Characterization of stemness features and construction of a stemness subtype classifier to predict survival and treatment responses in lung squamous cell carcinoma.

BACKGROUND: Cancer stemness has been proven to affect tumorigenesis, metastasis, and drug resistance in various cancers, including lung squamous cell carcinoma (LUSC). We intended to develop a clinically applicable stemness subtype classifier that could assist physicians in predicting patient prognosis and treatment response. METHODS: This study collected RNA-seq data from TCGA and GEO databases to calculate transcriptional stemness indices (mRNAsi) using the one-class logistic regression machine learning algorithm. Unsupervised consensus clustering was conducted to identify a stemness-based classification. Immune infiltration analysis (ESTIMATE and ssGSEA algorithms) methods were used to investigate the immune infiltration status of different subtypes. Tumor Immune Dysfunction and Exclusion (TIDE) and Immunophenotype Score (IPS) were used to evaluate the immunotherapy response. The pRRophetic algorithm was used to estimate the efficiency of chemotherapeutic and targeted agents. Two machine learning algorithms (LASSO and RF) and multivariate logistic regression analysis were performed to construct a novel stemness-related classifier. RESULTS: We observed that patients in the high-mRNAsi group had a better prognosis than those in the low-mRNAsi group. Next, we identified 190 stemness-related differentially expressed genes (DEGs) that could categorize LUSC patients into two stemness subtypes. Patients in the stemness subtype B group with higher mRNAsi scores exhibited better overall survival (OS) than those in the stemness subtype A group. Immunotherapy prediction demonstrated that stemness subtype A has a better response to immune checkpoint inhibitors (ICIs). Furthermore, the drug response prediction indicated that stemness subtype A had a better response to chemotherapy but was more resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Finally, we constructed a nine-gene-based classifier to predict patients' stemness subtype and validated it in independent GEO validation sets. The expression levels of these genes were also validated in clinical tumor specimens. CONCLUSION: The stemness-related classifier could serve as a potential prognostic and treatment predictor and assist physicians in selecting effective treatment strategies for patients with LUSC in clinical practice.

Interventricular systolic asynchrony predicts prognosis in patients with systemic sclerosis-associated pulmonary arterial hypertension.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a serious complication of SSc with high mortality. Interventricular systolic asynchrony (IVSA) is observed in PAH patients, but the effect of IVSA and its association with long-term mortality and clinical events in SSc-associated PAH are unclear. This study aimed to investigate the impact of IVSA on the prognosis of SSc-associated PAH. METHODS: Between March 2010 and July 2018, a total of 60 consecutive patients with SSc-associated PAH were enrolled. The end point was a composite of all-cause mortality and clinical worsening. Asynchrony was assessed by colour-coded tissue Doppler imaging (TDI) echocardiography. The myocardial sustained systole curves (Sm) of the basal portion of the right ventricular (RV) free wall and left ventricular (LV) lateral wall were obtained. IVSA was defined as the time difference from the onset of the QRS complex to the end of Sm between LV and RV. RESULTS: Patients with greater IVSA time differences presented with advanced pulmonary vascular resistance (PVR). The IVSA time difference was an independent predictive factor (Hazard Ratio (HR) = 1.018, 95% CI: 1.005, 1.031, P =0.005) for the composite end point and was significantly associated with PVR (r = 0.399, R2=0.092, P =0.002). Kaplan-Meier survival curves showed that patients with greater IVSA had worse prognoses (log-rank P =0.001). CONCLUSION: In conclusion, IVSA analysed by colour-coded TDI echocardiography provided added value as a noninvasive, easy-to-use approach for assessing the prognosis of patients with SSc-associated PAH. A significant IVSA time difference identifies the subgroup of patients at high risk of a poor prognosis.

Protein-based prognostic signature for predicting the survival and immunotherapeutic efficiency of endometrial carcinoma.

BACKGROUND: Endometrial cancer (EC) is the most frequent malignancy of the female genital tract worldwide. Our study aimed to construct an effective protein prognostic signature to predict prognosis and immunotherapy responsiveness in patients with endometrial carcinoma. METHODS: Protein expression data, RNA expression profile data and mutation data were obtained from The Cancer Proteome Atlas (TCPA) and The Cancer Genome Atlas (TCGA). Prognosis-related proteins in EC patients were screened by univariate Cox regression analysis. Least absolute shrinkage and selection operator (LASSO) analysis and multivariate Cox regression analysis were performed to establish the protein-based prognostic signature. The CIBERSORT algorithm was used to quantify the proportions of immune cells in a mixed cell population. The Immune Cell Abundance Identifier (ImmuCellAI) and The Cancer Immunome Atlas (TCIA) web tools were used to predict the response to immunochemotherapy. The pRRophetic algorithm was used to estimate the sensitivity of chemotherapeutic and targeted agents. RESULTS: We constructed a prognostic signature based on 9 prognostic proteins, which could divide patients into high-risk and low-risk groups with distinct prognoses. A novel prognostic nomogram was established based on the prognostic signature and clinicopathological parameters to predict 1, 3 and 5-year overall survival for EC patients. The results obtained with Clinical Proteomic Tumor Analysis Consortium (CPTAC), Human Protein Atlas (HPA) and immunohistochemical (IHC) staining data from EC samples in our hospital supported the predictive ability of these proteins in EC tumors. Next, the CIBERSORT algorithm was used to estimate the proportions of 22 immune cell types. The proportions of CD8 T cells, T follicular helper cells and regulatory T cells were higher in the low-risk group. Moreover, we found that the prognostic signature was positively associated with high tumor mutation burden (TMB) and high microsatellite instability (MSI-H) status in EC patients. Finally, ImmuCellAI and TCIA analyses showed that patients in the low-risk group were more inclined to respond to immunotherapy than patients in the high-risk group. In addition, drug sensitivity analysis indicated that our signature had potential predictive value for chemotherapeutics and targeted therapy. CONCLUSION: Our study constructed a novel prognostic protein signature with robust predictive ability for survival and efficiency in predicting the response to immunotherapy, chemotherapy and targeted therapy. This protein signature represents a promising predictor of prognosis and response to cancer treatment in EC patients.

Cross-cultural validation of the Chinese version of the EmPHasis-10 questionnaire in connective tissue disease patients with pulmonary arterial hypertension and its relationship with risk stratification.

BACKGROUNDS: The EmPHasis-10 questionnaire is a disease-specific quality of life (QoL) measurement in patients with pulmonary hypertension. We report the results of cross-cultural validation of the Chinese version of the EmPHasis-10 and its relationship with risk stratification in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). METHODS: The Emphasis-10 was administered to 75 CTD-PAH patients along with the 36-item Medical Outcomes Study Short Form Survey (SF-36) and EuroQol five dimensions questionnaire (EQ-5D). The diagnosis of PAH was confirmed by right heart catheterization. Demographic and clinical data were obtained. Multivariable logistic regression was conducted based on the low risk profile assessed by a 4-strata risk assessment model (COMPERA 2.0) at follow-up. RESULTS: Date from 75 patients with CTD-PAH were analysed. The EmPHasis-10 demonstrated satisfactory reliability (Cronbach α = 0.95) and convergent validity showed by the significant relationship with WHO Functional Class (P = 0.003), SF-36 (P < 0.001) and EQ-5D (P = 0.002). EmPHasis-10 was significantly associated with achieving the low risk profile at 12 months of follow-up (Odds ratio: 0.928, P = 0.029) after adjusting for WHO Functional Class. CONCLUSION: EmPHasis-10 has acceptable reliability and validity in CTD-PAH patients and may serve as an additional parameter in risk stratification.

Systemic characterization of alternative splicing related to prognosis and immune infiltration in malignant mesothelioma.

BACKGROUND: Malignant mesothelioma (MM) is a relatively rare and highly lethal tumor with few treatment options. Thus, it is important to identify prognostic markers that can help clinicians diagnose mesothelioma earlier and assess disease activity more accurately. Alternative splicing (AS) events have been recognized as critical signatures for tumor diagnosis and treatment in multiple cancers, including MM. METHODS: We systematically examined the AS events and clinical information of 83 MM samples from TCGA database. Univariate Cox regression analysis was used to identify AS events associated with overall survival. LASSO analyses followed by multivariate Cox regression analyses were conducted to construct the prognostic signatures and assess the accuracy of these prognostic signatures by receiver operating characteristic (ROC) curve and Kaplan-Meier survival analyses. The ImmuCellAI and ssGSEA algorithms were used to assess the degrees of immune cell infiltration in MM samples. The survival-related splicing regulatory network was established based on the correlation between survival-related AS events and splicing factors (SFs). RESULTS: A total of 3976 AS events associated with overall survival were identified by univariate Cox regression analysis, and ES events accounted for the greatest proportion. We constructed prognostic signatures based on survival-related AS events. The prognostic signatures proved to be an efficient predictor with an area under the curve (AUC) greater than 0.9. Additionally, the risk score based on 6 key AS events proved to be an independent prognostic factor, and a nomogram composed of 6 key AS events was established. We found that the risk score was significantly decreased in patients with the epithelioid subtype. In addition, unsupervised clustering clearly showed that the risk score was associated with immune cell infiltration. The abundances of cytotoxic T (Tc) cells, natural killer (NK) cells and T-helper 17 (Th17) cells were higher in the high-risk group, whereas the abundances of induced regulatory T (iTreg) cells were lower in the high-risk group. Finally, we identified 3 SFs (HSPB1, INTS1 and LUC7L2) that were significantly associated with MM patient survival and then constructed a regulatory network between the 3 SFs and survival-related AS to reveal potential regulatory mechanisms in MM. CONCLUSION: Our study provided a prognostic signature based on 6 key events, representing a better effective tumor-specific diagnostic and prognostic marker than the TNM staging system. AS events that are correlated with the immune system may be potential therapeutic targets for MM.

MiR-7-5p-mediated downregulation of PARP1 impacts DNA homologous recombination repair and resistance to doxorubicin in small cell lung cancer.

BACKGROUND: Chemo-resistance is one of the major challenges in the therapy of small cell lung cancer (SCLC). Multiple mechanisms are thought to be involved in chemo-resistance during SCLC treatment, but unfortunately, these mechanisms have not been well elucidated. Herein, we investigated the role of miRNA in the resistance of SCLC cells to doxorubicin (Dox). METHODS: MiRNA microarray analysis revealed that several miRNAs, including miR-7-5p, were specifically decreased in Dox-resistant SCLC cells (H69AR) compared to parental cells (H69). The expression level of miR-7-5p was confirmed by qRT-PCR in Dox-resistant cells (H69AR and H446AR cells) and their parental cells. Bioinformatic analysis indicated that poly ADP-ribose polymerase 1 (PARP1) is a direct target of miR-7-5p. The binding sites of miR-7-5p in the PARP1 3' UTR were verified by luciferase reporter and Western blot assays. To investigate the role of miR-7-5p in the chemo-resistance of SCLC cells to doxorubicin, mimic or inhibitor of miR-7-5p was transfected into SCLC cells, and the effect of miR-7-5p on homologous recombination (HR) repair was analyzed by HR reporter assays. Furthermore, the expression of HR repair factors (Rad51 and BRCA1) induced by doxorubicin was detected by Western blot and immunofluorescent staining in H446AR cells transfected with miR-7-5p mimic. RESULTS: The expression level of miR-7-5p was remarkably reduced (4-fold) in Dox-resistant SCLC cells (H69AR and H446AR cells) compared with that in parental cells (H69 and H446 cells). Poly ADP-ribose polymerase 1 (PARP1) is a direct target of miR-7-5p, and PARP1 expression was downregulated by miR-7-5p. MiR-7-5p impeded Dox-induced HR repair by inhibiting the expression of HR repair factors (Rad51 and BRCA1) that resulted in resensitizing SCLC cells to doxorubicin. CONCLUSIONS: Our findings provide evidence that miR-7-5p targets PARP1 to exert its suppressive effects on HR repair, indicating that the alteration of the expression of miR-7-5p may be a promising strategy for overcoming chemo-resistance in SCLC therapy.

Right Ventricular Function is Associated With Quality of Life in Patients With Systemic Lupus Erythematosus Associated Pulmonary Arterial Hypertension.

BACKGROUND: Right ventricular (RV) function has been identified as an important determinant of outcome in patients with pulmonary hypertension. We aimed to investigate the relationship between echocardiographic-derived RV function and health-related quality of life (HRQOL) in patients with systemic lupus erythematosus associated pulmonary arterial hypertension (SLE-APAH), and to identify the best echocardiographic parameter for evaluating RV function in these patients. METHODS: Sixty (60) consecutive patients with SLE-APAH (all female, mean age 33.6±8.2years) were recruited from May 2013 to November 2014. Echocardiograph, right heart catheterisation, SLE disease activity index (SLEDAI), and functional status and SF-36 generic questionnaire were assessed. RESULTS: Echocardiograph-derived RV systolic function was significantly correlated with haemodynamics (p<0.05), with tricuspid annular plane systolic excursion (TAPSE) showing the strongest correlation with pulmonary vascular resistance (R2=0.278, p<0.001) and cardiac index (R2=0.215, p<0.001). Patients with a TAPSE<17mm had a shorter 6-minute-walk-distance (6MWD), lower mixed venous oxygen saturation, and higher plasma N-terminal pro-brain natriuretic peptide (p<0.05). Patients with TAPSE <17mm had lower physical component summary (PCS) and mental component summary (MCS) scores than those with TAPSE ≥17mm (35.5±13.2 vs. 55.0±15.5; 46.3±15.3 vs. 64.8±18.8, respectively, all p<0.05). On multiple regression analysis, a TAPSE <17mm was independently related to lower PCS (ß -15.797, 95% confidence interval [CI] -24.746 to -6.848, p=0.001) and lower MCS (ß -12.887, 95% CI -24.018 to -1.755, p=0.024). CONCLUSIONS: TAPSE is a useful index for RV function assessment, and is associated with HRQOL in patients with SLE-APAH.

Predictors of health-related quality of life in patients with systemic lupus erythematosus associated pulmonary arterial hypertension.

OBJECTIVES: Understanding health-related quality of life (HRQoL) is important in the management of patients with systemic lupus erythematosus associated pulmonary arterial hypertension (SLE-APAH), however, little is known about HRQoL and its determinants in these patients. METHODS: A total of 60 female SLE-APAH patients with mean age of 33.5 years were prospectively recruited from May 2013 to November 2014. Right heart catheter, SF-36 generic questionnaire, disease activity and functional status were assessed in all patients. RESULTS: The median duration of SLE was 5 years. Thirty-five participants were with low disease activity (SLEDAI: 0-4). Patients with SLE-APAH reported significant impairment in HRQoL. The mean physical component summary (PCS) and mental component summary (MCS) scores were 46.4 and 56.9, respectively. Among haemodynamic measurements, higher pulmonary vascular resistance and lower cardiac output (CO) were associated with worse HRQoL. Lower body mass index (BMI), lower mean blood pressure and higher disease activity were also associated with poor HRQoL. Multivariate analysis revealed that lower SLEDAI and higher mean blood pressure were predictors for better PCS. However, higher CO (CO≥4L/min) was the only parameter independently associated with both better PCS and MCS. CONCLUSIONS: Self-reported HRQoL was impaired in patients with SLE-APAH. Higher CO was the most important predictor for better HRQoL in these patients.

Telangiectasia as a potential clinical marker of microvascular lesions in systemic sclerosis patients from EUSTAR data in China.

OBJECTIVES: To investigate the prevalence and clinical relevance of telangiectasia in Chinese patients with systemic sclerosis (SSc). METHODS: Data from 230 SSc EUSTAR patients from Peking Union Medical College Hospital (2009-2011) that fulfilled the 1980 American College of Rheumatology SSc classification criteria were prospectively collected. Demographic, clinical, and laboratory data were calculated between groups with and without telangiectasia, and a six-minute walk test, pulmonary function test (PFT), transthoracic echocardiography (TTE), right heart catheterisation (RHC) and modified Rodnan skin score (mRSS) were performed. RESULTS: 96 patients (41.7%) were diagnosed with telangiectasia. There were no significant differences between patients with and without telangiectasia based on gender, age at onset, Raynaud's phenomenon (RP) duration, or SSc classification. Disease duration both from RP onset of patients and from first non-RP manifestation of patients with telangiectasia was significantly longer than patients without (p<0.05). RP (97.9% vs. 90.3%), finger/toe sclerosis (96.9% vs. 88.1%), facial sclerosis (68.8% vs. 53.7%), digital ulcers (DUs; 40.6% vs. 23.1%), digital pitting (49.0% vs. 33.8%), joint contracture (20.8% vs. 10.4%) and erythrocyte sedimentation rate elevation (26.7% vs. 14.8%) were significantly greater in telangiectasia patients (p<0.05). There were no differences in autoantibody development between patients with and without telangiectasia (p>0.05). PFT showed that forced vital capacity (77.0±17.26 vs. 83.05±16.53, p=0.005) and diffusion capacity for CO of the lung (58.9±19.4 vs. 65.7±19.7, p=0.030) were lower, while forced expiratory volume ratio (87.02±7.8 vs. 84.33±7.1, p=0.029) was higher in SSc with telangiectasia. Pulmonary artery hypertension (PAH) prevalence (25.0% vs. 14.2%) was significantly greater in patients with telangiectasia. CONCLUSIONS: Telangiectasia are common in Chinese SSc patients and usually associated with DUs, RP, and PAH. Telangiectasia could be a clinical marker of microvascular disease in SSc.

Disease activity is related to acute response to vasodilator in pulmonary artery hypertension associated with systemic lupus erythematosus.

BACKGROUND: No previous study has been done on whether systemic lupus erythematosus (SLE) disease activity is related to the hemodynamics and right ventricular (RV) function in patients with SLE-associated pulmonary artery hypertension (SLE-APAH). METHODS AND RESULTS: This study prospectively recruited 54 patients (mean age, 32.8±8.4 years; 92.6% female) with SLE-APAH, including 34 patients with SLE disease activity index (SLEDAI) <5 (low score) and 20 with SLEDAI ≥5 (high score). All patients underwent right heart catheterization and iloprost inhalation, and echocardiography was performed before and immediately after iloprost inhalation. There was no difference in baseline mean pulmonary artery pressure (mPAP) between the 2 groups; pulmonary vascular resistance (PVR) was significantly higher and cardiac index was significantly lower in the low-SLEDAI group. The patients with low SLEDAI had larger RV size and worse RV systolic function on echocardiography. After iloprost inhalation, the patients with low SLEDAI had a greater decrease in mPAP and PVR than those with high SLEDAI, while significantly increased RV systolic function was found only in the low-SLEDAI group. CONCLUSIONS: SLE activity is related to hemodynamics and RV function in SLE-APAH patients, and those with low SLEDAI might have better acute response to vasodilator inhalation.

Investigating the impact of Wnt pathway-related genes on biomarker and diagnostic model development for osteoporosis in postmenopausal females.

The Wnt signaling pathway is essential for bone development and maintaining skeletal homeostasis, making it particularly relevant in osteoporosis patients. Our study aimed to identify distinct molecular clusters associated with the Wnt pathway and develop a diagnostic model for osteoporosis in postmenopausal Caucasian women. We downloaded three datasets (GSE56814, GSE56815 and GSE2208) related to osteoporosis from the GEO database. Our analysis identified a total of 371 differentially expressed genes (DEGs) between low and high bone mineral density (BMD) groups, with 12 genes associated with the Wnt signaling pathway, referred to as osteoporosis-associated Wnt pathway-related genes. Employing four independent machine learning models, we established a diagnostic model using the 12 osteoporosis-associated Wnt pathway-related genes in the training set. The XGB model showed the most promising discriminative potential. We further validate the predictive capability of our diagnostic model by applying it to three external datasets specifically related to osteoporosis. Subsequently, we constructed a diagnostic nomogram based on the five crucial genes identified from the XGB model. In addition, through the utilization of DGIdb, we identified a total of 30 molecular compounds or medications that exhibit potential as promising therapeutic targets for osteoporosis. In summary, our comprehensive analysis provides valuable insights into the relationship between the osteoporosis and Wnt signaling pathway.

Uncovering a novel DNA repair-related radiosensitivity model for evaluation of radiotherapy susceptibility in uterine corpus endometrial cancer.

Background: Uterine corpus endometrial cancer (UCEC) exhibit heterogeneity in their DNA repair capacity, which can impact their response to radiotherapy. Our study aimed to identify potential DNA repair-related biomarkers for predicting radiation response in UCEC. Methods: We conducted a thorough analysis of 497 UCEC samples obtained from TCGA database. Using LASSO-COX regression analysis, we constructed a radiosensitivity signature and subsequently divided patients into the radiosensitive (RS) and the radioresistant (RR) groups based on their radiosensitivity index. The GSVA and GSEA were performed to explore functional annotations. The CIBERSORT and ESTIMATE algorithms were utilized to investigate the immune infiltration status of the two groups. Additionally, we utilized the Tumor Immune Dysfunction and Exclusion (TIDE), Immunophenotype Score (IPS), and pRRophetic algorithms to predict the effectiveness of different treatment modalities. Results: We constructed a radiosensitivity index consists of four DNA repair-related genes. Patients in the RS group demonstrated significantly improved prognosis compared to patients in the RR group when treated with radiotherapy. We observed that the RS group exhibited a higher proportion of the POLE ultra-mutated subtype, while the RR group had a higher proportion of the copy number high subtype. GSVA enrichment analysis revealed that the RS group exhibited enrichment in DNA damage repair pathways. Notably, the RS group demonstrated a higher proportion of naïve B cells and follicular helper T cells, while regulatory T cells (Tregs) and memory B cells were more abundant in the RR group. Furthermore, patients in the RS-PD-L1-high subgroup exhibited enrichment in immune-related pathways and increased sensitivity to immunotherapy, which is likely to contribute to their improved prognosis. Additionally, we conducted in vitro experiments to validate the expression of radiosensitivity genes in non-radioresistant (AN3CA) and radioresistant (AN3CA/IR) endometrial cancer cells. Conclusions: In conclusion, our research successfully constructed a radiosensitivity signature with robust predictive capacity. These findings shed light on the association between immune activation, PD-L1 expression, and the response to immunotherapy in the context of radiotherapy.

Case Report: Temporary pacing using active fixation lead and invasive electrophysiology studies for immune checkpoint inhibitor associated reversible advanced atrioventricular block.

A case of immune checkpoint inhibitors (ICIs)-associated myocarditis with reversible advanced atrioventricular block (AVB) was reported. We innovatively used active fixation lead connected to an external device for prolonged temporary pacing until atrioventricular conduction recovered. Invasive electrophysiology studies were performed to evaluate atrioventricular conduction in detail. Long-term follow-up for nearly 120-days and repeated long-term electrocardiography was conducted to ensure the conduction system was truly recovered.

The clinical characteristics and outcomes of patients with systemic sclerosis with myocardial involvement.

BACKGROUND: Myocardial involvement (MI) is the primary cause of death in patients with systemic sclerosis (SSc). We analyzed patients with SSc and MI to identify their characteristics and outcome. METHOD: We retrospectively collected data from SSc patients with MI admitted to Peking Union Medical College Hospital between January 2012 and May 2021. SSc patients without MI were randomly selected as controls after matching age and gender at a ratio of 1:3. RESULTS: In total, 21 SSc patients (17 females) with MI were enrolled. The mean age at SSc onset was 42.3 ± 15.1 years old. Compared with controls, myositis (42.9% vs. 14.3%, P = 0.014) and elevation of CK (33.3% vs. 4.8%, P = 0.002) were more common in patients with MI. Of the 7 patients without cardiovascular symptoms, 3 /5 showed elevations in cardiac troponin-I (cTnI), 6 showed elevations of N-terminal brain natriuretic peptide (NT-proBNP). Eleven patients were followed up for a median period of 15.5 months and four patients developed newly occurring left ventricular ejection fraction (LVEF) < 50%. CONCLUSION: One third of SSc patients with MI were asymptomatic. Regular monitoring of CTnI, NT-proBNP and echocardiography is helpful for the diagnosis of MI during the early stages. Its prognosis is poor.

Case Report: Left bundle branch pacing in an amyloid light-chain cardiac amyloidosis patient with atrioventricular block.

Introduction: Amyloid light-chain cardiac amyloidosis is a progressive infiltrative disease characterized by the deposition of amyloid fibrils in the cardiac tissue, which can cause serious atrioventricular block requiring pacemaker implantation. Left bundle branch pacing has emerged as an alternative method for delivering physiological pacing to achieve electrical synchrony of the left ventricle. However, left bundle branch pacing in patients with amyloid light-chain cardiac amyloidosis has not been studied in detail. Therefore, in this study, we present a case of left bundle branch pacing in a patient with amyloid light-chain cardiac amyloidosis. Case summary: A 66-year-old male patient with amyloid light-chain cardiac amyloidosis presented with syncope for 1 month. Holter monitoring revealed intermittent third-degree atrioventricular block. Left bundle branch pacing was performed successfully. During the 1-year follow-up, it was observed that the left bundle branch capture threshold remained stable without any pacemaker-related complications or left ventricle systolic dysfunction, and there was no recurrence of syncope. Conclusion: Left bundle branch pacing appears to be a safe and feasible option for patients with amyloid light-chain cardiac amyloidosis experiencing atrioventricular block.

Determination of a DNA repair-related gene signature with potential implications for prognosis and therapeutic response in pancreatic adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) is one of the leading causes of cancer death worldwide. Alterations in DNA repair-related genes (DRGs) are observed in a variety of cancers and have been shown to affect the development and treatment of cancers. The aim of this study was to develop a DRG-related signature for predicting prognosis and therapeutic response in PAAD. Methods: We constructed a DRG signature using least absolute shrinkage and selection operator (LASSO) Cox regression analysis in the TCGA training set. GEO datasets were used as the validation set. A predictive nomogram was constructed based on multivariate Cox regression. Calibration curve and decision curve analysis (DCA) were applied to validate the performance of the nomogram. The CIBERSORT and ssGSEA algorithms were utilized to explore the relationship between the prognostic signature and immune cell infiltration. The pRRophetic algorithm was used to estimate sensitivity to chemotherapeutic agents. The CellMiner database and PAAD cell lines were used to investigate the relationship between DRG expression and therapeutic response. Results: We developed a DRG signature consisting of three DRGs (RECQL, POLQ, and RAD17) that can predict prognosis in PAAD patients. A prognostic nomogram combining the risk score and clinical factors was developed for prognostic prediction. The DCA curve and the calibration curve demonstrated that the nomogram has a higher net benefit than the risk score and TNM staging system. Immune infiltration analysis demonstrated that the risk score was positively correlated with the proportions of activated NK cells and monocytes. Drug sensitivity analysis indicated that the signature has potential predictive value for chemotherapy. Analyses utilizing the CellMiner database showed that RAD17 expression is correlated with oxaliplatin. The dynamic changes in three DRGs in response to oxaliplatin were examined by RT-qPCR, and the results show that RAD17 is upregulated in response to oxaliplatin in PAAD cell lines. Conclusion: We constructed and validated a novel DRG signature for prediction of the prognosis and drug sensitivity of patients with PAAD. Our study provides a theoretical basis for further unraveling the molecular pathogenesis of PAAD and helps clinicians tailor systemic therapies within the framework of individualized treatment.

Determination of a prediction model for therapeutic response and prognosis based on chemokine signaling-related genes in stage I-III lung squamous cell carcinoma.

Background: The chemokine signaling pathway plays an essential role in the development, progression, and immune surveillance of lung squamous cell carcinoma (LUSC). Our study aimed to systematically analyze chemokine signaling-related genes (CSRGs) in LUSC patients with stage I-III disease and develop a prediction model to predict the prognosis and therapeutic response. Methods: A total of 610 LUSC patients with stage I-III disease from three independent cohorts were included in our study. Least absolute shrinkage and selection operator (LASSO) and stepwise multivariate Cox regression analyses were used to develop a CSRG-related signature. GSVA and GSEA were performed to identify potential biological pathways. The ESTIMATE algorithm, ssGSEA method, and CIBERSORT analyses were applied to explore the correlation between the CSRG signature and the tumor immune microenvironment. The TCIA database and pRRophetic algorithm were utilized to predict responses to immunochemotherapy and targeted therapy. Results: A signature based on three CSRGs (CCL15, CXCL7, and VAV2) was developed in the TCGA training set and validated in the TCGA testing set and GEO external validation sets. A Kaplan-Meier survival analysis revealed that patients in the high-risk group had significantly shorter survival than those in the low-risk group. A nomogram combined with clinical parameters was established for clinical OS prediction. The calibration and DCA curves confirmed that the prognostic nomogram had good discrimination and accuracy. An immune cell landscape analysis demonstrated that immune score and immune-related functions were abundant in the high-risk group. Interestingly, the proportion of CD8 T-cells was higher in the low-risk group than in the high-risk group. Immunotherapy response prediction indicated that patients in the high-risk group had a better response to CTLA-4 inhibitors. We also found that patients in the low-risk group were more sensitive to first-line chemotherapeutic treatment and EGFR tyrosine kinase inhibitors. In addition, the expression of genes in the CSRG signature was validated by qRT‒PCR in clinical tumor specimens. Conclusion: In the present study, we developed a CSRG-related signature that could predict the prognosis and sensitivity to immunochemotherapy and targeted therapy in LUSC patients with stage I-III disease. Our study provides an insight into the multifaceted role of the chemokine signaling pathway in LUSC and may help clinicians implement optimal individualized treatment for patients.

Right Ventricle to Pulmonary Artery Coupling Predicts the Risk Stratification in Patients With Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is a serious complication of systemic sclerosis (SSc). PAH has high mortality, and risk assessment is critical for proper management. Whether the right ventricle to pulmonary artery (RV-PA) coupling accurately assesses risk status and predicts prognosis in patients with SSc-associated PAH has not been investigated. Methods: Between March 2010 and July 2018, 60 consecutive patients with SSc-associated PAH diagnosed by right heart catheterization were enrolled prospectively, and the mean follow-up period was 52.9 ± 27.0 months. The RV-PA coupling was assessed by the ratio of tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) which was obtained by transthoracic echocardiography. The simplified risk stratification strategy was applied to assess the risk level of participants, and the endpoint was a composite of all-cause death and clinical worsening. Results: The receiver operating characteristic (ROC) curve of the ability to determine high-risk patients identified the optimal cut-off value of the TAPSE/PASP ratio as 0.194 mm/mmHg, and the ratio appeared to be a reliable indicator in the stratification of patients with high risk (area under the curve = 0.878, ROC P-value = 0.003), which showed the highest positive likelihood ratio (LR) (5.4) and the lowest negative LR (0) among a series of echocardiographic parameters. The TAPSE/PASP ratio was an independent predictive factor (HR = 0.01, 95% CI: 0.00-0.77, P = 0.037) for the composite endpoint, and patients with a TAPSE/PASP ratio >0.194 had a better overall survival for both the composite endpoint (log-rank χ2 = 5.961, P = 0.015) and all-cause mortality (log-rank χ2 = 8.004, P = 0.005) compared to the patients with a TAPSE/PASP ≤ 0.194. Conclusion: RV-PA coupling assessed by the TAPSE/PASP ratio provides added value as a straightforward and non-invasive approach for predicting risk stratification of patients with SSc-associated PAH. Meanwhile, a lower TAPSE/PASP ratio identified a subgroup with worse prognosis.