CT morphological features and histogram parameters to predict micropapillary or solid components in stage IA lung adenocarcinoma.

Objectives: This study aimed to construct prediction models based on computerized tomography (CT) signs, histogram and morphology features for the diagnosis of micropapillary or solid (MIP/SOL) components of stage IA lung adenocarcinoma (LUAC) and to evaluate the models' performance. Methods: This clinical retrospective study included image data of 376 patients with stage IA LUAC based on postoperative pathology, admitted to Putian First Hospital from January 2019 to June 2023. According to the presence of MIP/SOL components in postoperative pathology, patients were divided into MIP/SOL+ and MIP/SOL- groups. Cases with tumors ≤ 3 cm and ≤ 2 cm were separately analyzed. Each subgroup of patients was then randomly divided into a training set and a test set in a ratio of 7:3. The training set was used to build the prediction model, and the test set was used for internal validation. Results: For tumors ≤ 3 cm, ground-glass opacity (GGO) [odds ratio (OR) = 0.244; 95% confidence interval (CI): 0.103-0.569; p = 0.001], entropy (OR = 1.748; 95% CI: 1.213-2.577; p = 0.004), average CT value (OR = 1.002; 95% CI: 1.000-1.004; p = 0.002), and kurtosis (OR = 1.240; 95% CI: 1.023-1.513; p = 0.030) were independent predictors of MIP/SOL components of stage IA LUAC. The area under the ROC curve (AUC) of the nomogram prediction model for predicting MIP/SOL components was 0.816 (95% CI: 0.756-0.877) in the training set and 0.789 (95% CI: 0.689-0.889) in the test set. In contrast, for tumors ≤ 2 cm, kurtosis was no longer an independent predictor. The nomogram prediction model had an AUC of 0.811 (95% CI: 0.731-0.891) in the training set and 0.833 (95% CI: 0.733-0.932) in the test set. Conclusion: For tumors ≤ 3 cm and ≤ 2 cm, GGO, average CT value, and entropy were the same independent influencing factors in predicting MIP/SOL components of stage IA LUAC. The nomogram prediction models have potential diagnostic value for identifying MIP/SOL components of early-stage LUAC.

Pancancer analysis of the correlations of HS6ST2 with prognosis, tumor immunity, and drug resistance.

HS6ST2 has ability to encodes a member of the heparan sulfate (HS) sulfotransferase gene family, which catalyze the transfer of sulfate to HS and a crucial regulator of cell growth, differentiation, adhesion, and migration. Although mounting evidence supports a vital role for HS6ST2 in tumorigenesis of some cancers, no pan-cancer analysis of HS6ST2 has been reported. Therefore, we aimed to explore the prognostic value of HS6ST2 in 33 cancer types and investigate its potential immune function. Based on data from The Cancer Genome Atlas, Cancer Cell Lines Encyclopedia, Genotype Tissue Expression, and GSCA, we used a range of bioinformatics approaches to explore the potential carcinogenic role of HS6ST2, analysis of HS6ST2 and prognosis, DNA methylation, RNA methylation, microsatellite instability (MSI), tumor mutation burden (TMB), and immune cell infiltration in different tumors. The results show that HS6ST2 was highly expressed in most cancers but lower in Breast invasive carcinoma, Kidney Chromophobe, Kidney renal clear cell carcinoma, Kidney renal papillary cell carcinoma, and Uterine Corpus Endometrial Carcinoma. Moreover, HS6ST2 is positively or negatively associated with prognosis in different cancers. HS6ST2 expression was not only associated with MSI in 5 cancer types and associated with TMB in 10 cancer types, and it's significantly correlated with DNA methylation in 13 types of cancer, but it's correlated with RNA methylation related genes in most cancer. HS6ST2 expression was correlated with immune cell infiltration, immune-related genes, tumor immune microenvironment, and drug resistance in various cancers. Eventually, HS6ST2 was validated in human lung adenocarcinoma tissues. Our study reveals that HS6ST2 can function as a prognostic marker in various malignant tumors because of its role in tumorigenesis and tumor immunity.

Over-expression of USP15/MMP3 predict poor prognosis and promote growth, migration in non-small cell lung cancer cells.

Aberrant ubiquitin modifications caused by an imbalance in the activities of ubiquitinases and de-ubiquitinases are emerging as important mechanisms underlying non-small cell lung cancer (NSCLC) progression. The deubiquitinating enzyme ubiquitin-specific peptidase 15 (USP15) has been identified as an important factor in oncogenesis and a potential therapeutic target. However, the expression profile and function of USP15 in NSCLC remain elusive. In the present study, we investigated the expression pattern and the potential biological functions of USP15 in NSCLC both in cells and animal models. Our data revealed that USP15 was highly expressed in NSCLC tissues and cells compared with normal counterpart. We subsequently knocked down USP15 expression in two NSCLC cell lines, which significantly suppressed cell proliferation. In addition, knocking down USP15 expression reduced NSCLC cell migration and invasion according to the results from Matrigel-Transwell analysis. NSCLC animal model results showed that USP15 knockdown also reduced NSCLC size. Biochemical analysis revealed that USP15 knockdown inhibited matrix metalloproteinase (MMP)3 and MMP9 expression. Furthermore, high levels of USP15 and MMP3 expression were associated with poor prognosis in NSCLC. In conclusion, the results from the present study suggest that the high expression of USP15 promotes NSCLC tumorigenesis. Therefore, it is proposed that USP15 and MMPs may represent novel biomarkers for NSCLC progression and prognosis.

Hypofractionated Radiotherapy in Combination With Chemotherapy Improves Outcome of Patients With Esophageal Carcinoma Tracheoesophageal Groove Lymph Node Metastasis.

This study investigated the efficiency and safety of hypofractionated radiotherapy (HFR) combined with paclitaxel chemotherapy for the treatment of postsurgery tracheoesophageal groove lymph node (TGLN) metastasis in patients with esophageal cancer (EC). Fifty-three EC patients with TGLN metastasis after surgery admitted to the Yancheng Third People's Hospital from January 2013 to June 2015 were included in this study. They were randomly divided into the HFR group (n = 25) and conventional fractioned radiotherapy (CFR) group (n = 28) based on the random grouping method. Patients in the HFR group received treatment with radiation of 60 Gy (5 fractions per week, total 20 fractions) combined with paclitaxel chemotherapy at a dose of 50 mg once per week for 4 weeks. Patients in the CFR group received radiation of 60 Gy (5 fractions per week, total 30 fractions) combined with paclitaxel chemotherapy at a dose of 50 mg once per week for 6 weeks. The adverse events and treatment outcomes in these two groups were analyzed. It was found that there was no significant difference in the incidence of radiation esophagitis in the HFR group compared with that of the CFR group (grades 3-4, 44.0 vs. 25.0%; P = 0.149). There was no statistical difference in the incidence of radiation pneumonitis between these two groups (grades 3-4, 16.0 vs. 7.1%; P = 0.314). No statistical difference was noticed in complete response (CR), partial response (PR), and no response (NR) between these two groups. The median overall survival (OS) in the HRF group was significantly longer compared with that of the CRF group (24.2 months (95% CI, 16.2-32.1 months) vs. 11.8 months (95% CI, 9.2-14.4 months); P = 0.024). Our results indicated that the combination of HFR and chemotherapy improved the prognosis of EC patients with TGLN metastasis with no increased adverse events.

Integrin-Linked Kinase Is Involved In the Proliferation and Invasion of Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is an aggressive type of cancer with high mortality rate in China, largely due to its high invasive and metastatic potential. The purposes of this study are to investigate the potential molecular mechanisms behind the aggressive nature of ESCC and search for new prognostic biomarkers. By employing the quantitative proteomic based strategy, we compared the proteomic profile between three ESCC samples and paired adjacent tissues. After bioinformatics analysis, four candidate proteins were validated in thirteen paired patient samples. Further validation of the key candidate, integrin-linked kinase (ILK), was carried out in one hundred patient samples. The specific inhibitor compound 22 (cpd22) was used to assess the influence of ILK to ESCC cell motility and invasiveness by applying wound-healing and transwell assay. Western blot analysis was performed to elucidate the signaling pathways involved in ILK-mediated ESCC invasion. Total 236 proteins were identified by proteomic analysis. Bioinformatics analysis suggested a key role of the collagen/integrin/ILK signaling pathway during ESCC progression. Further validation indicated that ILK is overexpressed in ESCC tissues and is correlated with poor patient prognosis. Inhibition of ILK kinase activity suppresses proliferation and blocks invasion and migration of ESCC cells. Signaling pathway analysis revealed that ILK regulates AKT phosphorylation on Ser473 but not GSK-3ß on Ser9 to promote proliferation and motility of ESCC cells. In conclusion, our results indicated that ILK may play a crucial role in ESCC invasion and metastasis and may serve as a prognostic biomarker and therapeutic target for ESCC.

Cardioprotection by exenatide: A novel mechanism via improving mitochondrial function involving the GLP-1 receptor/cAMP/PKA pathway.

Accumulating evidence suggests that glucagon-like peptide-1 (GLP-1) and its analogues exert cardioprotective effects via modulating cardiomyocyte metabolism. Mitochondria play a pivotal role in the regulation of cell metabolism. It was hypothesized that treatment with exenatide, a GLP-1 analogue, may exert cardioprotective effects by improving mitochondrial function in an in vitro model of hypoxia/reoxygenation (H/R). H9c2 cells were employed to establish an in vitro model of H/R. Exenatide was added to the cells for 30 min prior to exposure to hypoxia. The GLP-1 receptor antagonist exendin­(9­39), the cyclic adenosine monophosphate (cAMP) inhibitor Rp-cAMPS and the protein kinase A (PKA) inhibitor H-89 were added to the cells for 10 min prior to treatment with exenatide. The release of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) and cardiomyocyte apoptosis were evaluated. The characteristics of mitochondrial morphology and functions, including ATP synthesis, membrane potential (ΔΨm), mitochondrial permeability transition pore (mPTP), mitochondrial ATPase activity and oxidative stress, were determined. the mitochondrial uncoupling protein-3 (UCP-3) and nuclear respiratory factor-1 (Nrf-1) were also investigated by western blot analysis. Exenatide pretreatment significantly decreased LDH and CK-MB release and cardiomyocyte apoptosis in H9c2 cells subjected to H/R. More importantly, to the best of our knowledge, this is the first report of exenatide pretreatment decreasing mitochondrial abnormalities and reducing oxidative stress, while enhancing ATP synthesis, mitochondrial ATPase activity and ΔΨm in H9c2 cells subjected to H/R. Exenatide pretreatment also decreased mitochondrial calcium overload and inhibited the opening of mPTP in H9c2 cells subjected to H/R. Furthermore, exenatide pretreatment upregulated UCP-3 and Nrf-1 expression in H9c2 cells subjected to H/R. However, the abovementioned observed effects of exenatide were all abolished when exenatide was co-administered with exendin­(9­39), Rp-cAMPS and̸or H-89. Therefore, the GLP-1 analogue exenatide was found to exert cardioprotective effects in an in vitro model of H/R, and this cardioprotection may be attributed to the improvement of mitochondrial function. These effects are most likely associated with the activation of the GLP-1 receptor/cAMP/PKA signaling pathway.

Nomogram Based on Systemic Immune-Inflammation Index to Predict Overall Survival in Gastric Cancer Patients.

BACKGROUND: The systemic immune-inflammation index (SII), based on peripheral lymphocytes, neutrophils, and platelet count, has been used as a prognostic marker for several tumors. However, use of the SII has not been reported for gastric cancer. METHODS: We evaluated the prognostic value of the SII in primary and validation cohorts. We also established an effective prognostic nomogram for gastric cancer based on R language. The predictive accuracy and discriminative ability of the nomogram were determined using the concordance index (C index) and a calibration curve and were compared with TNM classifications. RESULTS: The Kaplan-Meier survival analysis results showed that the high SII was associated with poor prognosis of gastric cancer patients in the primary and validation cohorts. SII proved to be related to tumor location, histological grade, tumor size, TNM stage, and perineural infiltration in patients with gastric cancer and was an independent prognostic factor for patients with gastric cancer. SII has a better predictive ability than other existing prognostic indexes based on inflammation, such as NLR, PLR, and MLR. The nomogram established can accurately predict the 3- and 5-year survival rates of patients with gastric cancer after operation, and its accuracy is significantly higher than that of the 8th edition of the AJCC staging system. CONCLUSION: SII can independently predict the overall survival of patients with gastric cancer after operation, which is superior to the existing systemic inflammatory indexes. The prognostic nomogram based on SII is a reliable model for predicting the postoperative survival of patients with gastric cancer.

Development and validation of nomogram based on lncRNA ZFAS1 for predicting survival in lymph node-negative esophageal squamous cell carcinoma patients.

BACKGROUND: There is increasing evidence of a relationship between long non-coding RNA (lncRNA) and cancer. This study aimed to examine the prognostic value of the lncRNA ZFAS1 in esophageal squamous cell carcinoma (ESCC). RESULTS: The results showed that ZFAS1 expression was significantly higher in ESCC tissues compared with the corresponding adjacent normal tissues (P < 0.001). ESCC patients with high ZFAS1 expression had a poor overall survival (OS). Histological grade, T stage and ZFAS1 expression were integrated to develop the nomogram. The nomogram showed a significantly better prediction of OS for patients with lymph node-negative ESCC. The ROC curve also showed higher specificity and sensitivity for predicting 3- and 5-year ESCC patient survival compared with the AJCC staging system. The decision curve analysis also indicated a greater potential for the nomogram in clinical application compared with the AJCC staging system. Importantly, our findings were supported by a validation cohort. MATERIALS AND METHODS: We retrospectively investigated 398 lymph node-negative ESCC patients. Data from the primary cohort (n = 246) were used to develop a multivariate nomogram. The nomogram was internally validated for discrimination and calibration with bootstrap samples and was externally validated with an independent patient cohort (n = 152). CONCLUSIONS: Our proposed nomogram, which integrates clinicopathological factors and ZFAS1 expression, can accurately predict the prognosis of lymph node-negative ESCC patients without preoperative chemoradiotherapy.

Geniposide Prevents Hypoxia/Reoxygenation-Induced Apoptosis in H9c2 Cells: Improvement of Mitochondrial Dysfunction and Activation of GLP-1R and the PI3K/AKT Signaling Pathway.

BACKGROUND/AIMS: Myocardial ischemia/reperfusion injury is a major cause of morbidity and mortality associated with coronary heart disease. Many studies have demonstrated that natural products are promising chemotherapeutic drugs counteracting the loss of cardiomyocytes. Thus, the purpose of the present study was to investigate the effects of geniposide, a traditional Chinese herb extract from Gardenia jasminoides J. Ellis, on cardiomyocyte apoptosis induced by hypoxia/reoxygenation (H/R) in H9c2 cells, and their underlying mechanisms. METHODS: Cell viability and apoptosis ratio were assessed using the cell counting kit-8 assay and Annexin V/propidium iodide (PI) staining. The concentrations of lactate dehydrogenase (LDH), intracellular total superoxide dismutase (T-SOD), and malondialdehyde (MDA) were detected by microplate reader. The production of reactive oxygen species/reactive nitrogen species (ROS/RNS), the level of mitochondrial calcium, and mitochondrial membrane potential depolarization were measured by confocal laser scanning microscopy. Mitochondrial morphology was visualized using transmission electron microscopy. The expressions of Bcl-2 mRNA and Caspase-3 mRNA were measured by reverse transcription-polymerase chain reaction (RT-PCR). The protein levels of cleaved caspase-3, Bcl-2, Bax, AKT, p-AKTserine473, cytochrome-c were detected by western bloting. RESULTS: Geniposide pretreatment increased cell viability, decreased LDH levels in the supernatant, and inhibited cardiomyocyte apoptosis caused by H/R. Furthermore, geniposide reversed mitochondrial dysfunction by decreasing oxidative stress products (ROS/RNS and MDA), increasing anti-oxidative enzyme (T-SOD) level, improving mitochondrial morphology, attenuating mitochondrial calcium overload and blunting depolarization of mitochondrial membrane. Moreover, geniposide pretreatment increased Bcl-2 level and decreased Bax level, thus enhancing the Bcl-2/Bax ratio. Consistent with the above result, Bcl-2 mRNA expression was upregulated and caspase-3 mRNA expression was downregulated by geniposide. In addition, geniposide decreased the protein expression of cleaved caspase-3 and cytochrome-c and increased the level p-AKTserine473. The protective effects of geniposide were partially reversed by glucagon-like pepitide-1 receptor antagonist exendin-(9-39) and the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002. CONCLUSIONS: Our results suggest that geniposide pretreatment inhibits H/R-induced myocardial apoptosis by reversing mitochondrial dysfunction, an effect in part due to activation of GLP-1R and PI3K/AKT signaling pathway.

Radiosensitization of Non-Small Cell Lung Cancer Cells by Inhibition of TGF-ß1 Signaling With SB431542 Is Dependent on p53 Status.

Although medically inoperable patients with stage I non-small cell lung cancer cells (NSCLC) are often treated with stereotactic body radiation therapy, its efficacy can be compromised due to poor radiosensitivity of cancer cells. Inhibition of transforming growth factor-ß1 (TGF-ß1) using LY364947 and LY2109761 has been demonstrated to radiosensitize cancer cells such as breast cancer, glioblastoma, and lung cancer. Our previous results have demonstrated that another potent and selective inhibitor of TGF-ß1 receptor kinases, SB431542, could radiosensitize H460 cells both in vitro and in vivo. In the present study, we investigated whether SB431542 could radiosensitize other NSCLC cell lines, trying to explore the potential implication of this TGF-ß1 inhibitor in radiotherapy for NSCLC patients. The results showed that A549 cells were significantly radiosensitized by SB431542, whereas no radiosensitizing effect was observed in H1299 cells. Interestingly, both H460 and A549 cells have wild-type p53, while H1299 cells have deficient p53. To study whether the radiosensitizing effect of SB431542 was associated with p53 status of cancer cells, the p53 of H460 cells was silenced using shRNA transfection. Then it was found that the radiosensitizing effect of SB431542 on H460 cells was not observed in H460 cells with silenced p53. Moreover, X-irradiation caused rapid Smad2 activation in H460 and A549 cells but not in H1299 and H460 cells with silenced p53. The Smad2 activation postirradiation could be abolished by SB431542. This may explain the lack of radiosensitizing effect of SB431542 in H1299 and H460 cells with silenced p53. Thus, we concluded that the radiosensitizing effect of inhibition of TGF-ß1 signaling in NSCLC cells by SB431542 was p53 dependent, suggesting that using TGF-ß1 inhibitor in radiotherapy may be more complicated than previously thought and may need further investigation.

[Assess correlation between bleb morphology at long-term intraocular pressure effect in primary angle-closure glaucoma following trabeculectomy].

OBJECTIVE: To evaluate the correlation between morphologic appearance of blebs at 3 month and long-term intraocular pressure (IOP) effect in patients with primary angle-closure glaucoma (PACG) after trabeculectomy. METHODS: Multi-centered cases series. Data were collected from 176 patients aged ≥ 40 years with PACG who were participated in a randomized clinical trial that aimed at addressing the efficacy of augmented releasable sutures after trabeculectomy. The bleb morphology was graded using the Modified Indian Bleb Appearance Grading Scale (IBAGS) based on standard photos at 3 month after trabeculectomy. IOPs were measured with Goldmann applanation tonometer. The correlation between bleb components and other selected testing influencing factors and long-term IOP was tested by linear Logistic regression analysis. RESULTS: 150 patients (85.7%) completed 18 months of follow up. IOP was (15.6 ± 5.4) mm Hg at 18 month of post-operation. 135 eyes had an IOP ≤ 21 mm Hg without additional medications, 10 eyes ≥ 21 mm Hg, and the remaining 5 eyes required one or two medications to maintain normal IOP. Using IBAGS system, bleb was graded in 142 eyes as follows: H(0) in 3 eyes, H(1) in 45 eyes, H(2) in 90 eyes, and H(3) in 4 eyes, while V(0) was observed in 66 eyes, V(1-3) in 76 eyes. IOP at 18 months in bleb with microcysts was 2.77 mm Hg lower (ß = -2.77, 95%CI = -0.46 to -5.08) than those without microcysts and in bleb with non-vascular was 2.07 mm Hg lower (ß = -2.07, 95%CI = -0.15 to -3.98) than those with vascular at 3 months after surgery. IOP was significantly (ß = -1.20, 95%CI: -0.00 to -2.40) decreased by 1.2 mm Hg with 10 years of age increase (P < 0.05). CONCLUSIONS: Early filtering bleb with microcysts, vascular, and age are identified as important factors to predict long-term IOP effect in patients with PACG after trabeculectomy but not early morphological appearance of filtering bleb.

[Long-term follow-up study on Hunan aqueous drainage implantation combined with mitomycin C for refractory glaucoma].

PURPOSE: To investigate the long-term therapeutic effect of Hunan aqueous drainage (HAD) implantation with and without adjunctive intraoperative mitomycin C (MMC) for refractory glaucoma. METHODS: 154 cases (159 eyes) with refractory glaucoma underwent Hunan aqueous drainage (HAD) implantation from July 1995 to July 2001. Sixty-five eyes were combined with MMC (0.4 mg/ml, 1 to 5 mins). With success defined as the introcular pressure (IOP) greater than 6 mmHg but no greater than 21 mmHg at the last visit. RESULTS: The mean period of postoperative follow-up was 54.6 (range, 12-72) months. The IOP was lowered from preoperative (46.8 +/- 14.5) mmHg to postoperative (16.8 +/- 11.3) mmHg at the 1st year after surgery. The success rate with MMC and without MMC were 90.0%, 77.3% (P < 0.05) at the 1st year, 87.1%, 67.3% (P < 0.05) at the 2nd year, 83.3%, 61.1% (P < 0.05) at the 3rd year, 81.3%, 56.7% (P < 0.05) at the 4th year, and 75.0%, 50.0% (P < 0.05) at the 5th year using Kaplan-Meier life-table analysis. The height of the posterior bleb underwent standardized ocular echography at the 1st year was (3.8 +/- 0.9) mm and (2.1 +/- 1.4) mm, respectively. Ninty-five eyes (81.9%) with visual acuity remained or improved after the surgery (P > 0.05). The most frequent complications for long-term follow-up included elevated IOP (IOP > 22 mmHg) (19.8%), the iris adherent to the proximal orifice of the tube (15.5%), developed cataract formation (12.9%) and so on (P > 0.05). We didn't find any severe complications after using MMC. CONCLUSION: This study suggests that HAD implantation is an effective method in the management of refractory glaucoma in spite of its unneligible complications and combined with MMC can improve the prognosis.