Identification and immunological characteristics of anoikis-associated molecular clusters in lung adenocarcinoma.

Anoikis plays a crucial role in the progression, prognosis, and immune response of lung adenocarcinoma (LUAD). However, its specific impact on LUAD remains unclear. In this study, we investigated the intricate interplay of nesting apoptotic factors in LUAD. By analyzing nine key nesting apoptotic factors, we categorized LUAD patients into two distinct clusters. Further examination of immune cell profiles revealed that Cluster A exhibited greater infiltration of innate immune cells than did Cluster B. Additionally, we identified two genes closely associated with prognosis and developed a predictive model to differentiate patients based on molecular clusters. Our findings suggest that the loss of specific anoikis-related genes could significantly influence the prognosis, tumor microenvironment, and clinical features of LUAD patients. Furthermore, we validated the expression and functional roles of two pivotal prognostic genes, solute carrier family 2 member 1 (SLC2A1) and sphingosine kinase 1 (SPHK1), in regulating tumor cell viability, migration, apoptosis, and anoikis. These results offer valuable insights for future mechanistic investigations. In conclusion, this study provides new avenues for advancing our understanding of LUAD, improving prognostic assessments, and developing more effective immunotherapy strategies.

Ectopic Expression of TIGIT in Lung Adenocarcinoma and Its Clinical Significance.

This study aimed to investigate the T cell immunoreceptor with ITIM and Ig domains (TIGIT) expression in lung adenocarcinoma (LUAD). TIGIT expression was measured by western blot, reverse transcription quantitative polymerase chain reaction. Seventy-two paired surgical specimens were collected from patients with stage I-IV LUAD. The expression of TIGIT in surgical specimens was determined using immunohistochemistry. TIGIT was overexpressed in LUAD tissues. Moreover, overexpressed TIGIT was significantly associated with advanced clinical staging, lymph node metastasis, distant metastasis, and TP53 mutations in LUAD. Moreover, high expression of TIGIT was negatively correlated with purity of CD4+ T cells. High rations of TIGIT+CD4+ T cells predicted poor overall survival of LUAD patients. Additionally, high ratios of TIGIT+CD4+ T cells is closely related to CD4+ T cell depletion. Taken together, TIGIT was overexpressed in LUAD patients. High levels of TIGIT induced the alteration of CD4+ T cell based immunomodulation and predicted poor prognosis of LUAD patients. Therefore, TIGIT can be potential biomarker for LUAD.

NLK interacts with 14­3­3ζ to restore the expression of E­cadherin.

The Nemo­like kinase (NLK), a conserved serine/threonine kinase, plays a critical role in the regulation of a variety of transcription factors, with important roles in determining cell fate. Although recent studies have demonstrated decreased expression patterns of NLK in various types of human cancer, the functional mechanism of NLK in cancer development has not been elucidated. Here, in the present study overexpression of NLK was found to inhibit the growth and migration of the non­small cell lung cancer A549 cell line. NLK was subsequently found to interact with 14­3­3ζ (also known as YWHAZ), which is responsible for E­cadherin silencing during epithelial­mesenchymal transition (EMT). Furthermore, NLK overexpression was able to restore the expression of E­cadherin inhibited by 14­3­3ζ. Notably, NLK interacts with 14­3­3ζ and prevents its dimerization, which is essential for 14­3­3ζ stability and function. By fusing two copies of the 14­3­3ζ gene, via a Gly­rich linker, a non­dissociable dimer of 14­3­3ζ was formed. It was found that NLK was unable to restore the expression of E­cadherin inhibited by the overexpression of the fused dimer of 14­3­3ζ. In addition, the increased ability of migration induced by the overexpression of fused 14­3­3ζ dimer could not be altered by NLK overexpression. The results from the present study indicate that NLK is a negative regulator of 14­3­3ζ and plays a tumor suppressive role in the inhibition of cancer cell migration.

Pretreatment C-reactive protein to albumin ratio for predicting overall survival in advanced pancreatic cancer patients.

Although previous studies demonstrated that elevated C-reactive protein to albumin ratio (CAR) predicted poor prognosis in various solid tumors, little was known about the prognostic value of CAR in patients with advanced pancreatic cancer (APC). The aim of the present study was to assess CAR as one independent prognostic factor in predicting overall survival (OS) in APC patients who had received palliative chemotherapy. Data of 142 APC patients who received palliative chemotherapy between 2009 and 2014 were retrospectively documented. We classified the patients into two groups based on the optimal cutoff value of CAR identified by generating receiver operating characteristics (ROC) curve. The clinicopathological parameters were compared between two CAR groups. Pearson correlation test showed that the level of C-reactive protein (CRP) was inversely correlated with albumin (r = -0.387; P < 0.001). Kaplan-Meier analysis demonstrated overall survival (OS) was significantly longer in CAR < 0.156 group than CAR ≥ 0.156 group (11.2 vs 5.9 months, P < 0.001). CAR was an independent prognostic factor for OS in the Cox regression model (HR, 1.623; 95% CI, 1.093-2.410; P = 0.016). Furthermore, the discrimination ability of CAR (AUC = 0.648, P = 0.025) was slightly higher than that of other inflammation-based factors. Therefore, pretreatment CAR could be an independent prognostic biomarker for APC patients.

T-screen and yeast assay for the detection of the thyroid-disrupting activities of cadmium, mercury, and zinc.

In the present study, a two-hybrid yeast bioassay and a T-screen were used to screen for the thyroid receptor (TR)-disrupting activity of select metallic compounds (CdCl2, ZnCl2, HgCl2, CuSO4, MnSO4, and MgSO4). The results reveal that none of the tested metallic compounds showed TR-agonistic activity, whereas ZnCl2, HgCl2, and CdCl2 demonstrated TR antagonism. For the yeast assay, the dose-response relationship of these metallic compounds was established, and the concentrations producing 20 % of the maximum effect of ZnCl2, HgCl2, and CdCl2 were 9.1 × 10(-5), 3.2 × 10(-6), and 1.2 × 10(-6) mol/L, respectively. The T-screen also supported the finding that ZnCl2, HgCl2, and CdCl2 decreased the cell proliferation at concentrations ranging from 10(-6) to 10(-4) mol/L. Furthermore, the thyroid-disrupting activity of metallic compounds in environmental water samples collected from the Guanting Reservoir, Beijing, China was evaluated. Solid-phase extraction was used to separate the organic extracts, and a modified two-hybrid yeast bioassay revealed that the metallic compounds in the water samples could affect thyroid hormone-induced signaling by decreasing the binding of the thyroid hormone. The addition of ethylenediaminetetraacetic acid (30 mg/L) could eliminate the effects. Thus, the cause(s) of the thyroid toxicity in the water samples appeared to be partly related to the metallic compounds.

The Joint Effects of Lifestyle Factors and Comorbidities on the Risk of Colorectal Cancer: A Large Chinese Retrospective Case-Control Study.

BACKGROUND: Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality. In previous epidemiologic studies, the respective correlation between lifestyle factors and comorbidity and CRC has been extensively studied. However, little is known about their joint effects on CRC. METHODS: We conducted a retrospective case-control study of 1,144 diagnosed CRC patients and 60,549 community controls. A structured questionnaire was administered to the participants about their socio-demographic factors, anthropometric measures, comorbidity history and lifestyle factors. Logistic regression model was used to calculate the odds ratio (ORs) and 95% confidence intervals (95%CIs) for each factor. According to the results from logistic regression model, we further developed healthy lifestyle index (HLI) and comorbidity history index (CHI) to investigate their independent and joint effects on CRC risk. RESULTS: Four lifestyle factors (including physical activities, sleep, red meat and vegetable consumption) and four types of comorbidity (including diabetes, hyperlipidemia, history of inflammatory bowel disease and polyps) were found to be independently associated with the risk of CRC in multivariant logistic regression model. Intriguingly, their combined pattern- HLI and CHI demonstrated significant correlation with CRC risk independently (ORHLI: 3.91, 95%CI: 3.13-4.88; ORCHI: 2.49, 95%CI: 2.11-2.93) and jointly (OR: 10.33, 95%CI: 6.59-16.18). CONCLUSIONS: There are synergistic effects of lifestyle factors and comorbidity on the risk of colorectal cancer in the Chinese population.

Thyroid hormone disrupting activities of sediment from the Guanting Reservoir, Beijing, China.

In the present study, yeast bioassays were used to evaluate and characterize the thyroid receptor (TR) disrupting activities of the organic extracts and elutriates of the sediments from the Guanting Reservoir, Beijing, China. An accelerated solvent extraction was used to separate the organic extracts, which were subjected to a yeast bioassay. The organic extracts could affect thyroid hormone signaling by decreasing the binding of the thyroid hormone. The TR antagonistic activity equivalents (TEQbio) referring to amiodarone hydrochloride were calculated and the observed TEQbio-organic extracts ranged from 25.4 ± 3.7 to 176.9 ± 18.0 µg/g. Elutriate toxicity tests using the modified yeast bioassay revealed that the elutriates also significantly antagonized the TR, with the TEQbio-elutriates ranging from N.D. to 7.8 ± 0.8 µg/L. To characterize the toxic compounds, elutriates were extracted by using a C18 cartridge or treated with ethylenediaminetetraacetic acid (EDTA, 30 mg/L). The results suggested that the addition of EDTA eliminated over 74.3% of the total effects, and the chemical analysis revealed that heavy metals, some of which exhibited TR disrupting potency, for example Zn and Cd, were detectable with higher concentrations in the elutriates. Thus, the cause(s) of toxicity in the elutriate appear to be partly related to the heavy metals.

Identification of thyroid-receptor antagonists in water from the Guanting Reservoir, Beijing, China.

Thyroid hormone (TH) has long been known to be essential for normal brain development in both humans and animals, and increasing evidence suggests that environmental components may disrupt TH signaling. In the present study, two-hybrid yeast bioassay and chemical analysis were used to evaluate and identify thyroid-receptor (TR) disruptors in water from the Guanting Reservoir, Beijing, China. Modified yeast bioassay showed that the water samples could affect TH signaling. The bioassay-derived amiodarone hydrochloride equivalents ranged from 33.8 ± 3.3 to 308.5 ± 31.8 µg/L. Solid-phase extraction was used to separate the organic extracts, which were subjected to bioassay and chemical analysis. The organic extracts significantly antagonized the TR, which accounted for >86.0 % of the total effects. Thus, organic extracts may play a major role in the TR-disruption activity of the water. Phenols, organochlorine pesticides, and phthalate esters were detected in the organic extracts. Chemical analysis and toxic-equivalent calculation showed that a major cause of the TR antagonism of the water was dibutyl phthalate (80.1 to 122.7 %).

A yeast bioassay for direct measurement of thyroid hormone disrupting effects in water without sample extraction, concentration, or sterilization.

The present study introduces an improved yeast bioassay for rapid yet sensitive evaluation of thyroid hormone disruption at the level of thyroid receptor (TR) in environmental water samples. This assay does not require water sample preparation and thus requires very little hands-on time. Based on different ß-galactosidase substrates, two modified bioassays, a colorimetric bioassay and a chemiluminescent bioassay, were developed. The compounds tested included the known thyroid hormone 3,3',5-triiodo-l-thyronine (T3), the specific TR antagonist amiodarone hydrochloride (AH) and phthalate esters (PAEs), which potentially disrupt thyroid hormone signaling. The EC50 values for T3 were similar to those previously obtained using a 96-well plate bioassay. TR antagonism by AH was studied in the presence of 2.5 × 10(-7)M T3, and the concentration producing 20% of the maximum effect (RIC20) for AH was 3.1 × 10(-7)M and 7.8 × 10(-9)M for the colorimetric bioassay and chemiluminescent bioassay, respectively. None of the tested PAEs induced ß-galactosidase expression, but diethylhexyl phthalate, benzyl butyl phthalate and dibutyl phthalate demonstrated TR antagonism. Furthermore, water samples collected from Guanting reservoir in Beijing were evaluated. Although TR agonism was not observed, antagonism was detected in all water samples and is expressed as AH equivalents. The toxicology equivalent quantity values obtained by the chemiluminescent bioassay ranged from 21.2 ± 1.6 to 313.9 ± 28.8 µg L(-1) AH, and similar values were obtained for the colorimetric bioassay. The present study shows that the modified yeast bioassay can be used as a valuable tool for quantification of thyroid hormone disrupting effects in environmental water samples.