NCAPD2 augments the tumorigenesis and progression of human liver cancer via the PI3K­Akt­mTOR signaling pathway.

Non­SMC condensin I complex subunit D2 (NCAPD2) is a newly identified oncogene; however, the specific biological function and molecular mechanism of NCAPD2 in liver cancer progression remain unknown. In the present study, the aberrant expression of NCAPD2 in liver cancer was investigated using public tumor databases, including TNMplot, The Cancer Genome Atlas and the International Cancer Genome Consortium based on bioinformatics analyses, and it was validated using a clinical cohort. It was revealed that NCAPD2 was significantly upregulated in liver cancer tissues compared with in control liver tissues, and NCAPD2 served as an independent prognostic factor and predicted poor prognosis in liver cancer. In addition, the expression of NCAPD2 was positively correlated with the percentage of Ki67+ cells. Finally, single­cell sequencing data, gene­set enrichment analyses and in vitro investigations, including cell proliferation assay, Transwell assay, wound healing assay, cell cycle experiments, cell apoptosis assay and western blotting, were carried out in human liver cancer cell lines to assess the biological mechanisms of NCAPD2 in patients with liver cancer. The results revealed that the upregulation of NCAPD2 enhanced tumor cell proliferation, invasion and cell cycle progression at the G2/M­phase transition, and inhibited apoptosis in liver cancer cells. Furthermore, NCAPD2 overexpression was closely associated with the phosphatidylinositol 3­kinase (PI3K)­Akt­mammalian target of rapamycin (mTOR)/c­Myc signaling pathway and epithelial­mesenchymal transition (EMT) progression in HepG2 and Huh7 cells. In addition, upregulated NCAPD2 was shown to have adverse effects on overall survival and disease­specific survival in liver cancer. In conclusion, the overexpression of NCAPD2 was shown to lead to cell cycle progression at the G2/M­phase transition, activation of the PI3K­Akt­mTOR/c­Myc signaling pathway and EMT progression in human liver cancer cells.

DN-ODE: Data-driven neural-ODE modeling for breast cancer tumor dynamics and progression-free survivals.

Pharmacokinetic/Pharmacodynamic (PK/PD) modeling is crucial in the development of new drugs. However, traditional population-based PK/PD models encounter challenges when modeling for individual patients. We aim to explore the potential of constructing a pharmacodynamic model for individual breast cancer pharmacodynamics leveraging only limited data from early clinical trial phases. While previous studies on Neural Ordinary Differential Equations (ODEs) suggest promising results in clinical trial practices, they primarily focused on theoretical applications or independent PK/PD modeling. PD modeling from complex and irregular clinical trial data, especially when interacting with PK parameters, is still unclear. To achieve that, we introduce a Data-driven Neural Ordinary Differential Equation (DN-ODE) modeling for breast cancer tumor dynamics and progression-free survival data. To validate this approach, experiments are conducted with early-phase clinical trial data from the Amcenestrant (an oral treatment for breast cancer) dataset (AMEERA 1-2), aiming to predict pharmacodynamics in the later phase (AMEERA 3). DN-ODE model achieves RMSE scores of 8.78 and 0.21 in tumor size and progression-free survival, respectively, with R2 scores over 0.9 for each task. Compared to PK/PD methodologies, DN-ODE is able to predict robust individual tumor dynamics with only limited cycle data. We also introduce Principal Component Analysis visualizations for encoder results, demonstrating the DN-ODE's capability to discern individual distributions and diverse tumor growth patterns. Therefore, DN-ODE facilitates comprehensive drug efficacy assessments, pinpoints potential responders, and aids in trial design.

Deep representation learning from electronic medical records identifies distinct symptom based subtypes and progression patterns for COVID-19 prognosis.

OBJECTIVE: Symptoms are significant kind of phenotypes for managing and controlling of the burst of acute infectious diseases, such as COVID-19. Although patterns of symptom clusters and time series have been considered the high potential prediction factors for the prognosis of patients, the elaborated subtypes and their progression patterns based on symptom phenotypes related to the prognosis of COVID-19 patients still need be detected. This study aims to investigate patient subtypes and their progression patterns with distinct features of outcome and prognosis. METHODS: This study included a total of 14,139 longitudinal electronic medical records (EMRs) obtained from four hospitals in Hubei Province, China, involving 2,683 individuals in the early stage of COVID-19 pandemic. A deep representation learning model was developed to help acquire the symptom profiles of patients. K-means clustering algorithm is used to divide them into distinct subtypes. Subsequently, symptom progression patterns were identified by considering the subtypes associated with patients upon admission and discharge. Furthermore, we used Fisher's test to identify significant clinical entities for each subtype. RESULTS: Three distinct patient subtypes exhibiting specific symptoms and prognosis have been identified. Particularly, Subtype 0 includes 44.2% of the whole and is characterized by poor appetite, fatigue and sleep disorders; Subtype 1 includes 25.6% cases and is characterized by confusion, cough with bloody sputum, encopresis and urinary incontinence; Subtype 2 includes 30.2% cases and is characterized by dry cough and rhinorrhea. These three subtypes demonstrate significant disparities in prognosis, with the mortality rates of 4.72%, 8.59%, and 0.25% respectively. Furthermore, symptom cluster progression patterns showed that patients with Subtype 0 who manifest dark yellow urine, chest pain, etc. in the admission stage exhibit an elevated risk of transforming into the more severe subtypes with poor outcome, whereas those presenting with nausea and vomiting tend to incline towards entering the milder subtype. CONCLUSION: This study has proposed a clinical meaningful approach by utilizing the deep representation learning and real-world EMR data containing symptom phenotypes to identify the COVID-19 subtypes and their progression patterns. The results would be potentially useful to help improve the precise stratification and management of acute infectious diseases.

Changes in the correlation between substantia nigra hyperechogenicity area and Parkinson's disease severity at different Hoehn and Yahr stages.

BACKGROUND: It is debatable whether the area of substantia nigra hyperechogenicity (SN+) in transcranial sonography (TCS) is related to Parkinson's disease (PD) severity. Iron deposition, which is associated with the formation of SN+, may have different effects on dopamine nerve function as PD progresses. However, little research has explored the association between the SN + area and disease severity of PD in stages. METHODS: 612 PD patients with sufficient bone window were retrospectively included from a PD database, and disease severity was assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) scores. Based on the Hoehn and Yahr (H-Y) scale, we classified the patients into seven groups (H-Y stage 1, 1.5, 2, 2.5, 3, 4, and 5) and then analyzed the correlations between the SN + area and the UPDRS scores separately. RESULTS: Our results indicated a U-shaped relationship between the initial-SN + area and disease severity in PD: In the H-Y stage 1 group, the initial-SN + area was negatively correlated with the UPDRS total score (r = - 0.456, p < 0.001) and UPDRS-III score (r = - 0.497, p < 0.001). No correlation was observed in the groups of H-Y stages 1.5, 2, and 2.5. In the groups of H-Y stage ≥ 3, the initial-SN + area was positively correlated with the UPDRS total score and UPDRS-III score, with strongest correlation in the H-Y stage 5 group (all p values < 0.05). Moreover, the larger SN + area and average SN + area showed a similar evolutionary trend of correlation with UPDRS total score and UPDRS-III score. CONCLUSIONS: Our study indicated a U-shaped correlation between the SN + area with the UPDRS total score and UPDRS-III score as H-Y stage progressed. The evolution of the correlation may reflect the evolution of underlying pathological mechanisms related to iron deposition in the substantia nigra.

Social support and frailty progression in community-dwelling older adults.

Objectives: Despite the growing evidence regarding the influence of social factors on frailty in older adults, the effect of social support remains unclear. This study aims to assess the association between social support and frailty progression (transition and incidence) in a sample of community-dwelling older adults. Methods: Using a cohort study design, 1,059 older adults from the Berlin Initiative Study were followed up for 2.1 years. Multinomial and logistic regression analyses were performed to assess the association of social support using Oslo Social Support Scale-3 with frailty transition and incidence, respectively. Gender differences were explored using stratified analyses. Results: At baseline, frailty prevalence in the study population [mean (SD) age 84.3 (5.6) years; 55.8% women] reached 33.1% with 47.0, 29.4 and 23.6% of the participants reporting moderate, strong and poor social support, respectively. Over the follow-up period, social support was not significantly associated with the frailty transition categories in the adjusted model. Conversely, the adjusted logistic regression analysis showed that participants with poor social support had twice the odds of becoming frail compared to those with strong social support (OR 2.07; 95% CI 1.08-3.95). Gender-stratified analyses showed comparable estimates to the main analysis but were statistically non-significant. Discussion: Our study results underpin the role of social factors in frailty incidence and highlight social support as a potential target for frailty-preventing interventions in older adults. Therefore, it is important to adopt a biopsychosocial model rather than a purely biomedical model to understand and holistically improve the health of community-dwelling older adults.

The Beijing angle closure progression study: design and methodology.

Purpose: The purpose of this study is to summarize the design and methodology of a large-scale trial in northern China, the Beijing Angle Closure Progression Study (BAPS). This trial is designed to explore the 5-year incidence of primary angle-closure suspect (PACS) progressing to primary angle-closure (PAC) or primary angle-closure glaucoma (PACG) and to determine the possible risk factors of disease progression. Methods/design: The BAPS is a clinic-based, multicenter, noninterventional trial conducted on a sample of urban Chinese adults. Consecutive eligible patients who meet PACS diagnostic criteria will be recruited from eight participating centers, with the trial commencing on August 4, 2022. The target sample size is set at 825 subjects, with follow up planned for a minimum period of 5 years. Baseline examination will include presenting visual acuity, best corrected visual acuity, intraocular pressure (IOP), undilated slit-lamp biomicroscopy, stereoscopic evaluation of the optic disc, visual field test, optical coherence tomography evaluation of retinal nerve fiber layer, ultrasound biomicroscopy and IOLMaster. Questionnaires will also be used to collect detailed personal history. Patients are scheduled to visit the glaucoma clinic every 12 months and may visit the emergency room in case of acute attack of angle closure. Study endpoints include acute PAC episodes, elevated IOP, peripheral anterior synechiae, glaucomatous visual field defect, or glaucomatous abnormality of optic nerve. Discussion: The BAPS will provide data on the 5-year incidence of PACS progressing to PAC or PACG and determine the risk factors for disease progression. This study will also help redefine high-risk patients with PACS.

The prognostic role of an optimal machine learning model based on clinical available indicators in HCC patients.

Although methods in diagnosis and therapy of hepatocellular carcinoma (HCC) have made significant progress in the past decades, the overall survival (OS) of liver cancer is still disappointing. Machine learning models have several advantages over traditional cox models in prognostic prediction. This study aimed at designing an optimal panel and constructing an optimal machine learning model in predicting prognosis for HCC. A total of 941 HCC patients with completed survival data and preoperative clinical chemistry and immunology indicators from two medical centers were included. The OCC panel was designed by univariate and multivariate cox regression analysis. Subsequently, cox model and machine-learning models were established and assessed for predicting OS and PFS in discovery cohort and internal validation cohort. The best OCC model was validated in the external validation cohort and analyzed in different subgroups. In discovery, internal and external validation cohort, C-indexes of our optimal OCC model were 0.871 (95% CI, 0.863-0.878), 0.692 (95% CI, 0.667-0.717) and 0.648 (95% CI, 0.630-0.667), respectively; the 2-year AUCs of OCC model were 0.939 (95% CI, 0.920-0.959), 0.738 (95% CI, 0.667-0.809) and 0.725 (95% CI, 0.643-0.808), respectively. For subgroup analysis of HCC patients with HBV, aged less than 65, cirrhosis or resection as first therapy, C-indexes of our optimal OCC model were 0.772 (95% CI, 0.752-0.792), 0.769 (95% CI, 0.750-0.789), 0.855 (95% CI, 0.846-0.864) and 0.760 (95% CI, 0.741-0.778), respectively. In general, the optimal OCC model based on RSF algorithm shows prognostic guidance value in HCC patients undergoing individualized treatment.

GATIS score for predicting the prognosis of rectal neuroendocrine neoplasms: A Chinese multicenter study of 12-year experience.

BACKGROUND: There is currently a shortage of accurate, efficient, and precise predictive instruments for rectal neuroendocrine neoplasms (NENs). AIM: To develop a predictive model for individuals with rectal NENs (R-NENs) using data from a large cohort. METHODS: Data from patients with primary R-NENs were retrospectively collected from 17 large-scale referral medical centers in China. Random forest and Cox proportional hazard models were used to identify the risk factors for overall survival and progression-free survival, and two nomograms were constructed. RESULTS: A total of 1408 patients with R-NENs were included. Tumor grade, T stage, tumor size, age, and a prognostic nutritional index were important risk factors for prognosis. The GATIS score was calculated based on these five indicators. For overall survival prediction, the respective C-indexes in the training set were 0.915 (95% confidence interval: 0.866-0.964) for overall survival prediction and 0.908 (95% confidence interval: 0.872-0.944) for progression-free survival prediction. According to decision curve analysis, net benefit of the GATIS score was higher than that of a single factor. The time-dependent area under the receiver operating characteristic curve showed that the predictive power of the GATIS score was higher than that of the TNM stage and pathological grade at all time periods. CONCLUSION: The GATIS score had a good predictive effect on the prognosis of patients with R-NENs, with efficacy superior to that of the World Health Organization grade and TNM stage.

Time to glaucoma progression detection by optical coherence tomography and visual field in glaucoma individuals of African descent.

PURPOSE: To examine the time to glaucoma progression detection by retinal nerve fiber layer thickness (RNFLT) and visual field (VF) among African descent (AD) individuals. DESIGN: Retrospective cohort study. METHODS: Setting: Multi-center. STUDY POPULATION: We included AD glaucoma eyes from DIGS/ADAGES with ≥2-year/5-visits of optic nerve head RNFLT and 24-2 VF examinations. Intervention or Observation Procedure: Rates of VF mean deviation (MD) and RNFLT worsening were analyzed using linear mixed-effects models, and longitudinal data was simulated using the variability estimates. MAIN OUTCOME MEASURE: The simulated time to detect trend-based glaucoma progression was assessed with assumed rates of VF MD and RNFLT change derived from the cohort (25th, 50th, 75th percentile [p25, median, p75] slopes and mean slopes). Severity-stratified analyses were also performed. RESULTS: We included 184 eyes from 128 AD subjects (mean baseline age: 63.4 years; VF MD: -4.2 dB, RNFLT: 80.2 µm). The p25, median, mean and p75 rates of change were -0.43, -1.01, -1.15 and -1.64 µm/year for RNFLT, and 0.00, -0.21, -0.30 and -0.51 dB/year for VF MD, respectively. Compared to VF MD, RNFLT showed an overall shorter mean time to progression detection (time difference: 0.4-1.7 years), with the mean rates showing the largest difference (RNFLT: 5.2 years vs. VF MD: 6.9 years). Similarly, we found an overall shorter time to detect RNFLT progression, compared to that of VF MD progression, in mild glaucoma eyes (≥1 year earlier) and in moderate-advanced glaucoma eyes (∼0.5 year earlier). CONCLUSIONS: Computer simulation showed potentially shorter time to detect RNFLT progression than VF MD progression in AD eyes. Our findings support the importance of using RNFLT to detect progressive glaucoma in AD individuals.

Combination of pemetrexed with bevacizumab for non-small-cell lung cancer: a meta-analysis study.

BACKGROUND: Combining pemetrexed with bevacizumab may have some potential in improving the efficacy in patients with non-small-cell lung cancer (NSCLC), and this meta-analysis aims to explore the impact of pemetrexed addition to bevacizumab on treatment efficacy for NSCLC. METHODS: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched, and we included randomized controlled trials (RCTs) assessing the effect of pemetrexed addition to bevacizumab on treatment efficacy in patients with NSCLC. Overall survival and progression-free survival were included in this meta-analysis. RESULTS: Four RCTs were finally included in the meta-analysis. Overall, compared with bevacizumab for NSCLC, pemetrexed addition showed significantly improved overall survival (hazard ratio [HR] = 0.87; 95% confidence interval [CI] = 0.76 to 0.99; P = 0.03), survival rate (odd ratio [OR] = 1.41; 95% CI = 1.06 to 1.86; P = 0.02), progression-free survival (HR = 0.63; 95% CI = 0.55 to 0.72; P < 0.00001) and progression-free survival rate (OR = 1.92; 95% CI = 1.38 to 2.67; P < 0.00001), but led to the increase in grade ≥ 3 adverse events (OR = 2.15; 95% CI = 1.62 to 2.84; P < 0.00001). CONCLUSIONS: Pemetrexed addition may be effective to improve treatment efficacy for NSCLC compared to bevacizumab treatment.

Tandem gait step-width increases more rapidly in more severely affected people with Parkinson's disease.

INTRODUCTION: Tandem gait performance reportedly predicts fall risk in people with Parkinson's disease (PwPD) and help distinguish PwPD from atypical parkinsonism. In a cross-sectional study, we previously showed that tandem gait step-width widens with increasing Hoehn and Yahr (H&Y) staging scores. In this longitudinal study, we aimed to determine if progression in tandem gait deficits is dependent on disease severity in PwPD. METHODS: Participants underwent an instrumented tandem gait measurement every 6 months for at least 2 years. The mean and variability of 4 tandem gait parameters were calculated at each visit: step-width, step-length, step-time, and step-velocity. The change in these parameters over time for 3 H&Y groups (stage 1, 2 and 2.5+) compared to aging controls was determined using a random coefficients regression model. The annual percent change in tandem gait parameters was correlated with initial disease features using Kendall's τB. RESULTS: 66 participants were analyzed (46 PD, 20 controls). Mean step-width increased over time in an H&Y stage-dependent manner, with H&Y 2 and H&Y 2.5+ experiencing increases of 6% and 10% per year (p = 0.001 and 0.024 respectively). Annual percent-change in step-width was correlated with initial motor Unified Parkinson's Disease Rating Scale (UPDRS) scores (Kendall's τB = 0.229), total UPDRS scores (τB = 0.249), H&Y scores (τB = 0.266) and inversely correlated with Montreal Cognitive Assessment (MoCA) scores (τB = -0.209; ps ≤ 0.019). CONCLUSION: Tandem gait step-width widens over time more rapidly in more severely affected PD patients. These results suggest that tandem gait should be routinely clinically evaluated and considered in the management of imbalance in PwPD.

Association of continuous subcutaneous insulin therapy and diabetic retinopathy in type 1 diabetes: A national cohort study.

AIM: This study aimed to investigate the short-and long-term effect on diabetic retinopathy (DR) in individuals with type 1 diabetes treated with continuous subcutaneous insulin injections (CSII) compared to those using multiple daily injections (MDI). METHODS: We conducted a register-based matched cohort study utilizing data from the Danish Registry of Diabetic Retinopathy as well as several other national Danish health registers. Our cohort consisted of all individuals with type 1 diabetes who attended the Danish screening program for DR from 2013 to 2022. We included individuals registered with CSII treatment, and compared them to individuals using MDI, matched by age, sex, and DR level. Cox regression analysis was performed to evaluate the outcomes. RESULTS: The study included 674 individuals treated with CSII and 2006 matched MDI users. In our cohort 53.4 % were female and median age was 36 (IQR 27-47). Average follow-up risk-time was 4.8 years. There was no difference in the risk of DR worsening between the CSII group and MDI group (HR 1.05 [95%CI 0.91; 1.22], p = 0.49). However, an increased risk of focal photocoagulation was observed in the CSII group (HR 2.40 [95%CI 1.11; 5.19], p = 0.03). CONCLUSIONS: Our findings indicate that CSII treatment does not confer a significant difference in the overall short- and long-term risk of DR worsening or ocular intervention compared to MDI treatment. These results provide insights into the DR outcomes of CSII treatment in individuals with type 1 diabetes.

Comorbid onset of cardiovascular diagnosis and long-term confirmed disability progression in multiple sclerosis: A 15-year follow-up study.

BACKGROUND: People with multiple sclerosis (pwMS) have greater prevalence of comorbid cardiovascular diseases (CVD) when compared to the general population despite similar frequency of CV risk factors. OBJECTIVE: Determine the impact of comorbid-onset of CVD diagnosis on long-term confirmed disability progression (CDP). METHODS: 276 pwMS (29 clinically isolated syndrome, 130 relapsing-remitting and 117 progressive) were clinically followed an average of 14.9 years, with a mean of 14.4 clinical visits. Retrospective electronic medical records (EMR) review determined CVD diagnoses (hypertension, hyperlipidemia, diabetes, and heart disease) at baseline and over the follow-up. CDP was determined with ≥1.0 point Expanded Disability Status Scale (EDSS) increase from EDSS <5.5, or ≥ 0.5-point increase from ≥5.5, and was sustained on next clinical visit. RESULTS: A significantly shorter time to overall CDP was detected in 213 pwMS who had an existing (28 pwMS) or developed new onset (185 pwMS) of CVD, compared to 63 CVD-healthy pwMS over the follow-up (13.4 vs 15.9 years, Mantel-Cox p < 0.001), independent of baseline age and EDSS score. The CVD diagnosis preceded the CDP in 103 pwMS (55.7%), occurred after CDP in 71 pwMS (38.4%) and was concurrent in 11 pwMS (5.9%). Using mixed-effect models adjusted for significant age (F = 56.5, p < 0.001) and time effects (F = 67.8, p < 0.001), the CVD-onset diagnosis was associated with greater accrual of disability, as measured by longitudinal increase in EDSS score (F = 4.207, p = 0.04). Sex was not significant predictor of future disability in our cohort. CONCLUSION: PwMS with an existing or new onset of comorbid CVD diagnosis showed accelerated disability worsening over long-term. There was no temporal relationship between the onset of CVD and CDP within the group that had CVD-onset diagnosis.

Nomogram for predicting survival after first-line anti-PD-1-based immunotherapy in unresectable stage IV melanoma: a multicenter international study.

BACKGROUND: The introduction of anti-programmed cell death protein 1 (PD-1) immunotherapy has revolutionized the treatment landscape for melanoma, enhancing both response rates and survival outcomes in patients with advanced stages of the disease. Despite these remarkable advances, a noteworthy subset of patients (40%-60%) does not derive advantage from this therapeutic approach. This study aims to identify key predictive factors and create a user-friendly predictive nomogram for stage IV melanoma patients receiving first-line anti-PD-1-based immunotherapy, improving treatment decisions. MATERIALS AND METHODS: In this retrospective study, we included patients with unresectable stage IV melanoma who received first-line treatment with either anti-PD-1 monotherapy or anti-PD-1 plus anti-cytotoxic T-lymphocyte associated protein 4 between 2014 and 2018. We documented clinicopathological features and blood markers upon therapy initiation. By employing the random survival forest model and backward variable selection of the Cox model, we identified variables associated with progression-free survival (PFS) after the first-line anti-PD-1-based treatment. We developed and validated a predictive nomogram for PFS utilizing the identified variables. We assessed calibration and discrimination performance metrics as part of the evaluation process. RESULTS: The study involved 719 patients, divided into a training cohort of 405 (56%) patients and a validation cohort of 314 (44%) patients. We combined findings from the random survival forest and the Cox model to create a nomogram that incorporates the following factors: lactate dehydrogenase (LDH), S100, melanoma subtype, neutrophil-to-lymphocyte ratio (NLR), body mass index, type of immune checkpoint inhibitor, and presence of liver or brain metastasis. The resultant model had a C-index of 0.67 in the training cohort and 0.66 in the validation cohort. Performance remained in different patient subgroups. Calibration analysis revealed a favorable correlation between predicted and actual PFS rates. CONCLUSIONS: We developed and validated a predictive nomogram for long-term PFS in patients with unresectable stage IV melanoma undergoing first-line anti-PD-1-based immunotherapy.

TONSL promotes lung adenocarcinoma progression, immune escape and drug sensitivity.

PURPOSE: The tonsoku-like DNA repair protein (TONSL) encoded by the TONSL gene, located on chromosome 8q24.3, is crucial for repairing DNA double-strand breaks through homologous recombination. However, TONSL overexpression in lung adenocarcinoma (LUAD) promotes tumor development, leading to a poor prognosis. METHODS: TONSL was verified as a reliable prognostic marker for LUAD using bioinformatics, and clinical features related to LUAD prognosis were screened from the TCGA database to establish the relationship between risk factors and TONSL expression. In addition, TONSL expression in normal and LUAD tissues was verified using real-time quantitative polymerase chain reaction and immunohistochemistry. To elucidate the possible functions of TONSL, TONSL-related differentially expressed genes were screened, and functional enrichment analysis was performed. Subsequently, siRNA was used to knock down TONSL expression in lung cancer cells for cytobehavioral experiments. The effects of TONSL expression on tumor immune escape were analyzed using the ESTIMATE algorithm and tumor immune-infiltration analysis. In addition, the half-maximal inhibitory concentration of LUAD with varying TONSL expression levels in response to first-line chemotherapeutic drugs and epidermal growth factor receptor-tyrosine kinase inhibitors was analyzed for drug sensitivity. RESULTS: Up-regulation of TONSL in LUAD promotes the proliferation, migration, and invasion of lung cancer cells, thereby contributing to a poor prognosis. Furthermore, TONSL overexpression promotes immune escape and drug sensitivity in LUAD. CONCLUSION: TONSL serves as a reliable prognostic marker for LUAD, and its up-regulation is associated with increased immune escape and drug sensitivity. These findings suggest that TONSL holds potential as a novel therapeutic target for LUAD.

ARAP1-AS1: a novel long non-coding RNA with a vital regulatory role in human cancer development.

Long non-coding RNAs (lncRNAs) have garnered significant attention in biomedical research due to their pivotal roles in gene expression regulation and their association with various human diseases. Among these lncRNAs, ArfGAP With RhoGAP Domain, Ankyrin Repeat, And PH Domain 1 - Antisense RNA 1 (ARAP1-AS1) has recently emerged as an novel oncogenic player. ARAP1-AS1 is prominently overexpressed in numerous solid tumors and wields influence by modulating gene expression and signaling pathways. This regulatory impact is realized through dual mechanisms, involving both competitive interactions with microRNAs and direct protein binding. ARAP1-AS1 assumes an important role in driving tumorigenesis and malignant tumor progression, affecting biological characteristics such as tumor expansion and metastasis. This paper provides a concise review of the regulatory role of ARAP1-AS1 in malignant tumors and discuss its potential clinical applications as a biomarker and therapeutic target. We also address existing knowledge gaps and suggest avenues for future research. ARAP1-AS1 serves as a prototypical example within the burgeoning field of lncRNA studies, offering insights into the broader landscape of non-coding RNA molecules. This investigation enhances our comprehension of the complex mechanisms that govern the progression of cancer.

Predictive value of synaptic plasticity for functional decline in patients with multiple sclerosis.

Background: Previous research suggested that quadripulse (QPS)-induced synaptic plasticity is associated with both cognitive and motor function in patients with multiple sclerosis (MS) and does not appear to be reduced compared to healthy controls (HCs). Objective: This study aimed to explore the relationship between the degree of QPS-induced plasticity and clinically significant decline in motor and cognitive functions over time. We hypothesized that MS patients experiencing functional decline would exhibit lower levels of baseline plasticity compared to those without decline. Methods: QPS-induced plasticity was evaluated in 80 MS patients (56 with relapsing-remitting MS and 24 with progressive MS), and 69 age-, sex-, and education-matched HCs. Cognitive and motor functions, as well as overall disability status were evaluated annually over a median follow-up period of 2 years. Clinically meaningful change thresholds were predefined for each outcome measure. Linear mixed-effects models, Cox proportional hazard models, logistic regression, and receiver-operating characteristic analysis were applied to analyse the relationship between baseline plasticity and clinical progression in the symbol digit modalities test, brief visuospatial memory test revised (BVMT-R), nine-hole peg test (NHPT), timed 25-foot walk test, and expanded disability status scale. Results: Overall, the patient cohort showed no clinically relevant change in any functional outcome over time. Variability in performance was observed across time points in both patients and HCs. MS patients who experienced clinically relevant decline in manual dexterity and/or visuospatial learning and memory had significantly lower levels of synaptic plasticity at baseline compared to those without such decline (NHPT: ß = -0.25, p = 0.02; BVMT-R: ß = -0.50, p = 0.005). Receiver-operating characteristic analysis underscored the predictive utility of baseline synaptic plasticity in discerning between patients experiencing functional decline and those maintaining stability only for visuospatial learning and memory (area under the curve = 0.85). Conclusion: Our study suggests that QPS-induced plasticity could be linked to clinically relevant functional decline in patients with MS. However, to solidify these findings, longer follow-up periods are warranted, especially in cohorts with higher prevalences of functional decline. Additionally, the variability in cognitive performance in both patients with MS and HCs underscores the importance of conducting further research on reliable change based on neuropsychological tests.

The global patient-reported outcomes for multiple sclerosis initiative: bridging the gap between clinical research and care - updates at the 2023 plenary event.

Significant advancements have been achieved in delineating the progress of the Global PROMS (PROMS) Initiative. The PROMS Initiative, a collaborative endeavor by the European Charcot Foundation and the Multiple Sclerosis International Federation, strives to amplify the influence of patient input on MS care and establish a cohesive perspective on Patient-Reported Outcomes (PROs) for diverse stakeholders. This initiative has established an expansive, participatory governance framework launching four dedicated working groups that have made substantive contributions to research, clinical management, eHealth, and healthcare system reform. The initiative prioritizes the global integration of patient (For the purposes of the Global PROMS Initiative, the term "patient" refers to the people with the disease (aka People with Multiple Sclerosis - pwMS): any individual with lived experience of the disease. People affected by the disease/Multiple Sclerosis: any individual or group that is affected by the disease: E.g., family members, caregivers will be also engaged as the other stakeholders in the initiative). insights into the management of MS care. It merges subjective PROs with objective clinical metrics, thereby addressing the complex variability of disease presentation and progression. Following the completion of its second phase, the initiative aims to help increasing the uptake of eHealth tools and passive PROs within research and clinical settings, affirming its unwavering dedication to the progressive refinement of MS care. Looking forward, the initiative is poised to continue enhancing global surveys, rethinking to the relevant statistical approaches in clinical trials, and cultivating a unified stance among 'industry', regulatory bodies and health policy making regarding the application of PROs in MS healthcare strategies.

Impact of protein domains on the MEL2 granule, a cytoplasmic ribonucleoprotein complex maintaining faithful meiosis progression in rice.

Cytoplasmic ribonucleoprotein (RNP) granules are membraneless structures composed of various RNAs and proteins that play important roles in post-transcriptional regulation. While RNP granules are known to regulate the meiotic entry in some organisms, little is known about their roles in plants. In this study, we observed the cytoplasmic granular structures of rice RNA-binding protein MEIOSIS ARRESTED AT LEPTOTENE2 (MEL2), which contributes to the control of meiotic entry timing, in leaf protoplasts and spore mother cells. We performed colocalization analysis with known cytoplasmic RNP factors, and domain deletion analysis to assess their impact on granule formation and meiosis progression. Conservation of MEL2 domains across plant species was also explored. Our results indicated that MEL2 granules colocalized with processing body and stress granule factors. The maintenance of granule properties modulated by LOTUS domain and the intrinsically disordered region (IDR) is essential for proper MEL2 function in meiosis progression. MEL2-like proteins widely found in plant kingdom conserved LOTUS domain followed by the IDR despite their diverse domain structures, suggesting the functional conservation of these domains among plant species. This study highlights the role of MEL2 granule dynamics and its impact on meiotic transition and progression.

Demographic, Socioeconomic, and Clinical Factors Associated with Severe Vision Loss in Patients with Neovascular Glaucoma.

Purpose: To investigate the association between demographic, socioeconomic, and clinical factors and severe vision loss in patients with neovascular glaucoma (NVG). Patients and Methods: A retrospective chart review of patients referred to the University of Virginia (UVA), diagnosed with NVG, and treated for NVG between January 2010 and December 2020 was performed. Patients were grouped according to vision outcomes after 1 year of treatment: mild - moderate vision loss (best corrected visual acuity [BCVA] > light perception [LP]) and severe vision loss (BCVA ≤ LP). The associations between patient characteristics and BCVA were also examined. Results: Of the 89 patients (99 eyes), those with progression to severe vision loss presented with higher intraocular pressure (IOP) (p < 0.001) and lower visual acuity (p = 0.003) on average. However, there was no difference in IOP between the vision loss groups after one year of treatment. Univariate analysis showed a moderate association between a history of type 2 diabetes mellitus (T2DM) and severe vision loss (p = 0.033). Increasing age was associated with an increased likelihood of progression to severe vision loss (odds ratio [OR] 1.074, p = 0.008). Females were more likely to exhibit severe vision loss (OR 3.281, p = 0.036). Patients with Medicare (OR 0.098, p = 0.005) or private insurance (OR 0.110, p = 0.006) were less likely to progress to severe vision loss than those without insurance. Conclusion: Progression of vision loss in patients with NVG may be influenced by the stage of disease at diagnosis, age, sex, T2DM, and insurance status.