A novel model for predicting deep-seated candidiasis due to Candida glabrata among cancer patients: A 6-year study in a cancer center of China.

Followed by Candida albicans, Candida glabrata ranks as the second major species contributing to invasive candidiasis. Given the higher medical burden and lower susceptibility to azoles in C. glabrata infections, identifying these infections is critical. From 2016 to 2021, patients with deep-seated candidiasis due to C. glabrata and non-glabrata Candida met the criteria to be enrolled in the study. Clinical data were randomly divided into training and validation cohorts. A predictive model and nomogram were constructed using R software based on the stepwise algorithm and logistic regression. The performance of the model was assessed by the area under the receiver operating characteristic curve and decision curve analysis (DCA). A total of 197 patients were included in the study, 134 of them infected with non-glabrata Candida and 63 with C. glabrata. The predictive model for C. glabrata infection consisted of gastrointestinal cancer, co-infected with bacteria, diabetes mellitus, and kidney dysfunction. The specificity was 84.1% and the sensitivity was 61.5% in the validation cohort when the cutoff value was set to the same as the training cohort. Based on the model, treatment for patients with a high-risk threshold was better than 'treatment for all' in DCA, while opting low-risk patients out of treatment was also better than 'treatment for none' in opt-out DCA. The predictive model provides a rapid method for judging the probability of infections due to C. glabrata and will be of benefit to clinicians making decisions about therapy strategies.

Enhancing prognostic prediction of invasive candidiasis among cancer patients with a serum C5a-based scoring model.

PURPOSE: Invasive candidiasis poses a life-threatening risk, and early prognosis assessment is vital for timely interventions to reduce mortality. Serum C5a levels have recently been linked to prognosis, but confirmation in cancer patients is pending. METHODS: We detected the concentrations of serum C5a in hospitalized cancer patients with invasive candidiasis from 2020 to 2023, and retrospectively analyzed the clinical data. RESULTS: 372 cases were included in this study, with a 90-day mortality rate of 21.8%. Candida albicans (48.7%) remained the predominant pathogen, followed by Candida glabrata (25.5%), Candida tropicalis (12.4%), and Candida parapsilosis (8.3%). Gastrointestinal cancer was the most diagnosed pathology type (37.6%). Serum C5a demonstrated a noteworthy correlation with 90-day mortality, and employing a cutoff value of 36.7 ng/ml revealed significantly higher 90-day mortality in low-C5a patients (41.2%) compared to high-C5a patients (6.3%) (p < 0.001). We also identified no source control, no surgery, metastasis, or chronic renal failure independently correlated with the 90-day mortality. Based on this, a prognostic model combining C5a and clinical parameters was constructed, which performed better than models built solely on C5a or clinical parameters. Furthermore, we weighted scores to each parameter in the model and presented diagnostic sensitivity and specificity corresponding to different score points calculated by the model. CONCLUSION: We constructed a prognostic scoring model including serum C5a and clinical parameters, which would contribute to precise prognosis assessment and benefit the outcome among cancer patients.

Assessing the effect of scanning parameter on the size and density of pulmonary nodules: a phantom study.

BACKGROUND: Lung cancer remains a leading cause of death among cancer patients. Computed tomography (CT) plays a key role in lung cancer screening. Previous studies have not adequately quantified the effect of scanning protocols on the detected tumor size. The aim of this study was to assess the effect of various CT scanning parameters on tumor size and densitometry based on a phantom study and to investigate the optimal energy and mA image quality for screening assessment. METHODS: We proposed a new model using the LUNGMAN N1 phantom multipurpose anthropomorphic chest phantom (diameters: 8, 10, and 12 mm; CT values: - 100, - 630, and - 800 HU) to evaluate the influence of changes in tube voltage and tube current on the size and density of pulmonary nodules. In the LUNGMAN N1 model, three types of simulated lung nodules representing solid tumors of different sizes were used. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were used to evaluate the image quality of each scanning combination. The consistency between the calculated results based on segmentation from two physicists was evaluated using the interclass correlation coefficient (ICC). RESULTS: In terms of nodule size, the longest diameters of ground-glass nodules (GGNs) were closest to the ground truth on the images measured at 100 kVp tube voltage, and the longest diameters of solid nodules were closest to the ground truth on the images measured at 80 kVp tube voltage. In respect to density, the CT values of GGNs and solid nodules were closest to the ground truth when measured at 80 kVp and 100 kVp tube voltage, respectively. The overall agreement demonstrates that the measurements were consistent between the two physicists. CONCLUSIONS: Our proposed model demonstrated that a combination of 80 kVp and 140 mA scans was preferred for measuring the size of the solid nodules, and a combination of 100 kVp and 100 mA scans was preferred for measuring the size of the GGNs when performing lung cancer screening. The CT values at 80 kVp and 100 kVp were preferred for the measurement of GGNs and solid nodules, respectively, which were closest to the true CT values of the nodules. Therefore, the combination of scanning parameters should be selected for different types of nodules to obtain more accurate nodal data.

A TTP-incorporated scoring model for predicting mortality of solid tumor patients with bloodstream infection caused by Escherichia coli.

BACKGROUND: Few mortality-scoring models are available for solid tumor patients who are predisposed to develop Escherichia coli-caused bloodstream infection (ECBSI). We aimed to develop a mortality-scoring model by using information from blood culture time to positivity (TTP) and other clinical variables. METHODS: A cohort of solid tumor patients who were admitted to hospital with ECBSI and received empirical antimicrobial therapy was enrolled. Survivors and non-survivors were compared to identify the risk factors of in-hospital mortality. Univariable and multivariable regression analyses were adopted to identify the mortality-associated predictors. Risk scores were assigned by weighting the regression coefficients with corresponding natural logarithm of the odds ratio for each predictor. RESULTS: Solid tumor patients with ECBSI were distributed in the development and validation groups, respectively. Six mortality-associated predictors were identified and included in the scoring model: acute respiratory distress (ARDS), TTP ≤ 8 h, inappropriate antibiotic therapy, blood transfusion, fever ≥ 39 °C, and metastasis. Prognostic scores were categorized into three groups that predicted mortality: low risk (< 10% mortality, 0-1 points), medium risk (10-20% mortality, 2 points), and high risk (> 20% mortality, ≥ 3 points). The TTP-incorporated scoring model showed excellent discrimination and calibration for both groups, with AUC being 0.833 vs 0.844, respectively, and no significant difference in the Hosmer-Lemeshow test (6.709, P = 0.48) and the chi-square test (6.993, P = 0.46). Youden index showed the best cutoff value of ≥ 3 with 76.11% sensitivity and 79.29% specificity. TTP-incorporated scoring model had higher AUC than no TTP-incorporated model (0.837 vs 0.817, P < 0.01). CONCLUSIONS: Our TTP-incorporated scoring model was associated with improving capability in predicting ECBSI-related mortality. It can be a practical tool for clinicians to identify and manage bacteremic solid tumor patients with high risk of mortality.

Clinical Analysis of Bloodstream Infection of Escherichia coli in Patients with Pancreatic Cancer from 2011 to 2019.

Background: Pancreatic cancer patients were particularly predisposed to develop Escherichia coli (E. coli) bloodstream infection (BSI); however, little information is currently available. We set out to find E. coli BSI's risk factors in pancreatic cancer to provide valuable experience. Methods: We retrospectively analyzed the clinical data of pancreatic cancer patients (31 cases with E. coli BSI and 93 cases without BSI) by a case-control study. SPSS 17.0 was adopted to perform univariate and multivariate analyses. Bacterial resistance analysis was performed by Whonet 5.6. Results: Hospitalization days ≥7 days, number of admissions ≥2 times, surgery, chemotherapy, the type of antibiotics used ≥2 species, albumin<40.0 g/L, and prealbumin < 0.2 g/L were the potential risk factors for pancreatic cancer patients with E. coli BSI (P < 0.1). Multivariate logistic regression showed hospitalization days ≥7 days (OR = 11.196, 95% CI = 0.024-0.333, P < 0.001), surgery (OR = 32.053, 95% CI = 0.007-0.137, P < 0.001), and chemotherapy (OR = 6.174, 95% CI = 0.038-0.688, P=0.014) were the independent risk factors for E. coli BSI of pancreatic cancer patients. E. coli resistant to carbapenems was rare; they were susceptible to cephamycin and piperacillin/tazobactam. The 90-day mortality rate of the infected group was significantly higher than the control group (41.9% versus 8.6%, P < 0.001). Conclusions: Hospitalization days ≥7 days, surgery, and chemotherapy are the independent risk factors for E. coli BSI of pancreatic cancer patients, which allows us to identify patients at potential risk and perform preventive treatment in time.

A predictive nomogram for mortality of cancer patients with invasive candidiasis: a 10-year study in a cancer center of North China.

BACKGROUND: Invasive candidiasis is the most common fungal disease among hospitalized patients and continues to be a major cause of mortality. Risk factors for mortality have been studied previously but rarely developed into a predictive nomogram, especially for cancer patients. We constructed a nomogram for mortality prediction based on a retrospective review of 10 years of data for cancer patients with invasive candidiasis. METHODS: Clinical data for cancer patients with invasive candidiasis during the period of 2010-2019 were studied; the cases were randomly divided into training and validation cohorts. Variables in the training cohort were subjected to a predictive nomogram based on multivariate logistic regression analysis and a stepwise algorithm. We assessed the performance of the nomogram through the area under the receiver operating characteristic (ROC) curve (AUC) and decision curve analysis (DCA) in both the training and validation cohorts. RESULTS: A total of 207 cases of invasive candidiasis were examined, and the crude 30-day mortality was 28.0%. Candida albicans (48.3%) was the predominant species responsible for infection, followed by the Candida glabrata complex (24.2%) and Candida tropicalis (10.1%). The training and validation cohorts contained 147 and 60 cases, respectively. The predictive nomogram consisted of bloodstream infections, intensive care unit (ICU) admitted > 3 days, no prior surgery, metastasis and no source control. The AUCs of the training and validation cohorts were 0.895 (95% confidence interval [CI], 0.846-0.945) and 0.862 (95% CI, 0.770-0.955), respectively. The net benefit of the model performed better than "treatment for all" in DCA and was also better for opting low-risk patients out of treatment than "treatment for none" in opt-out DCA. CONCLUSION: Cancer patients with invasive candidiasis exhibit high crude mortality. The predictive nomogram established in this study can provide a probability of mortality for a given patient, which will be beneficial for therapeutic strategies and outcome improvement.

Caspase-8 Induces Lysosome-Associated Cell Death in Cancer Cells.

Caspase-8, a well-characterized initiator of apoptosis, has also been found to play non-apoptotic roles in cells. In this study, we reveal that caspase-8 can induce cell death in a special way, which does not depend on activation of caspases and mitochondrial initiation. Instead, we prove that caspase-8 can cause lysosomal deacidification and thus lysosomal membrane permeabilization. V-ATPase is a multi-subunit proton pump that acidifies the lumen of lysosome. Our results demonstrate that caspase-8 can bind to the V0 domain of lysosomal Vacuolar H+-ATPase (V-ATPase), but not the V1 domain, to block the assembly of functional V-ATPase and alkalinize lysosomes. We further demonstrate that the C-terminal of caspase-8 is mainly responsible for the interaction with V-ATPase and can suffice to inhibit survival of cancer cells. Interestingly, regardless of the protein level, it is the expression rate of caspase-8 that is the major cause of cell death. Taken together, we identify a previously unrevealed caspase-8-mediated cell death pathway different form typical apoptosis, which could render caspase-8 a particular physiological function and may be potentially applied in treatments for apoptosis-resistant cancers.

UNC5D, suppressed by promoter hypermethylation, inhibits cell metastasis by activating death-associated protein kinase 1 in prostate cancer.

Prostate cancer (PCa) death primarily occurs due to metastasis of the cells, but little is known about the underlying molecular mechanisms. This study aimed to evaluate the expression of UNC5D, a newly identified tumor suppressor gene, analyze its epigenetic alterations, and elucidate its functional relevance to PCa metastasis. Meta-analysis of publicly available microarray datasets revealed that UNC5D expression was frequently downregulated in PCa tissues and inversely associated with PCa metastasis. These results were verified in clinical specimens by real-time PCR and immunohistochemistry assays. Through methylation analysis, the downregulated expression of UNC5D in PCa tissues and cell lines was found to be attributable to the hypermethylation of the promoter. A negative correlation was observed between methylation and UNC5D mRNA expression in PCa samples. The ectopic expression of UNC5D in PCa cells effectively reduced their ability to migrate and invade both in vitro and in vivo, and siRNA-mediated knockdown of UNC5D yielded consistent results. UNC5D can recruit and activate death-associated protein kinase 1, which remained to be essential for its metastatic suppressor function. In conclusion, these results suggested that UNC5D as a novel putative metastatic suppressor gene that is commonly down-regulated by hypermethylation in PCa.

Evaluation of candidemia in epidemiology and risk factors among cancer patients in a cancer center of China: an 8-year case-control study.

BACKGROUND: Candidemia is the worldwide life-threaten disease, especially in cancer patients. This study was aimed to identify and evaluate the risk factors of candidemia in cancer patients, which will prompt the improvement on current therapeutic strategies and prognosis. METHODS: A retrospective, case-control study was conducted from inpatients of Tianjin Medical University Cancer Institute and Hospital, during 2006 to 2013. Analyses were performed between cancer patients with candidemia as study case, and patients with bacterial bloodstream infections as control. Each case was matched up with two controls, for gender and inpatient duration. Candida species, clinical characteristics, risk factors and outcomes were reviewed in details. RESULTS: Total number of 80 cases and 160 controls were enrolled and analyzed in this study. Candida albicans was identified as the most prevalent species and account for 55.0% candidemia, followed by Candida parapsilosis complex (21.3%), Candida tropicalis (8.8%), Candida glabrata complex (7.5%), Candida lusitaniae (3.8%), and Candida famata (3.8%). The crude mortality at 30-days of candidemia was up to 30.0%, which is significantly higher than bacterial bloodstream infections (p = 0.006). Logistical analysis demonstrated that total parenteral nutrition >5 days (p = 0.036), urinary catheter >2 days (p = 0.001), distant organ metastasis of cancer (p = 0.002) and gastrointestinal cancer (p = 0.042) were the independent risk factors for candidemia. CONCLUSIONS: Candidemia showed significant higher mortality than bacterial bloodstream infections, C. albicans was cited as the primary pathogen. Total parenteral nutrition, urinary catheter, distant organ metastasis of cancer and gastrointestinal cancer are independent predictors for candidemia, this findings provides potential therapeutic targets for improving the outcome.

Clinical prognostic factors for time to positivity in cancer patients with bloodstream infections.

PURPOSE: Time to positivity (TTP) has been used in recent years as a simple and rapid method for the additional characterization of the degree of bacteremia. However, prognostic factors for TTP in cancer patients with bloodstream infections have rarely been studied. The aim of this study was to investigate the clinical factors for TTP involving various isolated organisms in cancer patients. METHODS: We analyzed 386 episodes of bloodstream infections (BSIs) in patients with or without cancer during a 19 month period. Information on age, gender, tumor type, ICU stay, organisms, multidrug resistance (MDR), TTP and outcome was collected. Multivariate logistic regression analysis was performed. RESULTS: The mean TTP of Enterobacteriaceae in patients with hepatocellular carcinoma, gastroenterological cancer, and lung cancer was shorter than in non-cancer patients (9.86 ± 3.22, 10.05 ± 3.47, 8.85 ± 2.78 vs 13.11 ± 5.37 h). The mean TTP of nonfermentative bacilli in patients with lung cancer (12.37 ± 5.96 h) and hematologic diseases (8.72 ± 4.21 h) was also shorter than in non-cancer patients (20.74 ± 2.46 h), and the mean TTP of Staphylococcus isolates was significantly different between non-cancer patients (22.06 ± 3.71 h) and hematologic disease patients (11.93 ± 5.44 h). The presence of a benign tumor was a significant prognostic factor for a long TTP only in the Staphylococci group (OR 0.076, 95 % CI 0.014-0.412), according to multivariate analysis. MDR (OR 2.178, 95 % CI 1.196-4.239) was an independent significant predictor in the Enterobacteriaceae group, with a short TTP, and it was also a significant clinical factor for a long TTP in nonfermentative bacilli and the Staphylococci group (OR 5.037, 95 % CI 1.065-23.82; OR 0.167, 95 % CI 0.059-0.474). CONCLUSION: Time to positivity provides useful diagnostic and prognostic information for the differentiation of frequently isolated organisms. This information may help clinicians to use the correct antibiotics in a timely manner to treat cancer patients with BSIs based on clinical factor analysis.

Molecular surveillance of candidemia due to Candida albicans among cancer patients during 2009 to 2013 by microsatellite typing.

BACKGROUND: Since the high morbidity and mortality of candidemia among cancer patients, the epidemiology has been underlined. In recent years, Candida species genotyping has been established, which could provide detail characteristics of epidemiology and has been underscored for candidemia preventing strategies. METHODS: Data of cancer patients with candidemia and hospitalized in Tianjin Medical University Cancer Institute and Hospital (TMUCIH) during 2009-2013 were reviewed. Species identification was carried out by using VITEK-2 Compact. Microsatellite typing was performed for molecular analysis. SPSS 20.0 and MVSP 3.22 software were used for statistical and clustering analysis, respectively. RESULTS: Total of 36 isolates of Candida albicans were recovered from 36 cancer patients with nosocomial candidemia in TMUCIH during the period of 2009-2013 included in the study. Total of 17 genotypes were identified and 2 of them were endemic genotypes, which caused 21 (58.3%) of 36 episodes of candidemia. Hepatobiliary oncology, ICU and gastrointestinal oncology were the main wards of infections due to endemic strains. Gastrointestinal cancer and insertion of a nasogastric tube were the predictors of infections caused by endemic strains (p = 0.014 and p = 0.041, respectively). For the 36 cases, crude mortality was up to 30.6%, and there was no significant difference between infections due to endemic and non-endemic strains (p = 0.077). CONCLUSIONS: This study proved that endemic stains of C. albicans could exist for a long period and mainly in a few wards. Patients with gastrointestinal cancer or nasogastric tube insertion were more sensitive to endemic C. albicans.

Relative contribution of Hepatitis B and C Viruses in primary liver cancer in China: a systematic review and meta-analysis.

OBJECTIVES: China, which has the largest number of patients with primary liver cancer (PLCs), lacks data on the overall prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) in PLCs. We aimed to comprehensively assess the seroprevalence of HBV and HCV among PLCs in China. METHODS: We included and pooled observational studies reporting seroprevalence of HBsAg and anti-HCV antibodies among PLCs in China by searching PubMed, Web of Science, Cochrane, Scopus, Embase, CNKI, Wanfang, and CBM. Multivariate meta-regression and subgroup analyses were used to explore sources of heterogeneity, and publication bias was assessed by funnel plots and Egger's test. PROSPERO registration number is CRD42023450382. RESULTS: A total of 217 eligible studies were included in the meta-analysis. The estimated seroprevalence of HBV and HCV was 75.09% (95% CI 73.12-77.02) and 11.82% (95% CI 9.79-14.00), respectively. After stratifying and analysing subgroups by region and study period, we found geographic differences in HBV and HCV prevalence among PLCs, with an overall increasing trend in the proportion of HBV and a decreasing trend in the proportion of HCV as well as co-infections in the last 40 years. CONCLUSIONS: HBV and HCV infections still accounts for a high proportion of PLCs in China.

CYB561 promotes HER2+ breast cancer proliferation by inhibiting H2AFY degradation.

Breast cancer (BRCA) has a high incidence and mortality rate among women. Different molecular subtypes of breast cancer have different prognoses and require personalized therapies. It is imperative to find novel therapeutic targets for different molecular subtypes of BRCA. Here, we demonstrated for the first time that Cytochromeb561 (CYB561) is highly expressed in BRCA and correlates with poor prognosis, especially in HER2-positive BRCA. Overexpression of CYB561 could upregulate macroH2A (H2AFY) expression in HER2-positive BRCA cells through inhibition of H2AFY ubiquitination, and high expression of CYB561 in HER2-positive BRCA cells could promote the proliferation and migration of cells. Furthermore, we have demonstrated that CYB561 regulates H2AFY expression, thereby influencing the expression of NF-κB, a downstream molecule of H2AFY. These findings have been validated through in vivo experiments. In conclusion, we propose that CYB561 may represent a novel therapeutic target for the treatment of HER2-positive BRCA. Graphical abstract CYB561 promotes the proliferation of HER2+ BRCA cells: CYB561 enhances the expression of H2AFY by inhibiting its ubiquitination, which leads to an increase expression of NF-κB in the nucleus. H2AFY, together with NF-κB, promotes the proliferation of HER2+ BRCA cells.

Circ_0006949 as a potential non-invasive diagnosis biomarker promotes the proliferation of NSCLC cells via miR-4673/GLUL axis.

The 5-year survival for non-small cell lung cancer (NSCLC) remains <20 %, primarily due to the early symptoms of lung cancer are inconspicuous. Prompt identification and medical intervention could serve as effective strategies for mitigating the death rate. We therefore set out to identify biomarkers to help diagnose NSCLC. CircRNA microarray and qRT-PCR reveal that sputum circ_0006949 is a potential biomarker for the early diagnosis and therapy of NSCLC, which can enhance the proliferation and clone formation, regulate the cell cycle, and accelerate the migration and invasion of NSCLC cells. Circ_0006949 and miR-4673 are predominantly co-localized in the cytoplasm of NSCLC cell lines and tissues; it upregulates GLUL by adsorption of miR-4673 through competing endogenous RNAs mechanism. The circ_0006949/miR-4673/GLUL axis exerts pro-cancer effects in vitro and in vivo. Circ_0006949 can boost GLUL catalytic activity, and they are highly expressed in NSCLC tissues and correlate with poor prognosis. In summary, circ_0006949 is a potential biomarker for the early diagnosis and therapy of NSCLC. This novel sputum circRNA is statistically more predictive than conventional serum markers for NSCLC diagnosis. Non-invasive detection of patients with early-stage NSCLC using sputum has shown good potential for routine diagnosis and possible screening.

Autophagy and LC3-associated phagocytosis contribute negatively to the killing capability of THP-1-derived macrophages against Candida albicans at the mid-stage.

In innate immunity, macrophages play critical roles in defending against pathogens via the lysosomal degradation function of autophagy. Two distinct autophagy pathways have been identified in decades: canonical autophagy (referred to as autophagy) and LC3-associated phagocytosis (LAP). Since several conflicting findings about the anti-Candida capability of autophagy (or LAP) have been reported, they serve as the foe or friend for Candida survival is still unclearly. The current study showed that the fungicidal process of THP-1-derived macrophages (THP-1-MФ) against Candida albicans is divided into three stages as follows, the early stage (the first 12 h, increasing in the killing capability), the mid-stage (12-24 h, no change in killing capability), and the late stage (24-48 h, decreasing of the killing capability). Autophagic protein LC3B-II reached the peak in THP-1-MФ after 24 h inoculated either with C.albicans or whole glucan particles (WGP). Thus, both anti-Candida roles of autophagy and the LAP pathway have been detected at the mid-stage. For autophagy, after 24 h inoculation with C.albicans, ULK1 increased, but p-ATG13(s318) decreased obviously in THP-1-MФ, and the killing assay showed that autophagy is unhelpful for Candida killing capability. For the LAP pathway, Rubicon and ROS raised significantly in THP-1-MФ after 24 h inoculated with C.albicans; each inhibition would sharply cut down the LC3B-II accumulation, which indicated that LAP had been induced. However, mCherry-GFP-LC3 fluorescent assay exhibited that LAP phago-lysosomal fusion has been blocked, and Rubicon knockdown facilitated the Candida killing activity. These data indicated that autophagy presented as redundant to Candida defense, and LAP phago-lysosomal fusion obstruction impairs the Candida killing capability of THP-1-MФ at the mid-stage. That may explain the no change in Candida killing capability at the mid-stage.

ZNF133 is a potent suppressor in breast carcinogenesis through dampening L1CAM, a driver for tumor progression.

Due to the complexity and heterogeneity of breast cancer, the therapeutic effects of breast cancer treatment vary between subtypes. Breast cancer subtypes are classified based on the presence of molecular markers for estrogen or progesterone receptors and human epidermal growth factor 2. Thus, novel, comprehensive, and precise molecular indicators in breast carcinogenesis are urgently needed. Here, we report that ZNF133, a zinc-finger protein, is negatively associated with poor survival and advanced pathological staging of breast carcinomas. Moreover, ZNF133 is a transcription repressor physically associated with the KAP1 complex. It transcriptionally represses a cohort of genes, including L1CAM, that are critically involved in cell proliferation and motility. We also demonstrate that the ZNF133/KAP1 complex inhibits the proliferation and invasion of breast cancer cells in vitro and suppresses breast cancer growth and metastasis in vivo by dampening the transcription of L1CAM. Taken together, the findings of our study confirm the value of ZNF133 and L1CAM levels in the diagnosis and prognosis of breast cancer, contribute to a deeper understanding of the regulation mechanism of ZNF133 for the first time, and provide a new therapeutic strategy and precise intervention target for breast cancer.

High Expression of RAI14 in Triple-Negative Breast Cancer Participates in Immune Recruitment and Implies Poor Prognosis Through Bioinformatics Analyses.

Objective: The purpose of current research is to explore the function of retinoic acid-induced protein 14 (RAI14), being a reciprocal protein of carboxypeptidase N1 (CPN1), and as a biomarker for prognosis and immunoregulatory effects in breast cancers. Methods: Interacting proteins of CPN1 were characterized by co-immunoprecipitation (CO-IP) and mass spectrometry. We evaluated RAI14 expression and related clinical prognosis based on bioinformatics methods. The level of relevance between RAI14 and infiltrating immune cells biomarkers was investigated by using TIMER and certificated by immunohistochemical staining and cytology experiments. Results: RAI14 is an interacting protein of CPN1. Higher RAI14 expression in TNBC was significantly correlated with poor prognosis in TNBC, especially (RFS: HR = 1.32, p = 0.015; DFS: HR = 1.18, p = 0.035). The estrogen receptor (ER), P53 status, and histological types and triple-negative status were observed and correlated with RAI14 expression. Moreover, the level of RAI14 was positive in relation with the expression of CD163 (M2 macrophages marker, r = 0.393, p = 1.89e-06) and PD-1 (T-cell exhaustion marker, r = 0.626, p = 4.82e-03), indicating RAI14 levels were mainly related to M2 macrophages and T-cell exhaustion infiltration in TNBC. Furthermore, CPN1 overexpression was accompanied by RAI14 and PD-L1 upregulation, and a correlation was found among them. Conclusions: RAI14 is a potential downstream molecule of CPN1, which may be a potential prognostic biomarker and identification of an immunosuppressive tumor microenvironment in TNBC.

Urea as a By-Product of Ammonia Metabolism Can Be a Potential Serum Biomarker of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is highly malignant; nearly half of the new cases and deaths are in China. The poor prognosis of HCC is mainly due to late diagnosis; many new biomarkers have been developed for HCC diagnosis. However, few markers are quickly translated into clinical practice; early and differential diagnosis of HCC from cirrhosis and/or hepatitis is still a clinical challenge. Metabolomics and biochemical methods were used to reveal specific serum biomarkers of HCC. Most of the elevated metabolites in HCC and HBV patients were overlapped compared with controls. Urea was the specifically elevated serum biomarker of HCC patients. Moreover, urea combined with AFP and CEA can improve the sensitivity of HCC diagnosis. The plasma ammonia of HCC patients was significantly higher than healthy controls. Co-culture cell model revealed normal liver cells cooperated with cancer cells to metabolize ammonia into urea. The urea metabolism in cancer cells marginally depended on the expression of CPS1. However, the expression of CPS1 did not change with ammonium chloride, which might regulate the urea cycle through enzyme activity. The urea cycle could detoxify high concentrations of ammonia to promote cancer cell proliferation. Therefore, urea was a by-product of ammonia metabolism and could be a potential serum biomarker for HCC. The combined application of metabolomics and biochemical methods can discover new biomarkers for the early diagnosis of HCC and be quickly applied to clinical diagnosis.

Application of low-concentration contrast agents and low-tube-voltage computed tomography to chest enhancement examinations: A multicenter prospective study.

To evaluate the influence of low-concentration contrast agents and low-tube-voltage computed tomography on chest enhancement examinations, we conducted a multicenter prospective study. A total of 216 inpatients enrolled from 12 different hospitals were randomly divided into four groups: A: voltage, 120 kVp; iohexol, 350 mgI/mL; B: voltage, 100 kVp, iohexol, 350 mgI/mL; C: voltage, 120 kVp, iodixanol, 270 mgI/mL; and D: voltage, 100 kVp, iodixanol, 270 mgI/mL. Subjective image quality was assessed by two radiologists and compared by weighted kappa test. The objective image scores, scanning radiation doses, and pathological coincidence rates were analyzed. There were no significant differences in gender, age, height, weight, and body mass index between the four groups (p > 0.05). The consistency of the radiologists' ratings were good, with kappa value ranging from 0.736 (95% confidence interval: 0.54-0.933) to 0.809 (95% confidence interval: 0.65-0.968), and there was no difference in subjective image score between the four groups. The computed tomography value of group D had no difference with group A. The volume computed tomography dose index, dose length product, and effective dose of group D (6.93 ± 3.03, 241.55 ± 104.75, and 3.38 ± 1.47, respectively) were all significantly lower than those of group A (10.30 ± 4.37, 359.70 ± 152.65, and 5.04 ± 2.14, respectively). There was no significant difference in the imaging diagnosis accuracy rate between the four groups (p > 0.05). The results indicated that low-concentration contrast agents (270 mgI/mL) and low-tube-voltage (100 kVp) computed tomography can not only decrease radiation dose but also guarantee the image quality and meet the needs of imaging diagnosis in chest enhancement examinations, which make it possible for its generalization and application.

Inhibiting both proline biosynthesis and lipogenesis synergistically suppresses tumor growth.

Cancer cells often proliferate under hypoxia and reprogram their metabolism. However, how to find targets to effectively block the hypoxia-associated metabolic pathways remains unclear. Here, we developed a tool to conveniently calculate electrons dissipated in metabolic transformations. Based on the law of conservation of electrons in chemical reactions, we further built up an electron balance model for central carbon metabolism, and it can accurately outline metabolic plasticity under hypoxia. Our model specifies that glutamine metabolism reprogrammed for biosynthesis of lipid and/or proline actually acts as the alternative electron bin to enable electron transfer in proliferating cells under hypoxia. Inhibition of both proline biosynthesis and lipogenesis can synergistically suppress cancer cell growth under hypoxia and in vivo tumor onset. Therefore, our model helps to reveal combinations of potential targets to inhibit tumor growth by blocking hypoxia-rewired metabolism and provides a useful tool for future studies on cancer metabolism.