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Current Gene Therapy Jun 2024The Ribonucleoside-diphosphate Reductase subunit M2 (RRM2) is known to be overexpressed in various cancers, though its specific functional implications remain unclear....
INTRODUCTION
The Ribonucleoside-diphosphate Reductase subunit M2 (RRM2) is known to be overexpressed in various cancers, though its specific functional implications remain unclear. This aims to elucidate the role of RRM2 in the progression of Lung Adenocarcinoma (LUAD) by exploring its involvement and potential impact.
METHODS
RRM2 data were sourced from multiple databases to assess its diagnostic and prognostic significance in LUAD. We evaluated the association between RRM2 expression and immune cell infiltration, analyzed its function, and explored the effects of modulating RRM2 expression on LUAD cell characteristics through laboratory experiments.
RESULTS
RRM2 was significantly upregulated in LUAD tissues and cells compared to normal counterparts (p<0.05), with rare genetic alterations noted (approximately 2%). This overexpression clearly distinguished LUAD from normal tissue (area under the curve (AUC): 0.963, 95% confidence intervals (CI): 0.946-0.981). Elevated RRM2 expression was significantly associated with adverse clinicopathological characteristics and poor prognosis in LUAD patients. Furthermore, a positive association was observed between RRM2 expression and immune cell infiltration. Pathway analysis revealed a critical connection between RRM2 and the cell cycle signaling pathway within LUAD. Targeting RRM2 inhibition effectively suppressed LUAD cell proliferation, migration, and invasion while promoting apoptosis. This intervention also modified the expression of several crucial proteins, including the downregulation of CDC25A, CDC25C, RAD1, Bcl-2, and PPM1D and the upregulation of TP53 and Bax (p < 0.05).
CONCLUSION
Our findings highlight the potential utility of RRM2 expression as a biomarker for diagnosing and predicting prognosis in LUAD, shedding new light on the role of RRM2 in this malignancy.
PubMed: 38920074
DOI: 10.2174/0115665232286359240611051307 -
Nucleosides, Nucleotides & Nucleic Acids Jun 2024Identifying subtypes of lung adenocarcinoma (LUAD) patients based on mitochondrial energy metabolism and immunotherapy sensitivity is essential for precision cancer...
BACKGROUND
Identifying subtypes of lung adenocarcinoma (LUAD) patients based on mitochondrial energy metabolism and immunotherapy sensitivity is essential for precision cancer treatment.
METHODS
LUAD subtypes were identified using unsupervised consensus clustering, and results were subjected to immune and tumor mutation analyses. DEGs between subtypes were identified by differential analysis. Functional enrichment and PPI network analyses were conducted. Patients were classified into high and low expression groups based on the expression of the top 10 hub genes, and survival analysis was performed. Drugs sensitive to feature genes were screened based on the correlation between hub gene expression and drug IC value. qRT-PCR and western blot were used for gene expression detection, and CCK-8 and flow cytometry were for cell viability and apoptosis analysis.
RESULTS
Cluster-1 had significantly higher overall survival and a higher degree of immunoinfiltration and immunophenotypic score, but a lower TIDE score, DEPTH score, and TMB. Enrichment analysis showed that pathways and functions of DEGs between two clusters were mainly related to the interaction of receptor ligands with intracellular proteases. High expression of hub genes corresponded to lower patient survival rates. The predicted drugs with high sensitivity to feature genes were CDK1: Ribavirin (0.476), CCNB2: Hydroxyurea (0.474), Chelerythrine (0.470), and KIF11: Ribavirin (0.471). KIF11 and CCNB2 were highly expressed in LUAD cells and promoted cell viability and inhibited cell apoptosis.
CONCLUSION
This study identified two subtypes of LUAD, with cluster-1 being more suitable for immunotherapy. These results provided a reference for the development of precision immunotherapy for LUAD patients.
PubMed: 38920027
DOI: 10.1080/15257770.2024.2369093 -
ACS Applied Bio Materials Jun 2024β-Thalassemia especially transfusion-dependent thalassemia (TDT) associates with a hypercoagulable state, which is the main cause of thromboembolic events (TEE). Plasma...
A Compact Differential Dynamic Microscopy-based Device (cDDM): An Approach Tool for Early Detection of Hypercoagulable State in Transfusion-Dependent-β-Thalassemia Patients.
β-Thalassemia especially transfusion-dependent thalassemia (TDT) associates with a hypercoagulable state, which is the main cause of thromboembolic events (TEE). Plasma viscosity and rheological parameters could be essential markers for determining hypercoagulable state in β-thalassemia patients. The traditional methods for measuring viscosity are often limited by large sample volumes and are impractical for routine clinical monitoring. The compact differential dynamic microscopy-based device (cDDM), an optical microscopy for quantitative rheological assessment, was developed and applied for prognosis of the hypercoagulable state in β-TDT with and without splenectomy. The device was performed plasma viscosity measurement using low plasma volume (8 μL) and revealed a value as modulus of complex viscosity |η(ω)| in 7 min. We also parallelly demonstrated the correlation of the viscosity and related-coagulable parameters: complete blood count, prothrombin time (PT), activated partial thromboplastin time (APTT), protein C (PC), protein S (PS), CD62P and CD63 expression, and platelet aggregation test. The thalassemia plasma exhibited a higher value of |η(ω)| than healthy plasma, which can represent a different viscoelastic property among the groups. Even all related-coagulable parameters indicated hypercoagulable state in both nonsplenectomies and splenectomies β-TDT patients when compared to control, only high platelet numbers significantly correlated to high plasma viscosity in the splenectomy group. However, the other coagulable parameters have shown a trend of positive relationship with high plasma viscosity in all β-1thalassemia TDT patients. The relative results suggested that our device would be an approach tool for early detection of hypercoagulable state in transfusion-dependent-β-thalassemia patients, which can help to prevent TEE and the critical consequent-complications.
PubMed: 38920024
DOI: 10.1021/acsabm.4c00516 -
Journal of Mother and Child Feb 2024Van der Woude syndrome (VWS) is a rare congenital malformation characterized by lower lip pits among patients with a lip and/or palate cleft. It is transmitted by an...
BACKGROUND
Van der Woude syndrome (VWS) is a rare congenital malformation characterized by lower lip pits among patients with a lip and/or palate cleft. It is transmitted by an autosomal dominant inheritance with variable expressivity.
METHODS
The study group consisted of 24 consecutive patients (13 males and 11 females) with VWS operated on at a single center between 2009 and 2022. They suffered from: bilateral cleft lip and palate - 6 patients; unilateral cleft lip and palate - 9 patients; cleft lip - 1 patient; and isolated cleft palate - 8 patients.
RESULTS
In 16 (66%) cases pits of lower lip occurred on both side of midline, while in 8 (34%) the pits were detected unilaterally. The primary cleft repairs were performed according to one-stage principle at the mean age of 8.6 months (SD 1.4, range 6-12). In all patients lower lip pits repairs were performed after the primary cleft repairs as a separate procedure at the mean age of 37 months (SD 11.3 range 14-85). The mean number of all primary repairs of the syndrome-both cleft defect and lower lip pits repairs-was 2.46. Nine patients (37.5%) required additional secondary corrections of the lower lip due to the poor aesthetic post-operative outcome.
CONCLUSIONS
The frequent need for secondary corrections of residual lower lip deformities indicates the considerable difficulties in obtaining a satisfactory outcome of the repairs to lip pits caused by VWS. The average number of the primary surgical interventions in evaluated material remained low.
Topics: Humans; Cleft Lip; Female; Cleft Palate; Male; Retrospective Studies; Lip; Abnormalities, Multiple; Child, Preschool; Infant; Child; Treatment Outcome; Plastic Surgery Procedures; Cysts
PubMed: 38920016
DOI: 10.34763/jmotherandchild.20242801.d-24-00020 -
Minerva Urology and Nephrology Jun 2024The role of kidney-sparing surgery in patients with high-risk upper urinary tract urothelial carcinoma is controversial. The present study aimed to assess oncological... (Comparative Study)
Comparative Study
BACKGROUND
The role of kidney-sparing surgery in patients with high-risk upper urinary tract urothelial carcinoma is controversial. The present study aimed to assess oncological and functional outcomes of robot-assisted distal ureterectomy in patients with high-risk distal ureteral tumors.
METHODS
The ROBUUST 2.0 multicenter international (2015-2022) dataset was used for this retrospective cohort analysis. High-risk patients with distal ureteral tumors were divided based on type of surgery: robot-assisted distal ureterectomy or robot-assisted nephroureterectomy. A survival analysis was performed for local recurrence-free survival, distant metastasis-free survival, and overall survival. After adjusting for clinical features of the high-risk prognostic group, Cox proportional hazard model was plotted to evaluate significant predictors of time-to-event outcomes.
RESULTS
Overall, 477 patients were retrieved, of which 58 received robot-assisted distal ureterectomy and 419 robot-assisted nephroureterectomy, respectively, with a mean (±SD) follow-up of 29.6 months (±2.6). The two groups were comparable in terms of baseline features. At survival analysis, no significant difference was observed in terms of recurrence-free survival (P=0.6), metastasis-free survival (P=0.5) and overall survival (P=0.7) between robot-assisted distal ureterectomy and robot-assisted nephroureterectomy. At Cox regression analysis, type of surgery was never a significant predictor of worse oncological outcomes. At last follow-up patients undergoing robot-assisted distal ureterectomy had significantly better postoperative renal function.
CONCLUSIONS
Comparable outcomes in terms of recurrence-free survival, metastasis-free survival, and overall survival between robot-assisted distal ureterectomy and robot-assisted nephroureterectomy patients, and better postoperative renal function preservation in the former group were observed. Kidney-sparing surgery should be considered as a potential option for selected patients with high-risk distal ureteral UTUC.
Topics: Humans; Retrospective Studies; Male; Robotic Surgical Procedures; Female; Aged; Ureteral Neoplasms; Middle Aged; Carcinoma, Transitional Cell; Ureter; Nephroureterectomy; Treatment Outcome
PubMed: 38920013
DOI: 10.23736/S2724-6051.24.05737-9 -
Frontiers in Surgery 2024Lymph node (LN) status is a vital prognostic factor for patients. However, there has been limited focus on predicting the prognosis of patients with late-onset gastric...
INTRODUCTION
Lymph node (LN) status is a vital prognostic factor for patients. However, there has been limited focus on predicting the prognosis of patients with late-onset gastric cancer (LOGC). This study aimed to investigate the predictive potential of the log odds of positive lymph nodes (LODDS), lymph node ratio (LNR), and pN stage in assessing the prognosis of patients diagnosed with LOGC.
METHODS
The LOGC data were obtained from the Surveillance, Epidemiology, and End Results database. This study evaluated and compared the predictive performance of three LN staging systems. Univariate and multivariate Cox regression analyses were carried out to identify prognostic factors for overall survival (OS). Three machine learning methods, namely, LASSO, XGBoost, and RF analyses, were subsequently used to identify the optimal LN staging system. A nomogram was built to predict the prognosis of patients with LOGC. The efficacy of the model was demonstrated through receiver operating characteristic (ROC) curve analysis and decision curve analysis.
RESULTS
A total of 4,743 patients with >16 removed lymph nodes were ultimately included in this investigation. Three LN staging systems demonstrated significant performance in predicting survival outcomes ( < 0.001). The LNR exhibited the most important prognostic ability, as evidenced by the use of three machine learning methods. Utilizing independent factors derived from multivariate Cox regression analysis, a nomogram for OS was constructed.
DISCUSSION
The calibration, C-index, and AUC revealed their excellent predictive performance. The LNR demonstrated a more powerful performance than other LN staging methods in LOGC patients after surgery. Our novel nomogram exhibited superior clinical feasibility and may assist in patient clinical decision-making.
PubMed: 38919979
DOI: 10.3389/fsurg.2024.1376702 -
Frontiers in Genetics 2024Chemotherapy resistance remains a significant challenge in the treatment of pancreatic adenocarcinoma (PDAC), particularly in relation to gemcitabine (Gem), a commonly...
Chemotherapy resistance remains a significant challenge in the treatment of pancreatic adenocarcinoma (PDAC), particularly in relation to gemcitabine (Gem), a commonly used chemotherapeutic agent. MicroRNAs (miRNAs) are known to influence cancer progression and chemoresistance. This study investigates the association between miRNA expression profiles and gemcitabine resistance in PDAC. The miRNA expression profiles of a gemcitabine-sensitive (GS) PDAC cell line, MIA PaCa-2, and its gemcitabine-resistant (GR) progeny, MIA PaCa-2 GR, were analyzed. miRNA sequencing (miRNA-seq) was employed to identify miRNAs expressed in these cell lines. Differential expression analysis was performed, and Ingenuity Pathway Analysis (IPA) was utilized to elucidate the biological functions of the differentially expressed miRNAs. A total of 1867 miRNAs were detected across both cell lines. Among these, 97 (5.2%) miRNAs showed significant differential expression between the GR and GS cell lines, with 65 (3.5%) miRNAs upregulated and 32 (1.7%) miRNAs downregulated in the GR line. The most notably altered miRNAs were implicated in key biological processes such as cell proliferation, migration, invasion, chemosensitization, alternative splicing, apoptosis, and angiogenesis. A subset of these miRNAs was further analyzed in patient samples to identify potential markers for recurrent tumors. The differential miRNA expression profiles identified in this study highlight the complex regulatory roles of miRNAs in gemcitabine resistance in PDAC. These findings suggest potential targets for improving prognosis and tailoring treatment strategies in PDAC patients, particularly those showing resistance to gemcitabine. Future research should focus on validating these miRNAs as biomarkers for resistance and exploring their therapeutic potential in overcoming chemoresistance.
PubMed: 38919953
DOI: 10.3389/fgene.2024.1393353 -
International Journal of Chronic... 2024Inhaled corticosteroid (ICS) therapy has been demonstrated to reduce the risk of COPD exacerbations. It should only be prescribed to COPD patients who are not adequately... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Inhaled corticosteroid (ICS) therapy has been demonstrated to reduce the risk of COPD exacerbations. It should only be prescribed to COPD patients who are not adequately controlled by dual long-acting bronchodilator therapy and who have ≥2 exacerbations per year and a blood eosinophil count ≥300cells/µL. ICS therapy is widely prescribed outside guidelines to COPD patients, making ICS withdrawal an important consideration. This systematic review aims to provide an up-to-date analysis of the effect of ICS withdrawal on exacerbation frequency, change in lung function (FEV) and to determine the proportion of COPD patients who resume ICS therapy following withdrawal.
METHODS
Randomised controlled trials (RCTs) and observational studies which compared ICS withdrawal with ICS continuation treatment were included. Cochrane Central, Web of Science, CINHAL, Embase and OVID Medline were searched. Risk of bias was assessed using the Cochrane RoB2 tool and the Newcastle-Ottawa Scale. Quality assessment of RCTs was conducted using GRADE. Meta-analysis of post-hoc analyses of RCTs of ICS withdrawal, stratified by blood eosinophil count (BEC), was undertaken.
RESULTS
Ten RCTs (6642 patients randomised) and 6 observational studies (160,029 patients) were included in the results. When ICS was withdrawn and long-acting bronchodilator therapy was maintained, there was no consistent difference in exacerbation frequency or lung function change between the ICS withdrawal and continuation trial arms. The evidence for these effects was of moderate quality. There was insufficient evidence to draw a firm conclusion on the proportion of patients who resumed ICS therapy following withdrawal (estimated range 12-93% of the participants).
DISCUSSION
Withdrawal of ICS therapy from patients with COPD is safe and feasible but should be accompanied by maintenance of bronchodilation therapy for optimal outcomes.
Topics: Pulmonary Disease, Chronic Obstructive; Humans; Administration, Inhalation; Lung; Adrenal Cortex Hormones; Disease Progression; Forced Expiratory Volume; Treatment Outcome; Bronchodilator Agents; Randomized Controlled Trials as Topic; Observational Studies as Topic; Time Factors; Aged; Drug Administration Schedule; Risk Factors; Middle Aged; Female; Male
PubMed: 38919905
DOI: 10.2147/COPD.S436525 -
Oncoimmunology 2024Spartalizumab (PDR001) is a humanized IgG4 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We conducted a single-arm, phase 2 trial to investigate...
UNLABELLED
Spartalizumab (PDR001) is a humanized IgG4 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We conducted a single-arm, phase 2 trial to investigate the efficacy and safety of spartalizumab in patients with refractory esophageal squamous cell carcinoma (ESCC). Patients with histologically confirmed ESCC who experienced disease progression after platinum-based chemotherapy received 300 mg of intravenous spartalizumab every three weeks until disease progression or occurrence of unacceptable toxicity. The primary endpoint was centrally assessed objective response according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events were closely monitored throughout the study. From March 2020 through April 2021, 44 patients with ESCC were enrolled. Of the 44 patients, the objective response rate was 20.5% (95% confidence interval: 8.5-32.4). With a median follow-up of 10.9 months, median progression-free survival and overall survival were 3.2 months and 11.2 months, respectively. In addition, the median duration of response was 24.7 months. The most common grade 3 or 4 adverse event was grade 3 dysphagia (eight [18%] patients). Biomarker analyses explored programmed cell death ligand 1 and CD20 as potential predictive markers for PD-1 blockade. Spartalizumab showed promising activity with a manageable safety profile, indicating its potential as a new treatment option for patients with refractory ESCC.
TRIAL REGISTRATION
The trial was registered at ClinicalTrials.gov under the identifier NCT03785496.
Topics: Humans; Male; Female; Esophageal Squamous Cell Carcinoma; Middle Aged; Aged; Esophageal Neoplasms; Antibodies, Monoclonal, Humanized; Neoplasm Recurrence, Local; Adult; Progression-Free Survival; Aged, 80 and over; Programmed Cell Death 1 Receptor
PubMed: 38919826
DOI: 10.1080/2162402X.2024.2371563 -
International Journal of Breast Cancer 2024Intraoperative radiation therapy (IORT) has gained popularity in recent years as an alternative to external beam whole breast radiation therapy (WBRT) for early-stage...
Intraoperative radiation therapy (IORT) has gained popularity in recent years as an alternative to external beam whole breast radiation therapy (WBRT) for early-stage breast cancer. Here, we report 43-month recurrence and survival outcomes in a multiethnic cohort treated with IORT in a clinical context. Two hundred and eleven patients with low-risk features were treated with IORT for early-stage breast cancer from 2014 to 2021. Selection criteria were based on Group Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) guidelines: preferably unifocal intraductal carcinoma (IDC), aged > 50, tumor size ≤ 2.0 cm, and without lymph node involvement. All patients received 20 Gy of radiation dose during the lumpectomy. Information on patient and tumor characteristics was collected. The mean age of this cohort was 67.5 years; 95.2% of patients are Jewish, and the rest are Bedouins (4.7%). Most tumors were intraductal carcinoma (97.2%) and stage 1 (94.8%). The mean follow-up time was 43.4 months. Bedouins had larger tumor sizes (mean 1.21 vs. 1.13 cm) and were younger at diagnosis than Jewish patients (mean 65.4 vs. 67.6 years), although the differences are not significant. The overall recurrence rate was 1.4%. One case of local recurrence (0.5%) and two cases of metastasis (0.9%) were observed during the study period. One patient died from metastasis. Our findings suggest that IORT in selected low-risk patients can achieve an excellent prognosis with low rates of recurrence and metastasis.
PubMed: 38919804
DOI: 10.1155/2024/5551907