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Correction of stereological parameters from biased samples on nucleated particle phases. I. Nuclear volume fraction.

Stereologists are aware that the experimental evaluation of component volume fractions and surface-to-volume ratios are subject to systematic errors whenever the requirements for cell identification impose the necessity for component-biased sectioning. Mathematical corrections of biased volume proportion data have recently been published; these corrections assume that the components under analysis are spherical, and that the nucleated particle phase is monodispersed. In this report, general methods for obtaining corrections of biased nuclear volume fraction data are set out for polydispersed phases of nucleated particles, in terms of the relevant shapes and joint size distribution of nucleus and cell; the scope and limitations of these methods are thereby discussed. Explicit corrections of an immediate applicability are obtained, together with their standard errors, for monodispersed phases where nucleus and cell are two dissimilar biaxial ellipsoids (spheroids). When nucleus and cell are two concentric and similar convex bodies of a certain class--to which triaxial ellipsoids belong--the corrections are shown to be very simple. The corrections for the spheroid-spheroid systems are easily accessible with the aid of a small programmable calculator, whereas those for the sphere-spheroid models are directly obtainable from two nomograms.

Cell Nucleus

Evaluation of a multivariate prostate-specific antigen and percentage of free prostate-specific antigen logistic regression model in the diagnosis of prostate cancer.

The use of prostate-specific antigen (PSA) in the diagnosis of prostate cancer is controversial due to false-positive results caused by benign prostatic hyperplasia. Several groups have suggested the usefulness of the percentage of free PSA (%fPSA) in patients with PSA levels between 4 and 10 microg/l. Based on previously obtained results, biopsy is carried out in our hospital if the PSA is greater than 10 microg/l or if the %fPSA is lower than 20% and PSA is between 4-10 microg/l. In this study, we have compared these results with those obtained with a logistic regression model based on the determination of PSA and %fPSA. The diagnostic efficacy of the logistic regression model is greater than that of the currently used model. The posterior construction of a nomogram based on the data obtained greatly facilitates the application of the logistic regression model.

Aged

Risk factors for in-hospital nonhemorrhagic stroke in patients with acute myocardial infarction treated with thrombolysis: results from GUSTO-I.

BACKGROUND: Nonhemorrhagic stroke occurs in 0.1% to 1.3% of patients with acute myocardial infarction who are treated with thrombolysis, with substantial associated mortality and morbidity. Little is known about the risk factors for its occurrence. METHODS AND RESULTS: We studied the 247 patients with nonhemorrhagic stroke who were randomly assigned to one of four thrombolytic regimens within 6 hours of symptom onset in the GUSTO-I trial. We assessed the univariable and multivariable baseline risk factors for nonhemorrhagic stroke and created a scoring nomogram from the baseline multivariable modeling. We used time-dependent Cox modeling to determine multivariable in-hospital predictors of nonhemorrhagic stroke. Baseline and in-hospital predictors were then combined to determine the overall predictors of nonhemorrhagic stroke. Of the 247 patients, 42 (17%) died and another 98 (40%) were disabled by 30-day follow-up. Older age was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by higher heart rate, history of stroke or transient ischemic attack, diabetes, previous angina, and history of hypertension. These factors remained statistically significant predictors in the combined model, along with worse Killip class, coronary angiography, bypass surgery, and atrial fibrillation/flutter. CONCLUSIONS: Nonhemorrhagic stroke is a serious event in patients with acute myocardial infarction who are treated with thrombolytic, antithrombin, and antiplatelet therapy. We developed a simple nomogram that can predict the risk of nonhemorrhagic stroke on the basis of baseline clinical characteristics. Prophylactic anticoagulation may be an important treatment strategy for patients with high probability for nonhemorrhagic stroke, but further study is needed.

Age Factors

Validation of the S and C components of the three-process model of alertness regulation.

This paper summarizes work to validate and develop further the homeostatic and circadian component of a quantitative (computerized) three-process model for predicting alertness/sleepiness in daily living. The model uses sleep data as input and contains circadian and homeostatic components (amount of prior wake and amount of prior sleep), which are summed to yield predicted alertness on a scale between 1 and 16. The present validation was carried out using regression analysis, with sleepiness-related electroencephalographic parameters (alpha power density) from field and laboratory studies as criteria. The results showed that variations in alpha-power density in truck drivers, train drivers and laboratory subjects could be predicted with considerable accuracy (r2 > 0.70) from the model, as could subjective alertness. Levels < or = 7 on the 16-point scale were defined as critically low alertness. The paper also describes a simplified, graphic, paper version of the computation model, visualized as a two-dimensional "alertness nomogram". It is suggested that the studied components of the model may serve as tools for evaluating work/rest schedules in terms of sleep-related safety risks.

Adult

A nomogram for predicting optimal dosage of cyclosporine in renal transplant patients: taking physiological factors into consideration for regimen during immunosuppressive therapy.

We constructed a nomogram for determining the optimal regimen of cyclosporine (CyA), based on physiological changes that occur during immunosuppressive therapy. The nomogram consists of a fixed model and a variable model. In the fixed model, the oral dose of CyA (D, mg/kg) is given by the multiple linear function of logarithmic CyA trough level (TL, ng/ml), the surrogate apparent total body clearance of CyA (CL/fsu, l/h/kg, being equal to D/TL/12), and the erythrocyte-to-plasma distribution ratio of CyA (CyA-EP), as defined by: D = 4.938 x log(TL) + 1.5037 x CL/fsu - 0.0326 x CyA-EP - 10.7156. In the variable model, the CL/fsu is given by the CyA-EP and the patient's intrinsic parameters (P1, P2), using a nonlinear equation: CL/fsu = P1 x exp(P2 x CyA-EP)/CyA-EP. An optimal CyA dose to maintain a desired trough level was calculated, and the validity of the nomogram was found satisfactory for clinical use. This offers a very concise and practical method for the therapeutic monitoring of CyA. Because the pharmacokinetics of CyA depends on physiological changes due to several disease states, and because the CyA-EP reflects the pharmacokinetics of CyA and the patient's disease state, the proposed nomogram is believed to provide an optimal dosage adjustment, taking physiological factors into consideration.

Adolescent

Screening and treatment of bacterial vaginosis during pregnancy: a model for determining benefit.

Bacterial vaginosis is associated with an increased risk of preterm birth. The treatment of bacterial vaginosis has recently been shown to decrease the risk of preterm delivery, especially in high-risk populations. However, the benefit of routine screening and treatment in the general population is uncertain. Using the information from several recent studies, a graph and nomogram generated from a mathematical model allow the obstetrician to determine the benefit of routine screening and treatment of bacterial vaginosis in his or her obstetrical population, depending on the prevalence of bacterial vaginosis and the total preterm delivery rate in that obstetrician's practice. If the prevalence of bacterial vaginosis and the incidence of preterm delivery are low, then routine screening would be expected to prevent small numbers of preterm births, and therefore may not be cost-effective.

Cost-Benefit Analysis

A model for collaboration in quality improvement projects: implementing a weight-based heparin dosing nomogram across an integrated health care delivery system.

BACKGROUND: At Aurora Health Care, an integrated delivery system based in Milwaukee, a system-level clinical quality improvement department was established in 1995 to facilitate collaboration on clinical quality improvement (QI) initiatives. THE COLLABORATIVE MODEL: A model was developed to use expertise within the system and avoid unnecessary duplication of efforts, while maintaining buy-in for the project's interventions at the point of service delivery. It was believed that a single team could design the improvement efforts or guidelines, and then work at a more local level with a different group of people to implement the processes. APPLYING THE MODEL TO THE HEPARIN QI PROJECT: Anticoagulation with heparin is considered the mainstay of treatment for pulmonary embolism and deep venous thrombosis. However, a large gap was found between present anticoagulation practices and published best practice in regards to achieving a key process measure. To reduce the overall time to achieving effective anticoagulation, a system-level team created an intervention primarily consisting of a preprinted order sheet, including the weight-based heparin dosing nomogram, and an education plan for physicians and other health care professionals. Significant improvement was observed at all pilot sites with overall rates of adequate anticoagulation within the first 24 hours improving from 73% to 95%. DISCUSSION: The system was able to standardize care at four of its five major hospitals and provide for better patient outcomes to a larger segment of the community, and then to replicate the heparin project to four additional sites during a six-month period. This model has been successfully applied to other quality improvement projects.

Anticoagulants

Nomogram for dosing warfarin at steady state.

The predictive performance of a nomogram for dosing warfarin was compared with that of a computer program. The nomogram and the computer program were developed from the log-linear model describing warfarin pharmacodynamics at steady state. The nomogram's dose-response curves were generated by using previously reported pharmacodynamic and pharmacokinetic values for an outpatient population receiving warfarin. The series of dose-response curves were plotted by altering the pharmacodynamic values over a range of 3 standard deviations. The ability of the nomogram to predict the steady-state prothrombin time ratio (PTR) after an adjustment in the dosage of warfarin was evaluated, and the results were compared with those of a commercially available program involving Bayesian regression. Data for 65 outpatients were evaluated. The mean +/- S.D. nomogram-predicted, computer-predicted, and measured PTRs were 1.63 +/- 0.27, 1.64 +/- 0.24, and 1.66 +/- 0.23, respectively. The mean prediction errors for the nomogram and the computer program were -0.037 and -0.026, respectively, and the mean percent absolute prediction errors were 11.6% and 11.0%, respectively. Neither method was biased, and differences between the results for the two methods were not significant. The predictive performance of the warfarin dosing nomogram was comparable to that of the computer program.

Bayes Theorem

Diagnostic X-ray shielding design based on an empirical model of photon attenuation.

A series of nomograms that simplify determination of diagnostic X-ray shielding requirements with lead are presented. All recommendations of the NCRP, except that to "add one half value layer" in determining secondary barriers, were followed in the production of these curves. For secondary barriers, the shielding required to reduce the weekly exposure to the applicable MPD has been determined. This eliminates the over-shielding inherent in the "add one HVL" approximation and allows a variety of more cost effective materials to be considered for secondary barriers.

Hospital Departments

Apnea testing in suspected brain dead children--physiological and mathematical modelling.

OBJECTIVE: To study the validity and safety of the traditional apnea test in children, and to evaluate a mathematical equation estimating the hemodynamic response to the apnea test. DESIGN: A prospective clinical study. SETTING: Pediatric ICU. PATIENTS AND PARTICIPANTS: 38 pediatric patients suffering severe brain injury aged 2 months to 17 years, undergoing apnea testing for brain death. MEASUREMENTS AND RESULTS: Apnea tests were performed 61 times (once in 19 patients, twice in 15, and 3 times in 4 patients). Mean PaCO2 was 41.1 +/- 10.6 mmHg before apnea and increased to 68.0 +/- 17.6 at 5 min. PaCO2 increased to 81.8 +/- 20.1 and 86.0 +/- 25.6 at 10 and 15 min, respectively. There was a mean PaCO2 increase by 5.38 +/- 1.4 mmHg/min in the first 5 min, and 2.75 +/- 0.5 mmHg/min during the next 5 min. We found a statistically significant (p < 0.05) linear relationship between the natural logarithm of PaCO2, time, and the logarithm of the initial level of PaCO2. An inverse linear relationship (p < 0.05) was found between systemic mean arterial pressure (MAP) and initial level of PaCO2 presented as mathematical correlations and nomograms. CONCLUSIONS: By using our model for predicting MAP and PCO2 prior to apnea testing, hemodynamic embarrassment can be anticipated and prevented, thus allowing a safer procedure in the detection of brain death. Despite the fact that continuous cardiorespiratory monitoring is important, hemodynamic disturbances can be estimated before the apnea test, thus allowing a safer approach to brain death detection.

Adolescent

[A nomogram of duplex ultrasound quantification of peripheral arterial stenoses. Studies of the cardiovascular model and in angiography patients].

BACKGROUND AND METHODS: Blood flow velocity measurements were performed with duplex ultrasound in vitro (flow phantom) and in 62 patients who underwent angiography due to peripheral vascular disease. RESULTS: Intrastenotic peak systolic velocity (PSV) divided by proximally recorded PSV (peak velocity ratio, PVR) exhibited a strong correlation with percent diameter reduction: r2 = 0.86; N = 106 stenoses. A PVR value > or = 2.4 indicated a more than 50% stenosis with a sensitivity of 87% and a specificity of 94%. Calculation of PVR may normalize for patient variation and allow noninvasive quantification of lumen narrowing with high sensitivity and specificity. The intraobserver variability (95% CI) of stenosis quantification using PVR values was 10%. A nomogram simplifies estimation of lumen narrowing after measurement of intrastenotic and proximal PSV values. CONCLUSION: Quantification of peripheral artery stenoses can be performed easily and noninvasively with duplex ultrasound using the peak velocity ratio (PVR).

Aged

The prognostic significance of ubiquitination-related genes in multiple myeloma by bioinformatics analysis.

BACKGROUND: Immunoregulatory drugs regulate the ubiquitin-proteasome system, which is the main treatment for multiple myeloma (MM) at present. In this study, bioinformatics analysis was used to construct the risk model and evaluate the prognostic value of ubiquitination-related genes in MM. METHODS AND RESULTS: The data on ubiquitination-related genes and MM samples were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The consistent cluster analysis and ESTIMATE algorithm were used to create distinct clusters. The MM prognostic risk model was constructed through single-factor and multiple-factor analysis. The ROC curve was plotted to compare the survival difference between high- and low-risk groups. The nomogram was used to validate the predictive capability of the risk model. A total of 87 ubiquitination-related genes were obtained, with 47 genes showing high expression in the MM group. According to the consistent cluster analysis, 4 clusters were determined. The immune infiltration, survival, and prognosis differed significantly among the 4 clusters. The tumor purity was higher in clusters 1 and 3 than in clusters 2 and 4, while the immune score and stromal score were lower in clusters 1 and 3. The proportion of B cells memory, plasma cells, and T cells CD4 na&#xef;ve was the lowest in cluster 4. The model genes KLHL24, HERC6, USP3, TNIP1, and CISH were highly expressed in the high-risk group. AICAr and BMS.754,807 exhibited higher drug sensitivity in the low-risk group, whereas Bleomycin showed higher drug sensitivity in the high-risk group. The nomogram of the risk model demonstrated good efficacy in predicting the survival of MM patients using TCGA and GEO datasets. CONCLUSIONS: The risk model constructed by ubiquitination-related genes can be effectively used to predict the prognosis of MM patients. KLHL24, HERC6, USP3, TNIP1, and CISH genes in MM warrant further investigation as therapeutic targets and to combat drug resistance.

Humans

Spirometric nomograms for normal children and adolescents in Puerto Rico.

OBJECTIVE: The use of spirometric reference values specific to the population being tested is preferable. A study carried out in Puerto Rico is used here to develop nomograms for normal children and adolescents based on age and height, two variables that have been found to be good predictors of pulmonary function. MATERIAL AND METHODS: The data for healthy individuals aged 5 to 18 were extracted (108 girls and 107 boys) from a larger study of spirometric measurements collected on 4527 individuals attending medical services in Puerto Rico. Several models were tested for the prediction of FEV1, FVC and the ratio FEV1/FVC. The best models were selected for each gender, and nomograms were developed showing the fifth, twenty-fifth, fiftieth, seventy-fifth, and ninety-fifth percentile of the predicted values according to age and height separately. RESULTS: The best models were those using the logarithm of the pulmonary function and the cube of height (R2 = 0.79-0.81), and age without transformation (R2 = 0.73-0.77). Corresponding nomograms were developed based on these models. The ratio showed little variation for different ages and heights. CONCLUSIONS: Pulmonary function can be efficiently predicted by age and height. Nomograms provide a simple way to use spirometric references that can be incorporated to clinical practice.

Adolescent

Prognostic significance of the initial electrocardiogram in patients with acute myocardial infarction. GUSTO-I Investigators. Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries.

CONTEXT: Early risk stratification of patients with myocardial infarction is critical to determine optimum treatment strategies and enhance outcomes, but knowledge of the prognostic importance of the initial electrocardiogram (ECG) is limited. OBJECTIVE: To assess the independent value of the initial ECG for short-term risk stratification after acute myocardial infarction. DESIGN: Retrospective analysis of the Global Utilization of Streptokinase and t-PA (alteplase) for Occluded Coronary Arteries (GUSTO-I) clinical trial database. SETTING: A total of 1081 hospitals in 15 countries. PATIENTS: From the 41 021 patients enrolled in the overall study, we selected those who presented within 6 hours of chest pain onset with ST-segment elevation and no confounding factors (paced rhythms, ventricular rhythms, or left bundle-branch block) on the ECG performed before thrombolysis was administered (n=34 166). MAIN OUTCOME MEASURE: Ability of initial ECG to predict all-cause mortality at 30 days. RESULTS: Most ECG variables were associated with 30-day mortality in a univariable analysis. In a multivariable analysis combining the initial ECG variables and clinical predictors of mortality, the sum of the absolute ST-segment deviation (both ST elevation and ST depression: odds ratio [OR], 1.53; 95% confidence interval [CI], 1.38-1.69), ECG, heart rate (OR, 1.49; 95% CI, 1.41-1.59), QRS duration (for anterior infarct: OR, 1.55; 95% CI, 1.43-1.68), and ECG evidence of prior infarction (for new inferior infarct: OR, 2.47; 95% CI, 2.02-3.00) were the strongest ECG predictors of mortality. A nomogram based on the multivariable model produced excellent discrimination of 30-day mortality (C-index, 0.830). CONCLUSIONS: In patients presenting with myocardial infarction accompanied by ST-segment elevation, components of the initial ECG help predict 30-day mortality. This information should be valuable in early risk stratification, when the opportunity to reduce mortality is greatest, and may help in assessing outcomes adjusted for patient risk.

Aged

Estimation of vulnerable zones due to accidental release of toxic materials resulting in dense gas clouds.

Heavy gas dispersion models have been developed at IIT (hereinafter referred as IIT heavy gas models I and II) with a view to estimate vulnerable zones due to accidental (both instantaneous and continuous, respectively) release of dense toxic material in the atmosphere. The results obtained from IIT heavy gas models have been compared with those obtained from the DEGADIS model [Dense Gas Dispersion Model, developed by Havens and Spicer (1985) for the U.S. Coast Guard] as well as with the observed data collected during the Burro Series, Maplin Sands, and Thorney Island field trials. Both of these models include relevant features of dense gas dispersion, viz., gravity slumping, air entrainment, cloud heating, and transition to the passive phase, etc. The DEGADIS model has been considered for comparing the performance of IIT heavy gas models in this study because it incorporates most of the physical processes of dense gas dispersion in an elaborate manner, and has also been satisfactorily tested against field observations. The predictions from IIT heavy gas models indicate a fairly similar trend to the observed values from Thorney Island, Burro Series, and Maplin experiments with a tendency toward overprediction. There is a good agreement between the prediction of IIT Heavy Gas models I and II with those from DEGADIS, except for the simulations of IIT heavy gas model-I pertaining to very large release quantities under highly stable atmospheric conditions. In summary, the performance of IIT heavy gas models have been found to be reasonably good both with respect to the limited field data available and various simulations (selected on the basis of relevant storages in the industries and prevalent meteorological conditions performed with DEGADIS). However, there is a scope of improvement in the IIT heavy gas models (viz., better formulation for entrainment, modification of coefficients, transition criteria, etc.). Further, isotons (nomograms) have been prepared by using IIT heavy gas models for chlorine, which provide safe distance for various storage amounts for 24 meteorological scenarios prevalent in the entire year. These nomograms are prepared such that a nonspecialist can use them easily for control and management in case of an emergency requiring the evacuation of people in the affected region. These results can also be useful for siting and limiting the storage quantities.

Accidents, Occupational

scRNA-seq and bulk RNA-seq reveal the characteristics of macrophage copper metabolism and establish a risk signature in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent malignancy with an urgent need for improved prognostic stratification and treatment-response prediction. This study aimed to explore a macrophage copper metabolism-associated prognostic model and to investigate the relationship between this risk model and the tumor immune microenvironment. METHODS: The FindClusters function was used to analyze cell clusters, and CellChat and CellPhoneDB/LIANA were employed for cell-cell communication analysis. Copper metabolism-related genes were sourced from the MSigDB database. A prognostic risk model was established using least absolute shrinkage and selection operator (LASSO) analysis and multivariate Cox regression analysis, and a nomogram was constructed by integrating the prognostic model with clinicopathological factors. Additional analyses were performed to map the seven model genes in single-cell data, assess model uncertainty and robustness, evaluate macrophage/copper/cuproptosis-related transcriptional programs, and examine the correlations between risk score, immune infiltration and predicted drug sensitivity. RESULTS: Using single-cell RNA sequencing (scRNA-seq) data, we identified four macrophage subpopulations. Macrophages with high SPP1 expression showed close interaction with T cell populations and were associated with copper ion metabolism. By incorporating 141 copper metabolism-related genes and using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort, we constructed a seven-gene risk prediction model. Additional single-cell mapping showed that the model genes were detectable in the HCC single-cell dataset and showed a macrophage-associated expression pattern. The model showed moderate prognostic discrimination in TCGA-LIHC, whereas its external performance was heterogeneous and remained evaluable across external cohorts, with performance varying among datasets. Immune and mechanism-related analyses suggested that the risk signature was associated with macrophage-related infiltration, copper metabolism and cuproptosis-related transcriptional programs. Drug sensitivity analysis nominated Daporinad as a computationally predicted candidate compound, supporting Daporinad as a pharmacogenomic candidate for follow-up investigation. CONCLUSIONS: By integrating scRNA-seq and bulk RNA sequencing (RNA-seq) data, we constructed a macrophage copper metabolism-associated prognostic signature for HCC. The risk score was associated with survival, immune microenvironment features and predicted drug response, providing a transcriptomic framework for risk stratification and therapeutic hypothesis generation.

Hepatocellular carcinoma (HCC)

Development and validation of a comprehensive prognostic model for 28-day ICU mortality in non-traumatic subarachnoid hemorrhage: an analysis based on the MIMIC-IV database.

BACKGROUND: Due to the complex pathophysiology of non-traumatic subarachnoid hemorrhage (SAH), accurate risk prediction remains a challenge. Our aim is to develop and validate a comprehensive prognostic model that integrates demographic characteristics, vital signs, laboratory parameters, and more, to provide clinical decision-making support in real-world practice. METHODS: We conducted a retrospective cohort study of 785 Non-traumatic subarachnoid hemorrhage patients. The cohort was randomly divided into a training set (n&#xa0;=&#xa0;549) and a validation set (n&#xa0;=&#xa0;236). Feature selection was performed using LASSO regression, followed by backward stepwise Cox regression for optimization. A nomogram was constructed based on independent predictive factors, and model performance was assessed using discrimination, calibration, and decision curve analysis. To prevent immortal-time bias, all predictors were anchored to a fixed early (first-24-hour) measurement window, treatment variables were modelled as binary indicators rather than cumulative exposures, and a five-model sensitivity analysis with baseline-severity adjustment was performed. RESULTS: The development of our model followed a systematic approach: first, 15 potential predictive factors were selected via LASSO regression, which were then refined to 12 independent predictors using backward stepwise Cox regression. The final predictive factors included: Ventilation, AHT, Nimodipine 60&#xa0;mg, Age, SAPS.II, Input amount, Calcium total, Platelet count, White blood cells, Anion gap, pH, and Chloride. The integrated model demonstrated excellent predictive ability for 7-day, 14-day, and 21-day mortality in both the training set (AUC: 0.972, 0.934, 0.898) and the validation set (AUC: 0.968, 0.948, 0.911). Calibration curves and decision curve analysis confirmed the model's reliability and clinical utility across different time points. We constructed a nomogram for individualized risk prediction. Univariate Kaplan-Meier survival analysis demonstrated significant stratification of survival outcomes by each predictor, while restricted cubic spline analysis revealed non-linear relationships between continuous variables and mortality risk. Random survival forest analysis identified the top three predictive factors (Nimodipine 60&#xa0;mg, Ventilation, AHT) and compared them with our full 12-variable model, confirming superior performance of the integrated model at all time points. At the 28-day primary endpoint, the model achieved a time-dependent AUC of 0.898 (training) and 0.904 (validation); after restricting predictors to the early baseline window, the leakage-controlled model retained good discrimination (validation C-index 0.803). CONCLUSIONS: Our ICU 28-day mortality prognosis model demonstrated robust performance in predicting ICU 28-day mortality in non-traumatic subarachnoid hemorrhage. The model, through the nomogram, provides individualized risk assessment, aiding clinical decision-making and patient stratification.

Humans

Crucial role of telomere maintenance-related genes in survival prediction and subtype identification in colorectal cancer.

BACKGROUND: Telomere maintenance-related genes (TMRGs) are implicated in Colorectal cancer (CRC) development, but their prognostic value and clinical relevance remain insufficiently explored. This study aims to develop a TMRG-based prognostic model and elucidate its clinical utility in CRC management. METHODS: The Cancer Genome Atlas database was utilized to download RNA-seq data from 638 CRC and 51 control samples. Differential expressed genes were screened and intersected with 2086 TMRGs, resulting in the identification of 976 TMRGs. Through univariate and multivariate Cox regression analysis, a prognostic model comprising three telomere maintenance-related biomarkers (PDE1B, TFAP2B, and HSPA1A) was developed and validated using an external dataset. By integrating the model risk score with clinical features, a nomogram was constructed to predict the survival outcomes of CRC patients. Additionally, an in-depth investigation of the immuno-infiltration, functional variation and drug sensitivity analysis were performed in two risk subgroups defined by the prognostic model. Finally, the functional significance of PDE1B in CRC cell lines was investigated through MTT assays, cell colony formation assays, transwell assays and flow cytometry. RESULTS: A total of 976 DE-TMRGs were enriched in telomere/DNA replication pathways. A three-gene signature (PDE1B, TFAP2B, and HSPA1A) stratified patients into high- and low-risk groups with divergent survival (AUC >0.60, validated externally). High-risk patients had advanced N/M stages, elevated M0/M2 macrophages, reduced CD4+ memory T cells, and upregulated immune checkpoints. Nomogram integrating risk score, age, and N/M stage accurately predicted 1-/3-/5-year survival. Low-risk patients showed greater 5-fluorouracil sensitivity. PDE1B expression was significantly reduced in CRC tissues and correlated with advanced stages. Functional assays confirmed PDE1B overexpression suppressed proliferation, migration, invasion, and induced apoptosis in CRC cells. CONCLUSION: This study identifies a moderately predictive telomere maintenance-related gene signature as an independent prognostic predictor in CRC. The risk stratification model effectively discriminates patients with distinct survival patterns, tumor microenvironments, and therapeutic responses, while the integrated nomogram offers additional reference information for survival analysis, albeit with only moderate predictive accuracy. These findings indicate telomere maintenance-related gene signature could serve as a preliminary auxiliary risk stratification tool for postoperative CRC patients, PDE1B may also serve as a potential epithelial tumor-suppressor target for future preclinical studies.

PDE1B