 0·010) but NS with respect to sex (P for interaction = 0·184) or smoking status (P for interaction = 0·396). No significant association was found between DII and moderate-to-moderately severe depression in adults with stroke. In conclusion, an increase in DII score was associated with a higher likelihood of severe depression in older adults with stroke.

UBXN11 Predicts as a Poor Index for Colorectal Cancer and Contributes to the Tumorigenesis by Activating NF-κB Signaling.

BACKGROUND: The complex mechanisms of colorectal cancer (CRC) pathogenesis and progression remain poorly understood. This study endeavors to unravel the role of UBXN11within the context of CRC. METHODS: UBXN11 expression level in CRC, stomach adenocarcinoma and esophageal carcinoma, and the overall survival in corresponding cancers were analyzed using UALCAN database. Human CRC cell lines and xenograft mouse model with UBXN11 overexpression were established to investigate the pathological role of UBXN11 in CRC progression. Luciferase assay, qPCR, and Western blot were performed to dissect the interaction between UBXN11 and NF-κB signaling. RESULTS: Heightened UBXN11 expression was observed in various digestive tract tumors, which was positively correlated with the reduced overall survival rates in CRC patients. Overexpression of UBXN11 significantly enhanced CRC cell proliferation in vitro and promoted tumor growth in vivo. Mechanistically, UBXN11 promoted CRC tumorigenesis through increasing the activation of NF-κB signaling pathway. CONCLUSIONS: This study underscores the pivotal role of UBXN11 in CRC progression and paves the way for novel therapeutic strategies for CRC treatment.

Age and incidence of occult pancreaticobiliary reflux in patients with benign gallbladder diseases.

BACKGROUND: Occult pancreaticobiliary reflux (OPBR) has a significant correlation with diseases of the gallbladder and biliary system. This study examined the incidence of OPBR by age in patients with benign gallbladder diseases. METHODS: We assessed 475 patients with benign gallbladder diseases who underwent surgery at Shanghai East Hospital from December 2020 to December 2021. Bile samples collected during surgery were tested for amylase. Patients with bile amylase >110 U/L (n = 64) were classified as the OPBR group; the rest (n = 411) as controls. RESULTS: Of the participants, 375 had gallbladder stone (GS), 170 had gallbladder polyp (GP), and 49 had gallbladder adenomyomatosis (GA). The OPBR group was generally older, with OPBR incidence increasing with age, peaking post-45. Rates by age were: 4.9% (<35), 5.2% (35-44), 20.7% (45-54), 22.5% (55-64) and 17.6% (≥65), mainly in GS patients. ROC analysis for predicting OPBR by age yielded an area under the curve of 0.656, optimal cut-off at 45 years. Logistic regression indicated age > 45, GP, male gender, and BMI ≥ 24 kg*m-2 as independent OPBR predictors in GS patients. Based on these variables, a predictive nomogram was constructed, and its effectiveness was validated using the ROC curve, calibration curve and decision curve analysis (DCA). Further stratification revealed that among GS patients ≤ 45, concurrent GA was an OPBR risk; for > 45, it was GP and male gender. CONCLUSIONS: The incidence of OPBR in GS patients is notably influenced by age, with those over 45, especially males without GP, being at heightened risk.

Glutathione degradable manganese-doped polydopamine nanoparticles for photothermal therapy and cGAS-STING activated immunotherapy of lung tumor.

Photothermal therapy (PTT), which utilizes nanomaterials to harvest laser energy and convert it into heat to ablate tumor cells, has been rapidly developed for lung tumor treatment, but most of the PTT-related nanomaterials are not degradable, and the immune response associated with PTT is unclear, which leads to unsatisfactory results of the actual PTT. Herein, we rationally designed and prepared a manganese ion-doped polydopamine nanomaterial (MnPDA) for immune-activated PTT with high efficiency. Firstly, MnPDA exhibited 57.2% photothermal conversion efficiency to accomplish high-efficiency PTT, and secondly, MnPDA can be stimulated by glutathione (GSH) to the release of Mn2+, and it can produce ·OH in a Fenton-like reaction with the overexpressed H2O2 and stimulate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. These two synergistically can effectively remove lung tumor cells that have not been ablated by PTT, resulting in an 86.7% tumor suppression rate under laser irradiation of MnPDA in vivo, and further significantly activated the downstream immune response, as evidenced by an increased ratio of cytotoxic T cells to immunosuppressive Treg cells. Conclusively, the GSH degradable MnPDA nanoparticles can be used for photothermal therapy and cGAS-STING-activated immunotherapy of lung tumors, which provides a new idea and strategy for the future treatment of lung tumors.

Paclitaxel may inhibit migration and invasion of gastric cancer cells via nod-like receptor family pyrin domain-containing 3/caspase-1/Gasdermin E mediated pyroptosis pathway.

Gastric cancer (GC) is a gastric epithelium-derived malignancy insensitive to post-surgical radiotherapy. Paclitaxel, an anti-microtubule drug, has been proven to induce apoptosis of GC cells; however, its exact mechanism of action is unclear. Therefore, the molecular mechanism by which paclitaxel inhibits the proliferation, migration and invasion of GC cells was investigated in this study. First off, SNU-719 cells were co-cultured with paclitaxel and/or Caspase1 inhibitor VX765. Then the proliferation ability of the cells was detected by MTT after paclitaxel treatment (0, 10, 20, 40, and 80 nM), the migration ability by scratch assay, and the invasion ability by Transwell assay. Next, the levels of interleukin (IL)-1ß and IL-18 in cell culture supernatant were detected by the enzyme linked immunosorbent assay (ELISA). And the level of lactate dehydrogenase (LDH) in the supernatant was measured by a corresponding kit. Finally, western blot was performed to detect the concentrations of Gasdermin E (GSDME), GSDME-N, nod-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, cleaved caspase-1 protein in GC cells. As a result, paclitaxel inhibited the proliferation, migration, and invasion of SNU-719 cells in a concentration-dependent manner. Moreover, it induced the pyroptosis of SNU-719 cells. After cell co-culture with VX765 paclitaxel showed decreased inhibitory effect on the migration and invasion of SNU-719 cells. VX765, additionally, suppressed the NLRP3/caspase-1/GSDME mediated pyroptosis pathway activated by paclitaxel. In a nutshell, paclitaxel may inhibit the migration and invasion of GC cells SNU-719 through the NLRP3/caspase-1/GSDME mediated pyroptosis pathway.

Clinical significance of serum oxidative stress and serum uric acid levels before surgery for hepatitis B-related liver cancer.

BACKGROUND: The incidence and mortality of liver cancer are among the highest of all malignant tumors in China. The high recurrence rate after conventional hepatectomy is worrying. There is a lack of effective prognostic indicators for liver cancer. AIM: To explore the clinical significance of preoperative serum oxidative stress and serum uric acid (UA) levels in hepatitis B-related liver cancer. METHODS: The medical records of 110 hepatitis B-related liver cancer patients who underwent hepatectomy in Gansu Provincial Hospital were retrospectively analyzed. Recurrence in patients within 3 years after surgery was determined. The logistic regression model and Pearson or Spearman correlation were used to analyze the correlation between oxidative stress level and UA, and the recurrence of hepatitis B-related liver cancer. RESULTS: Compared with the non-recurrence group, the levels of superoxide dismutase (SOD) and glutathione (GSH) in the recurrence group were lower and the levels of malondialdehyde (MDA) and UA were higher (all P < 0.05). UA, SOD, MDA, and GSH were risk factors for postoperative recurrence in hepatitis B-related liver cancer patients (P < 0.05). UA was positively correlated with MDA (r = 0.395, P < 0.001) and negatively correlated with GSH (r = -0.204, P = 0.032). The area under the receiver operating characteristic curve (AUC) of SOD, MDA, GSH, and UA in predicting the prognosis was 0.276, 0.910, 0.199, and 0.784, respectively (all P < 0.001). CONCLUSION: The preoperative serum SOD, GSH, MDA, and UA levels had significant predictive effects on postoperative recurrence of hepatitis B-related liver cancer.

Eight Zhes Decoction ameliorates the lipid dysfunction of nonalcoholic fatty liver disease using integrated lipidomics, network pharmacology and pharmacokinetics.

Nonalcoholic fatty liver disease (NAFLD) has developed into the most common chronic liver disease and can lead to liver cancer. Our laboratory previously developed a novel prescription for NAFLD, "Eight Zhes Decoction" (EZD), which has shown good curative effects in clinical practice. However, the pharmacodynamic material basis and mechanism have not yet been revealed. A strategy integrating lipidomics, network pharmacology and pharmacokinetics was used to reveal the active components and mechanisms of EZD against NAFLD. The histopathological results showed that EZD attenuated the degrees of collagen deposition and steatosis in the livers of nonalcoholic steatofibrosis model mice. Furthermore, glycerophospholipid metabolism, arachidonic acid metabolism, glycerolipid metabolism and linoleic acid metabolism with phospholipase A2 group IVA (PLA2G4A) and cytochrome P450 as the core targets and 12,13-cis-epoxyoctadecenoic acid, 12(S)-hydroxyeicosatetraenoic acid, leukotriene B4, prostaglandin E2, phosphatidylcholines (PCs) and triacylglycerols (TGs) as the main lipids were found to be involved in the treatment of NAFLD by EZD. Importantly, naringenin, artemetin, canadine, and bicuculline were identified as the active ingredients of EZD against NAFLD; in particular, naringenin reduces PC consumption by inhibiting the expression of PLA2G4A and thus promotes sufficient synthesis of very-low-density lipoprotein to transport excess TGs in the liver. This research provides valuable data and theoretical support for the application of EZD against NAFLD.

Genetic polymorphisms of CYP24A1 gene and cancer susceptibility: a meta-analysis including 40640 subjects.

BACKGROUND: Whether cytochrome P450 24A1 (CYP24A1) polymorphism is associated with cancer susceptibility, the individual study results are still controversial. Therefore, we performed a comprehensive study to identify the association of CYP24A1 polymorphisms (rs4809960, rs6068816, rs2296241, rs4809957, rs2762939) with cancer susceptibility. METHODS: Electronic databases including Cochrane Library, PubMed, and Embase were systematically retrieved for relevant publications. Fixed or random-effect model was selected to calculate odds ratios (ORs) with their 95% confidence intervals (95%CI). RESULTS: Eighteen published articles were identified. The results indicated that rs4809960 polymorphism was associated with a decreased cancer risk in Caucasian (TT vs. TC+CC: P=0.035; C vs. T: P=0.016) and Asian population (CC vs. TC+TT: OR P=0.044; TT vs. TC+CC: P=0.021; CC vs. TT: P=0.020; C vs. T: P=0.008) and breast cancer risk (TT vs. TC+CC: P = 0.007; TC vs. TT: P=0.004; C vs. T: P=0.033). A significant association was found between rs2296241 polymorphism and esophageal squamous cell carcinoma risk (AA vs. GG+AG: P = 0.023) and prostate cancer susceptibility (A vs. G: P=0.022). Furthermore, rs4809957 polymorphism was associated with prostate cancer susceptibility in Caucasian (GG vs. GA+AA: P=0.029; GA vs. GG: P=0.022) and breast cancer susceptibility (AA vs. GG+GA: P=0.012; AA vs. GG, P=0.010; A vs. G: P=0.024). Additionally, rs6068816 polymorphism significantly decreased the lung cancer (CC vs. CT+TT: P = 0.016; TT vs. CC: P = 0.044; CT vs. CC: P = 0.036; T vs. C: P = 0.016) and breast cancer risk (TT vs. CC+CT: P = 0.043; TT vs. CC: P = 0.039). No association was found for rs2762939 polymorphism with overall cancer risk. However, for rs2296241, rs4809957, and rs6068816 polymorphisms, there were no significant differences after the Bonferroni correction. CONCLUSION: The meta-analysis suggested that rs4809960 was associated with cancer risk and might be a genetic marker for predicting cancer risk. More large-scale and large-sample studies are necessary to further confirm these results.

Changes in the Physical Properties and Volatile Odor Characteristics of Shiitake Mushrooms (Lentinula edodes) in Far Infrared Radiation Drying.

The effects of far infrared radiation drying (FID) on physical properties (drying kinetics, color, shrinkage ratio, rehydration ratio, and microstructural characterization) and volatile odor characteristics (volatile odor profile distinction and volatile compounds) of shiitake mushrooms were evaluated in this study. During the FID, the drying time decreased with the increase in drying temperature, and it had a less significant effect in the lower temperature range. The increase in drying temperature led to increasing shrinkage and collapse in the microstructure, resulting in a decreased rehydration rate and highlighting the influence of microstructure characteristics on macroscopic properties. Higher drying temperatures employed in the FID process were found to be associated with a decreasing L* value and an increasing ΔE value. The application of principal component analysis can effectively distinguish the significant effect of FID on the volatile odor profiles of shiitake mushrooms. Compared to raw shiitake mushrooms, FID treatment has endowed samples with a greater variety of volatile compounds. After processing with FID, there have been increases in volatile components such as sulfur compounds, acids, nitrogen compounds, and aldehydes, while volatile components like alcohols, ketones, and hydrocarbons have shown decreases.

Experimental assessment of robust reference genes for qRT-PCR in lung cancer studies.

Stable internal reference genes are crucial for quantitative real-time PCR (qRT-PCR) analyses in lung cancer studies. Widely used reference genes are mostly chosen by intuition or from pan-cancer transcriptome data and lack experimental validation by qRT-PCR in the context of lung cancer. This study evaluated the stability of candidate reference genes in lung cancer cell lines under normal homeostasis, hypoxia, and serum deprivation to screen for robust reference genes for qRT-PCR in lung cancer studies. The stability of reference gene combinations was also assessed. We found that most of the stably expressed genes from pan-cancer transcriptome analyses were not sufficiently stable under some of the tested conditions. CIAO1, CNOT4, and SNW1 were found to be the most stable reference genes under various conditions. Greater stability was achieved by combining more reference genes. We further used the hypoxia biomarker hypoxia-inducible factor (HIF)-2α to demonstrate that choosing inappropriate reference genes can lead to incorrect qRT-PCR results. We also found that the stable reference genes were irrelevant to malignancy, which may explain their stability under various conditions that cancer cells often encounter. This study provides a list of validated and stable qRT-PCR reference genes and reference gene combinations for lung cancer that may standardize qRT-PCR experiments in future lung cancer studies.

The Effect of Cutting Fluid on Machined Surface Integrity of Ultra-High-Strength Steel 45CrNiMoVA.

The surface integrity of ultra-high-strength steel has a significant influence on service performance, and cutting fluid plays an important role in maintaining surface integrity in production. In this paper, the surface integrity of ultra-high-strength steel 45CrNiMoVA was investigated under three cutting fluids: HY-103 (micro-emulsion), TRIM E709 (emulsion), and Vasco 7000 (micro-emulsion) from the aspects of cutting force, surface morphology, residual stress, micro hardness, microstructure, etc. The results showed that the changing trend of the cutting forces in three directions is HY-103 > Vasco 7000 > TRIM E709. The TRIM E709 contains the maximum lubricants, which reduce cutting force and Sa roughness, while the Vasco 7000 contains the minimum corrosive elements, which results in the least pitting. Both tangential and axial stresses under cutting fluid are tensile stresses. TRIM E709 and Vasco 7000 are reduced axially by 4.45% and 7.60% relative to HY-103, respectively. The grain refinement layer depths of HY-103, TRIM E709, and Vasco 7000 are 9 µm, 4 µm, and 8 µm, respectively, and TRIM E709 can induce recrystallized grains to grow along {001} of the sample cross section, which results from the lowest cooling rate. This work may provide an innovative control strategy for cutting fluid to improve surface integrity and service performance.

The effectiveness of tivantinib for MET-high hepatocellular carcinoma: A protocol for meta analysis.

BACKGROUND: The efficacy of tivantinib for MET-high hepatocellular carcinoma remains controversial. We conduct this meta-analysis to explore the efficacy of tivantinib versus placebo for MET-high hepatocellular carcinoma. METHODS: We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through November 2022 and included randomized controlled trials (RCTs) assessing the efficacy and safety of tivantinib versus placebo for MET-high hepatocellular carcinoma. RESULTS: Three RCTs were included in the meta-analysis. Overall, compared with control group for MET-high hepatocellular carcinoma, tivantinib showed no obvious impact on overall survival (hazard ratio [HR] = 0.77; 95% confidence interval [CI] = 0.52-1.13; P = .18) or progression-free survival (HR = 0.78; 95% CI = 0.56-1.08; P = .14). In addition, tivantinib was associated with the increase in grade ≥3 neutropenia (odd ratio [OR] = 11.76; 95% CI = 2.77-49.89; P = .0008) and leukopenia (OR = 14; 95% CI = 1.68-116.82; P = .01), but demonstrated no impact on the incidence of grade ≥ 3 anemia (OR = 2.74; 95% CI = 0.14-53.43; P = .51). CONCLUSIONS: Tivantinib may not benefit to the treatment of MET-high hepatocellular carcinoma.

Effect of Cutting Fluid on Machined Surface Integrity and Corrosion Property of Nickel Based Superalloy.

Superalloy parts place high demands on machined surface integrity and serviceability. In the machining process of superalloys, the cutting fluid is usually used to improve the machining performance. Cutting fluids with cooling and lubrication functions have a relatively large effect on the surface microstructure and residual stress as well. The corrosion damage caused by cutting fluid to the machined surface, during machining and residual, are also worth considering. In this paper, the machining performance of typical binary Ni Cr solid solution, age-hardened, nickel-based superalloy NiCr20TiAl T6, under two commonly used cutting fluids, Blasocut and E709, was analyzed, including cutting performance, surface quality, machining surface corrosion characteristics, and so on. The results showed that the surface residual stress could be improved by adding both cutting fluids compared with the deionized water. Blasocut had better lubrication properties, which could reduce friction and heat production. Pitting holes were found on the polished surface after 45 days with E709 cutting fluid, which was more corrosive than Blasocut. According to this research, a reasonable cutting fluid can be selected to reduce the surface corrosion and improve the service life and performance of parts.

Role of Sox3 in Estradiol-Induced Sex Reversal in Pelodiscus sinensis.

The Chinese soft-shelled turtle Pelodiscus sinensis, an economically important species in China, exhibits significant sexual dimorphism. Males are more valuable than females owing to their wider calipash and faster growth. Estradiol (E2)-induced sex reversal is used to achieve all-male breeding of turtles; however, the mechanism of this sex reversal remains unclear. In this study, we characterized the Sox3 gene, whose expression level was high in the gonads and brain and exhibited significant sexual dimorphism in the ovary. During embryonic development, Sox3 was highly expressed at the initiation of ovarian differentiation. E2 and Sox3-RNAi treatment before sexual differentiation led to 1352, 908, 990, 1011, and 975 differentially expressed genes in five developmental stages, respectively, compared with only E2 treatment. The differentially expressed genes were clustered into 20 classes. The continuously downregulated and upregulated genes during gonadal differentiation were categorized into Class 0 (n = 271) and Class 19 (n = 606), respectively. KEGG enrichment analysis showed that Sox3 significantly affected sexual differentiation via the Wnt, TGF-ß, and TNF signaling pathways and mRNA surveillance pathway. The expression of genes involved in these signaling pathways, such as Dkk4, Nog, Msi1, and Krt14, changed significantly during gonadal differentiation. In conclusion, the deletion of Sox3 may lead to significant upregulation of the mRNA surveillance pathway and TNF and Ras signaling pathways and downregulation of the Wnt and TGF-ß signaling pathways, inhibiting E2-induced sex reversal. These findings suggest that Sox3 may play a certain promoting effect during E2-induced sex reversal in P. sinensis.

Tandem Mass Tag-Based Quantitative Proteomics Analysis of Gonads Reveals New Insight into Sexual Reversal Mechanism in Chinese Soft-Shelled Turtles.

Chinese soft-shelled turtles display obvious sex dimorphism. The exogenous application of hormones (estradiol and methyltestosterone) can change the direction of gonadal differentiation of P. sinensis to produce sex reversed individuals. However, the molecular mechanism remains unclear. In this study, TMT-based quantitative proteomics analysis of four types of P. sinensis (female, male, pseudo-female, and pseudo-male) gonads were compared. Quantitative analysis of 6107 labeled proteins in the four types of P. sinensis gonads was performed. We identified 440 downregulated and 423 upregulated proteins between pseudo-females and males, as well as 394 downregulated and 959 upregulated proteins between pseudo-males and females. In the two comparisons, the differentially expressed proteins, including K7FKG1, K7GIQ2, COL4A6, K7F2U2, and K7FF80, were enriched in some important pathways, such as focal adhesion, endocytosis, apoptosis, extracellular matrix-receptor interaction, and the regulation of actin cytoskeleton, which were upregulated in pseudo-female vs. male and downregulated in pseudo-male vs. female. In pathways such as ribosome and spliceosome, the levels of RPL28, SRSF3, SNRNP40, and HNRNPK were increased from male to pseudo-female, while they decreased from female to pseudo-male. All differentially expressed proteins after sexual reversal were divided into six clusters, according to their altered levels in the four types of P. sinensis, and associated with cellular processes, such as embryonic development and catabolic process, that were closely related to sexual reversal. These data will provide clues for the sexual reversal mechanism in P. sinensis.

Anticoagulation therapy for pulmonary embolism involving a myxoma mimicking, giant type C thrombus: A case report.

Right heart thrombus (RHTh) with concurrent acute pulmonary embolism (PE) is rare and can seriously destabilize hemodynamics, leading to an emergency situation with high mortality. Diagnosis and treatment of RHTh with acute PE are not yet standardized. There are few reports of acute PE concurrent with RHTh and even less is known about patients with a right heart mural thrombus. For physicians, the diagnostic choice and treatment of these patients are particularly difficult due to the lack of knowledge. Here, we report a rare case of partial mural RHTh (type C RHTh) with acute PE. The mural mass in the right heart was initially diagnosed as atrial myxoma according to transthoracic echocardiography (TTE), and both pulmonary embolus and the mural mass were completely absorbed after administering Rivaroxiban. This case suggests that TTE alone is insufficient to identify and diagnoses a right heart mural mass such as this. However, novel oral anticoagulants may be effective at alleviating PE with type C RHTh.

A water-soluble 1,8-naphthalimide-based fluorescent pH probe for distinguishing tumorous tissues and inflammation in mice.

A water-soluble fluorescent probe BPN, by introducing a piperazine as the pH-sensitive fluorescence signaling motif to the hydrophilic propionic acid-substituted 1,8-naphthalimide fluorophore, is highly sensitive to pH changes within cytoplasm matrix in living cells, as well as pH-related diseases models. Owing to the protonation-induced inhibition of the photoinduced electron transfer (PET) from piperazine to naphthalimide fluorophore, BPN displayed a significant fluorescence enhancement (more than 131-fold) upon the pH decreasing from 11.0 to 3.0. The linear range was between pH 6.4 to 8.0 with a pKa value of 6.69 near the physiological pH, which was suitable for cytosolic pH research. Furthermore, BPN exhibited a large Stokes shift (142 nm), good water solubility, excellent photostability, high selectivity and low cytotoxicity. All these advantages were particularly beneficial for intracellular pH imaging. Using BPN, we demonstrated the real-time monitoring of cytosolic pH changes in living cells. Most importantly, BPN has not only been successfully applied for distinguishing inflammation in mice, but also the surgical specimens of cancer tissue, making it of great potential application in cancer diagnosis.

Genomic Analysis Reveals the Prognostic and Immunotherapeutic Response Characteristics of Ferroptosis in Lung Squamous Cell Carcinoma.

INTRODUCTION: Recent studies have reported that ferroptosis is an iron-dependent cell death process and is a potential therapeutic target in various tumours. The purpose of this study was to establish a new algorithm based on the ferroptosis score to ascertain the prognosis and response to immunotherapy of patients with lung squamous cell carcinoma (LUSC). METHODS: The RNA-seq data of patients with LUSC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases and merged after removing the inter batch differences. Based on the expression of the ferroptosis-related genes, unsupervised consistent cluster analysis was performed to obtain various ferroptosis-related subgroups. These subgroups were analysed to obtain differentially expressed genes (DEGs). Subsequently, multiple gene clusters were obtained by unsupervised consistent cluster analysis based on the expression of the DEGs. The Boruta algorithm was used to calculate the ferroptosis score. RESULTS: There were significant differences in prognosis amongst the various ferroptosis-related and gene clusters. In addition, the gene set variation analysis revealed that the different ferroptosis-related clusters and gene clusters demonstrated differences in biological pathways. The ferroptosis scores positively correlated with the tumour mutation burden, and patients with lower scores had a better prognosis. In addition, the ferroptosis score was accurate in predicting the effectiveness of immunotherapy. CONCLUSION: There were significant differences in the prognosis and immunotherapy response of patients with LUSC with different ferroptosis scores. Therefore, a comprehensive clinical evaluation of the ferroptosis score of each patient with LUSC is clinically significant.

Pyogenic thigh abscess caused by Streptococcus constellatus subsp. constellatus in a patient with exacerbation of bronchiectasis: a case report.

Streptococcus constellatus (S. constellatus) is a Gram-positive commensal bacterium that is commonly found in the oral, nasal, pharyngeal, gastrointestinal, and urogenital tracts. It can be further consisted by three subspecies: subsp, constellatus, subsp. pharynges, and subsp. viborgensis. As an opportunistic pathogen, S. constellatus can cause abscesses and bacteremia, so infection requires timely and accurate identification in clinical practice. There are a few case reports describing the range of infections caused by S. constellatus, which include intracardiac, thoracic, intracranial, and abdominal infections. Here we report the first case of thigh abscess caused by S. constellatus subsp. constellatus which was rarely insensitive to penicillin in a patient with exacerbation of bronchiectasis. The patient improved significantly after receiving antibiotic therapy with ceftriaxone and vancomycin, as well as percutaneous catheter drainage guided by color ultrasonography. The thigh abscess did not recur during follow-up. This case report demonstrates that although S. constellatus is a rare infectious pathogen, it is important to gain a better understanding of the range of possible infections to ensure timely diagnosis. Furthermore, although the prognosis of most patients with such infections is relatively good, the timely identify the resistant strains and administration of sensitive antibiotics along with abscess drainage may ensure effective treatment.

Design, Synthesis and Biological Evaluation of Coumarin Derivatives as NEDD8 Activating Enzyme Inhibitors in Pancreatic Cancer Cells.

BACKGROUND: NEDD8 (neural precursor cell expressed developmentally downregulated protein 8) is one of the ubiquitin-like proteins which is activated by the NEDD8 activating enzyme (NAE). The overexpressed NAE can cause a variety of diseases such as numerous cancer types and inflammatory diseases. The selective inhibition of NAE could mediate the rate of ubiquitination and the subsequent degradation of proteins associated with cancer so as to achieve the purpose of treatment. OBJECTIVE: In this article, we decided to study the synthesis and screening of coumarin scaffold derivatives against cancer cell lines, specifically the human pancreatic cancer cell line BxPC-3. METHODS: Twenty-four targeted compounds were synthesized, and their anti-proliferative activity against three cancer cell lines, cytotoxicity against three normal cell lines through CCK-8 and MTT assay were evaluated to screen out the candidate compound. Then the target was further confirmed by both enzyme and cell-based experiments, as well as cell apoptosis research. RESULTS: Several new 4-position substituted coumarin derivatives (12a~x) were synthesized and most of them exhibit antiproliferative activity in three cancer cell lines. A series of experiments were performed to identify the best candidate compound 12v. This compound displayed the highest potency against BxPC-3 with an IC50 value of 0.28 µM. It can also inhibit NAE activity in enzyme and cellbased assay, and induce CRLs-mediated accumulation of the substrate and apoptosis in BxPC-3 cells. Meanwhile, it exhibited relatively low toxicity in three normal cells. CONCLUSION: Based on these results, we found that compound 12v inhibited NAE activity in enzyme and cell-based systems and induced apoptosis in BxPC-3 cells. Additionally, it also had a low toxicity. These results suggested that 12v may be promising lead compounds for the development of new anticancer drugs.